TREATMENT READING

Childhood Cancer Genomics (PDQ®), part 3

Source sections for this topic, with the original link and date. Patient and professional reading are labelled separately.

Not medical advice · Not a complete treatment or trial directory

Made by Triangle.

Selected text from the National Cancer Institute, with the original link and date. Made by Triangle. This page is not an NCI PDQ summary. Source topics may be broader than an individual diagnosis.

155 sections

Health professional · Sarcomas / Rhabdomyosarcoma

Genomics of rhabdomyosarcoma

Source: Childhood Cancer Genomics (PDQ®)–Health Professional Version, National Cancer Institute.

Source updated: April 30, 2025. Captured 2026-09-09.

The four histological categories recognized in the 5th edition of the World Health Organization (WHO) Classification of Tumors of Soft Tissue and Bone have distinctive genomic alterations and are briefly summarized below.[26,47,48]

Sources: 26 · 47 · 48

Embryonal rhabdosarcoma: Characterized by loss of heterozygosity at 11p15 and by a high frequency of variants in genes in the RAS pathway. For the purposes of this section, patients with embryonal rhabdomyosarcoma are considered negative for PAX3::FOXO1 and PAX7::FOXO1 gene fusions (i.e., fusion-negative rhabdomyosarcoma).

Alveolar rhabdomyosarcoma: Characterized by gene fusions involving FOXO1 with either PAX3 or PAX7 (i.e., FOXO1 fusion–positive rhabdomyosarcoma). Cases with alveolar rhabdomyosarcoma histology without FOXO1 gene fusions have clinical behavior, gene alteration patterns, and transcriptomic profiles like cases with embryonal rhabdomyosarcoma. Therefore, the discussion below focuses only on alveolar rhabdomyosarcoma with FOXO1 gene fusions.[49-53]

Sources: 49 · 53

Spindle cell/sclerosing rhabdomyosarcoma: Characterized by variants of MYOD1 in older patients and by VGLL2 and NCOA2 gene rearrangements in young children.

Pleomorphic rhabdomyosarcoma: Characterized by complex karyotypes with numerical and unbalanced structural changes that are indistinguishable from those of undifferentiated pleomorphic sarcomas.

The distribution of gene variants and gene amplifications (for CDK4 and MYCN) differs between patients with embryonal histology lacking a PAX::FOXO1 gene fusion (fusion-negative rhabdomyosarcoma) and patients with PAX::FOXO1 gene fusions (fusion-positive rhabdomyosarcoma). See Table 7 below and the text that follows. These frequencies are derived from a combined cohort of the Children's Oncology Group (COG) and United Kingdom rhabdomyosarcoma patients (n = 641).[54]

Sources: 54

Table 7. Frequency of Gene Alterations in Patients With Fusion-Negative (FN) and Fusion-Positive (FP) Rhabdomyosarcomaa
Gene	% FN Cases With Gene Alteration	% FP Cases With Gene Alteration
aAdapted from Shern et al.[54]
NRAS	17%	1%
KRAS	9%	1%
HRAS	8%	2%
FGFR4	13%	0%
NF1	15%	4%
BCOR	15%	6%
TP53	13%	4%
CTNNB1	6%	0%
CDK4	0%	13%
MYCN	0%	10%

Sources: 54

Details of the genomic alterations that predominate within each of the WHO histological categories are as follows.

Fusion-negative rhabdomyosarcoma (embryonal histology): Embryonal rhabdomyosarcoma tumors often show loss of heterozygosity at 11p15 and gains on chromosome 8.[55-58] Embryonal tumors have a higher background variant rate and a higher single-nucleotide variant rate than do alveolar rhabdomyosarcoma tumors, and the number of somatic variants increases with older age at diagnosis.[58,59] The most common recurring variants include those in the RAS pathway (e.g., NRAS, KRAS, HRAS, and NF1), which together are observed in approximately one-half of cases.[54] Variants in NRAS are the most frequent RAS pathway gene variants beyond infancy, while variants in HRAS predominate during infancy.[54] The presence of a RAS variant does not confer prognostic significance. Among the RAS pathway genes, germline pathogenic variants in NF1 and HRAS predispose to rhabdomyosarcoma. In a study of 615 children with rhabdomyosarcoma, 347 had tumors with embryonal histology. Of these, nine patients had NF1 germline pathogenic variants, and five patients had HRAS germline pathogenic variants, representing 2.6% and 1.4% of embryonal histology cases, respectively.[60]Other genes with recurring variants in fusion-negative rhabdomyosarcoma tumors include FGFR4, PIK3CA, CTNNB1, FBXW7, and BCOR, all of which are present in fewer than 15% of cases.[54,58,59]TP53 variants:TP53 variants are observed in 10% to 15% of patients with fusion-negative rhabdomyosarcoma and occur less commonly (about 4%) in patients with alveolar rhabdomyosarcoma.[54] In other childhood cancers (e.g., Wilms tumor), TP53 variants are associated with anaplastic histology,[61] and the same is true for embryonal rhabdomyosarcoma. In a study of 146 rhabdomyosarcoma patients with known TP53 status, approximately two-thirds of tumors with TP53 variants showed anaplasia (69%), but only one-quarter of tumors with anaplasia had TP53 variants.[62]The presence of TP53 variants was associated with reduced EFS in both nonrisk-stratified and risk-stratified analyses for both a COG and a U.K. rhabdomyosarcoma cohort.[54] The poor prognosis associated with TP53 variants was observed for both embryonal and alveolar patients. Based on these results, the COG plans to consider TP53 variant as a high-risk defining characteristic in its upcoming trials.[63]Rhabdomyosarcoma is one of the childhood cancers associated with Li-Fraumeni syndrome. In a study of 614 pediatric patients with rhabdomyosarcoma, 11 patients (1.7%) had TP53 germline pathogenic variants. Variants were less common in patients with alveolar histology (0.6%), compared with patients with nonalveolar histologies (2.2%).[60] Rhabdomyosarcoma with nonalveolar anaplastic morphology may be a presenting feature for children with Li-Fraumeni syndrome and germline TP53 variants.[64] DICER1 variants in embryonal rhabdomyosarcoma:DICER1 variants are observed in a small subset of patients with embryonal rhabdomyosarcoma, most commonly arising in tumors of the female genitourinary tract.[54] More specifically, most cases of cervical embryonal rhabdomyosarcoma,[66-68] which most commonly occurs in adolescents and young adults,[69,70] have DICER1 variants. In contrast, DICER1 variants are rarely observed in patients with vaginal primary sites, an entity occurring primarily in girls younger than 2 or 3 years.[67,69] DICER1 variants are also common in embryonal rhabdomyosarcoma arising in the uterine corpus, but this presentation is primarily observed in adults.[67,71] Cervical rhabdomyosarcoma generally shows a sarcoma botryoides histological pattern, and many cases show areas of cartilaginous differentiation, a feature also observed in other tumor types with DICER1 variants.[69,70,72] In support of the distinctive biology of embryonal rhabdomyosarcoma with DICER1 variants, these cases have a DNA methylation pattern that is distinctive from that of other embryonal rhabdomyosarcoma cases.[68] A diagnosis of cervical rhabdomyosarcoma is an indication for genetic testing for DICER1 syndrome.[67,73]

Sources: 55 · 58 · 58 · 59 · 54 · 54 · 60 · 54 · 58 · 59 · 54 · 61 · 62 · 54 · 63 · 60 · 64 · 54 · 66 · 68 · 69 · 70 · 67 · 69 · 67 · 71 · 69 · 70 · 72 · 68 · 67 · 73

Among eight consecutively presenting children with rhabdomyosarcoma and TP53 germline pathogenic variants, all showed anaplastic morphology. Among an additional seven children with anaplastic rhabdomyosarcoma and unknown TP53 germline variant status, three of the seven children had functionally relevant TP53 germline pathogenic variants. The median age at diagnosis of the 11 children with TP53 germline pathogenic variant status was 40 months (range, 19–67 months).[64]

Sources: 64

In another series, 26 of 31 patients with germline TP53 pathogenic variants had tumors with embryonal histology. Of the 16 tumors that were submitted for central pathology review, 12 had focal or diffuse anaplasia. The median age of patients in this group was 2.3 years.[65]

Sources: 65

Fusion-positive rhabdomyosarcoma (alveolar histology): About 70% to 80% of alveolar tumors are characterized by translocations between the FOXO1 gene on chromosome 13 and either the PAX3 gene on chromosome 2 (t(2;13)(q35;q14)) or the PAX7 gene on chromosome 1 (t(1;13)(p36;q14)).[55,74,75] Other rare fusions include PAX3::NCOA1 and PAX3::INO80D.[58] Translocations involving the PAX3 gene occur in approximately 60% of alveolar rhabdomyosarcoma cases, while the PAX7 gene appears to be involved in about 20% of cases.[74] Patients with solid-variant alveolar histology have a lower incidence of PAX::FOXO1 gene fusions than do patients showing classical alveolar histology.[76] The alveolar histology that is associated with the PAX7 gene in patients with or without metastatic disease appears to occur at a younger age and may be associated with longer EFS rates than those associated with PAX3 gene rearrangements.[77-82] Patients with alveolar histology and the PAX3 gene are older and have a higher incidence of invasive tumor (T2). Around 20% of cases showing alveolar histology have no detectable PAX gene translocation.[50,76] These patients have clinical behaviors, gene alteration patterns, and transcriptomic profiles that align with patients who have embryonal rhabdomyosarcoma and are now classified together with embryonal rhabdomyosarcoma, as fusion-negative rhabdomyosarcoma.[49-53]For the diagnosis of alveolar rhabdomyosarcoma, a FOXO1 gene rearrangement may be detected with good sensitivity and specificity using either fluorescence in situ hybridization or reverse transcription–polymerase chain reaction.[83] In addition to FOXO1 rearrangements, alveolar tumors are characterized by a lower mutational burden than are fusion-negative tumors, with fewer genes having recurring mutations.[58,59] The most frequently observed alterations in fusion-positive tumors are focal amplification of CDK4 (13%) or MYCN (10%), with small numbers of patients having recurring mutations in other genes (e.g., BCOR, 6%; NF1, 4%; TP53, 4%; and PIK3CA, 2%).[54] TP53 mutations in alveolar rhabdomyosarcoma appear to connote a high risk of treatment failure.[54]

Sources: 55 · 74 · 75 · 58 · 74 · 76 · 77 · 82 · 50 · 76 · 49 · 53 · 83 · 58 · 59 · 54 · 54

Spindle cell/sclerosing histology: Spindle cell/sclerosing rhabdomyosarcoma has been proposed as a separate entity in the WHO Classification of Tumors of Soft Tissue and Bone.[84] Within the spindle cell/sclerosing rhabdomyosarcoma category, several entities have distinctive molecular and clinical characteristics, described below.Congenital/infantile spindle cell rhabdomyosarcoma: Several reports have described cases of congenital or infantile spindle cell rhabdomyosarcoma with gene fusions involving VGLL2 and NCOA2 (e.g., VGLL2::CITED2, TEAD1::NCOA2, VGLL2::NCOA2, SRF::NCOA2).[85,86]MYOD1-altered spindle cell/sclerosing rhabdomyosarcoma: In older children and adults with spindle cell/sclerosing rhabdomyosarcoma, a specific MYOD1 variant (p.L122R) has been observed in a large proportion of patients.[85,89-91] In the combined cohort of COG and U.K. rhabdomyosarcoma patients (n = 641), variants in MYOD1 were found in 3% (17 of 515) of all fusion-negative rhabdomyosarcoma cases and in no fusion-positive cases. The presenting age of patients with MYOD1 variants was 10.8 years.[54] Most cases in this cohort showed spindle or sclerosing features, but cases with densely packed cells that mimicked the dense pattern of embryonal rhabdomyosarcoma were also observed. Most cases in this cohort (15 of 17, 88%) had either head and neck or parameningeal region primary sites. Activating PIK3CA variants are seen in about one-half of cases with MYOD1 variants.[54,92] The presence of the MYOD1 variant is associated with a markedly increased risk of local and distant failure.[54,85,89,90] Intraosseous spindle cell rhabdomyosarcoma: Primary intraosseous rhabdomyosarcoma is a very uncommon presentation for rhabdomyosarcoma. Most cases present with gene rearrangements involving TFCP2, with either FUS or EWSR1.[93-97] Rhabdomyosarcoma with a FUS::TFCP2 or EWSR1::TFCP2 gene fusion most commonly presents in young adults, although cases in older children and adolescents have been reported.[93,96,97] Craniofacial bones are the most common primary tumor location, and positivity for ALK and cytokeratins by immunohistochemistry is commonly observed. Other characteristics of this entity include a complex genomic profile, with most cases showing deletion of the CDKN2A tumor suppressor gene.[96] Intraosseous spindle cell rhabdomyosarcoma with a FUS::TFCP2 or EWSR1::TFCP2 gene fusion shows an aggressive clinical course. In one study, the median OS was only 8 months.[96]

Sources: 84 · 85 · 86 · 85 · 89 · 91 · 54 · 54 · 92 · 54 · 85 · 89 · 90 · 93 · 97 · 93 · 96 · 97 · 96 · 96

For congenital/infantile spindle cell rhabdomyosarcoma, a study reported that 10 of 11 patients showed recurrent fusion genes. Most of these patients had truncal primary tumors, and there were no paratesticular tumors. Novel VGLL2 rearrangements were observed in seven patients (63%), including the VGLL2::CITED2 fusion in four patients and the VGLL2::NCOA2 fusion in two patients.[85] Three patients (27%) harbored different NCOA2 gene fusions, including TEAD1::NCOA2 in two patients and SRF::NCOA2 in one patient. In this report, all fusion-positive congenital/infantile spindle cell rhabdomyosarcoma patients with long-term follow-up data were alive and well, and no patients developed distant metastases.[85]

Sources: 85 · 85

While most studies of congenital/infantile spindle cell rhabdomyosarcoma have shown favorable outcomes, it was reported that four patients developed metastatic disease and two patients had fatal outcomes. Disease progression occurred a median of 3.5 years from diagnosis (range, 1–8 years).[87] All four patients had unresectable tumors and were treated with chemotherapy. However, most literature reported cases in which surgical resection was achieved. At disease progression, a tumor from one patient had a TP53 variant, and a tumor from another patient showed a homozygous CDKN2A and CDKN2B deletion.

Sources: 87

A study of 40 patients with congenital/infantile spindle cell rhabdomyosarcoma (defined by diagnosis at age ≤12 months) found that almost all patients had localized disease (n = 39) and that one-half of patients who underwent molecular testing (13 of 26) had rearrangements of NCOA2 and/or VGLL2.[88] Because testing was limited to NCOA2 and VGLL2, it is possible that more comprehensive genomic analysis would identify a higher proportion of patients with relevant gene fusions. The 5-year EFS rate for the 13 patients with either a VGLL2 and/or a NCOA2 fusion was 90% (95% CI, ±19%), and the overall survival (OS) rate was 100% (95% CI, ±9%).

Sources: 88

Further study is needed to better define the prevalence and prognostic significance of gene rearrangements in VGLL2, NCOA2, and other relevant genes in young children with congenital/infantile spindle cell rhabdomyosarcoma.

Recurrent and refractory rhabdomyosarcomas from pediatric (n = 105) and young-adult patients (n = 15) underwent tumor sequencing in the National Cancer Institute–Children's Oncology Group (NCI-COG) Pediatric MATCH trial. Actionable genomic alterations were found in 53 of 120 tumors (44.2%), and patients with these alterations qualified for treatment on MATCH study arms.[7] Variants of MAPK pathway genes (HRAS, KRAS, NRAS, NF1) were most frequent and were reported in 32 of 120 tumors (26.7%). Amplifications of cyclin-dependent kinase genes (CDK4, CDK6) were detected in 15 of 120 tumors (12.5%).

Sources: 7

For information about the treatment of childhood rhabdomyosarcoma, see Childhood Rhabdomyosarcoma Treatment.

Sources: Childhood Rhabdomyosarcoma Treatment

This page is made by Triangle. The reading above is selected source text, not a treatment recommendation, and it is not medical advice.

Health professional

Langerhans Cell Histiocytosis

Source: Childhood Cancer Genomics (PDQ®)–Health Professional Version, National Cancer Institute.

Source updated: April 30, 2025. Captured 2026-09-09.

Health professional · Langerhans Cell Histiocytosis

Genomics of LCH

Source: Childhood Cancer Genomics (PDQ®)–Health Professional Version, National Cancer Institute.

Source updated: April 30, 2025. Captured 2026-09-09.

Health professional · Langerhans Cell Histiocytosis / Genomics of LCH

BRAF, NRAS, and ARAF variants

Source: Childhood Cancer Genomics (PDQ®)–Health Professional Version, National Cancer Institute.

Source updated: April 30, 2025. Captured 2026-09-09.

The genomic basis of LCH was advanced by a 2010 report of an activating variant of the BRAF oncogene (V600E) that was detected in 35 of 61 cases (57%).[1] Multiple subsequent reports have confirmed the presence of BRAF V600E variants in 50% or more of LCH cases in children.[2-4] Other BRAF variants that result in signal activation have been described.[3,5] ARAF variants are infrequent in LCH but, when present, can also lead to RAS-MAPK pathway activation.[6]

Sources: 1 · 2 · 4 · 3 · 5 · 6

The presence of the BRAF V600E variant in blood and bone marrow was studied in a series of 100 patients, 65% of whom tested positive for the BRAF V600E variant by a sensitive quantitative polymerase chain reaction technique.[2] Circulating cells with the BRAF V600E variant could be detected in all high-risk patients and in a subset of low-risk multisystem patients. The BRAF V600E allele was detected in circulating cell-free DNA in 100% of patients with risk-organ–positive multisystem LCH, 42% of patients with risk-organ–negative LCH, and 14% of patients with single-system LCH.[7]

Sources: 2 · 7

The myeloid dendritic cell origin of LCH was confirmed by finding CD34-positive stem cells with the variant in the bone marrow of high-risk patients. In those with low-risk disease, the variant was found in more mature myeloid dendritic cells, suggesting that the stage of cell development at which the somatic variant occurs is critical in defining the extent of disease in LCH.

Pulmonary LCH in adults was initially reported to be nonclonal in approximately 75% of cases,[8] while a later study of BRAF variants showed that 25% to 50% of adult patients with lung LCH had evidence of BRAF V600E variants.[8,9] Another study of 26 pulmonary LCH cases found that 50% had BRAF V600E variants and 40% had NRAS variants.[10] Approximately the same number of variants are polyclonal as are monoclonal. It has not been determined whether clonality and BRAF pathway variants are concordant in the same patients, which might suggest a reactive rather than a neoplastic condition in smoker's lung LCH and a clonal neoplasm in other types of LCH.

Sources: 8 · 8 · 9 · 10

In a study of 117 patients with LCH, 83 adult patients with pulmonary LCH underwent molecular analysis. Nearly 90% of these patients had variants in the MAPK pathway.[11][Level of evidence C3] Of the 69 patients who had their biopsy samples further analyzed using a next-generation sequencing panel of 74 genes, 36% had BRAF V600E variants, 29% had BRAF N486-P490 deletions, 15% had MAP2K1 variants or deletions, and 4% had NRAS variants. Only one patient had a KRAS variant. Additionally, 11 patients had their biopsy samples analyzed using whole-exome sequencing. An average of 14 variants were found per patient, which is markedly higher than the average of one variant found per pediatric patient.[12] There were no clinical correlates, including presence of a BRAF V600E variant and smoking status. Of the 117 patients with LCH, 60% experienced a relapse.

Sources: 11 · Level of evidence C3 · 12

The RAS-MAPK signaling pathway (see Figure 8) transmits signals from a cell surface receptor (e.g., a growth factor) through the RAS pathway (via one of the RAF proteins [A, B, or C]) to phosphorylate MEK and then the extracellular signal-regulated kinase (ERK), which leads to nuclear signals affecting cell cycle and transcription regulation. The V600E variant of BRAF leads to continuous phosphorylation, and thus activation, of MEK and ERK without the need for an external signal. Activation of ERK occurs by phosphorylation, and phosphorylated ERK can be detected in virtually all LCH lesions.[1,13]

Sources: 1 · 13

In a mouse model of LCH, the BRAF V600E variant was shown to inhibit a chemokine receptor (CCR7)–mediated migration of dendritic cells, forcing them to accumulate in the LCH lesion.[14] This variant also causes an increased expression of BCL2L1, which results in resistance to apoptosis. This process leads to the cells being less responsive to chemotherapy. The BRAF V600E variant also causes growth arrest of hematopoietic progenitor cells and a senescence-associated secretory phenotype that further promotes accumulation of the pathological cells.[15]

Sources: 14 · 15

Another mouse model with the BRAF V600E variant under control of Scl or Map17 gene promoters added additional insights into the biology of neurodegenerative LCH.[16] These studies confirmed the hematopoietic origin of CD11a-positive macrophages with BRAF V600E variants. This process disrupts the blood-brain barrier and causes loss of Purkinje cells and progressive neurodegeneration by resistance to apoptosis and production of senescent associated secretory proteins, which include inflammatory cytokines IL-1, IL-6, and matrix metalloproteinases. Treatment with a MAP kinase inhibitor and a senolytic agent (navitoclax) decreased the pathogenic cell numbers and led to clinical improvement in the mice.

Sources: 16

In summary, LCH is now considered a myeloid neoplasm primarily driven by activating variants of the MAPK pathway. Fifty percent to 60% of the activating variants are caused by BRAF V600E variants, which are enriched in patients with multisystem risk organ–positive LCH and in patients with neurodegenerative-disease LCH.[17] Ongoing studies are assessing whether low-level variant detection in peripheral blood can be used as a minimal residual disease marker to assist in therapeutic decisions.

Sources: 17

Health professional · Langerhans Cell Histiocytosis / Genomics of LCH

Other RAS-MAPK pathway alterations

Source: Childhood Cancer Genomics (PDQ®)–Health Professional Version, National Cancer Institute.

Source updated: April 30, 2025. Captured 2026-09-09.

Because RAS-MAPK pathway activation (elevated phosphor-ERK) can be detected in all LCH cases, including those without BRAF variants, the presence of genomic alterations in other components of the pathway was suspected. The following genomic alterations were identified:

MAP2K1 variants. Whole-exome sequencing on biopsy samples of BRAF-altered versus BRAF–wild-type LCH tissue revealed that 7 of 21 BRAF–wild-type specimens had MAP2K1 variants, while no BRAF-altered specimens had MAP2K1 variants.[13] The variants in MAP2K1 (which codes for MEK1) were activating, as indicated by their induction of ERK phosphorylation.[13]Another study showed MAP2K1 variants exclusively in 11 of 22 BRAF–wild-type cases.[18] One study showed that MAP2K1 and other variants associated with pediatric and adult LCH were mutually exclusive of BRAF variants.[19] The authors found a variety of variants in other pathways (e.g., JNK, RAS-ERK, and JAK-STAT) in pediatric and adult patients with BRAF V600E or MAP2K1 variants. Another study evaluated the kinase alterations and myeloid-associated variants in 73 adult patients with LCH.[20] They reported a median of two variants per adult patient, as opposed to children who usually have only one variant. BRAF V600E was found in 31%, BRAF indel in 29%, and MAP2K1 in 19% of patients with LCH. A variety of other protein kinase and related pathways were found in 89% of adult patients with LCH. MAP2K1 variants were exclusive of BRAF variants.

Sources: 13 · 13 · 18 · 19 · 20

In-frame BRAF deletions and FAM73A::BRAF gene fusions. In-frame BRAF deletions and in-frame FAM73A::BRAF gene fusions have occurred in the group of BRAF V600E and MAP2K1 variant–negative cases.[12]

Sources: 12

In summary, studies support the universal activation of ERK in LCH. ERK activation in most cases of LCH is explained by BRAF and MAP2K1 alterations.[1,12,13] Altogether, these variants in the MAP kinase pathway account for nearly 80% of the causes of the universal activation of ERK in LCH.[1,12,13] The remaining cases have a range of variants that include small deletions in BRAF, BRAF gene fusions (discussed above), as well as variants in ARAF, MAP3K1, NRAS, ERBB3, PI3CA, CSF1R, and other rare targets.[19,17][Level of evidence C1]

Sources: 1 · 12 · 13 · 1 · 12 · 13 · 19 · 17 · Level of evidence C1

Health professional · Langerhans Cell Histiocytosis / Genomics of LCH

Clinical implications

Source: Childhood Cancer Genomics (PDQ®)–Health Professional Version, National Cancer Institute.

Source updated: April 30, 2025. Captured 2026-09-09.

Clinical implications of the described genomic findings include the following:

LCH is included in a group of other pediatric tumors with activating BRAF variants, such as select nonmalignant conditions (e.g., benign nevi) [21] and low-grade malignancies (e.g., pilocytic astrocytoma).[22,23] All of these conditions have a generally indolent course, with spontaneous resolution occurring in some cases. This distinctive clinical course may be a manifestation of oncogene-induced senescence.[21,24]

Sources: 21 · 22 · 23 · 21 · 24

In some pediatric studies, BRAF V600E variants have been associated with more severe multisystem disease, treatment failure, increased reactivations, and an increased risk of neurodegeneration (see below).[25] These clinical correlates were recently investigated for non-BRAF V600E variants in an international study. Similar to the BRAF V600E cohort, all patients with multisystem risk organ–positive LCH had detectable variants in peripheral blood mononuclear cells. Of seven patients with multisystem risk organ–negative LCH, four had detectable variants. No patients with single-system disease had detectable variants in peripheral blood mononuclear cells. The authors concluded that other MAPK pathway variants are associated with risk status, similar to BRAF V600E variants.[17]BRAF V600E variants can be targeted by BRAF inhibitors (e.g., vemurafenib and dabrafenib) or by the combination of BRAF inhibitors plus MEK inhibitors (e.g., dabrafenib/trametinib and vemurafenib/cobimetinib). These agents and combinations are approved for adults with melanoma. Treatment of melanoma in adults with combinations of a BRAF inhibitor and a MEK inhibitor showed significantly improved progression-free survival outcomes compared with treatment using a BRAF inhibitor alone.[26,27]Several case reports and two case series have also demonstrated the efficacy of BRAF inhibitors for the treatment of LCH in children.[28-33] However, the long-term role of this therapy is complicated because most patients will relapse when the inhibitors are discontinued. For more information, see the sections on Treatment of recurrent, refractory, or progressive high-risk disease: multisystem LCH and Targeted therapies for the treatment of single-system and multisystem disease.

Sources: 25 · 17 · 26 · 27 · 28 · 33 · Treatment of recurrent, refractory, or progressive high-risk disease: multisystem LCH · Targeted therapies for the treatment of single-system and multisystem disease

Circulating BRAF V600E–altered cells have been found in 59% of patients who developed neurodegenerative-disease LCH, compared with 15% of patients who did not develop neurodegenerative-disease LCH. Detectable altered circulating cells had a sensitivity of 0.59 and specificity of 0.86 for developing the neurodegenerative disease. Even after therapy, some patients with neurodegenerative-disease LCH had circulating BRAF V600E–altered cells.[34]

Sources: 34

With additional research, the observation of the BRAF V600E variant (or potentially MAP2K1 variants) in circulating cells or cell-free DNA may become a useful diagnostic tool to define high-risk versus low-risk disease.[2] Additionally, for patients who have a somatic variant, persistence of circulating cells with the variant may be useful as a marker of residual disease.[2]

Sources: 2 · 2

For information about the treatment of childhood LCH, see Langerhans Cell Histiocytosis Treatment.

Sources: Langerhans Cell Histiocytosis Treatment

Health professional

Neuroblastoma

Source: Childhood Cancer Genomics (PDQ®)–Health Professional Version, National Cancer Institute.

Source updated: April 30, 2025. Captured 2026-09-09.

Health professional · Neuroblastoma

Molecular features of neuroblastoma

Source: Childhood Cancer Genomics (PDQ®)–Health Professional Version, National Cancer Institute.

Source updated: April 30, 2025. Captured 2026-09-09.

Children with neuroblastoma can be divided into subsets with different predicted risks of relapse based on clinical factors and biological markers at the time of diagnosis.

Low-risk or intermediate-risk neuroblastoma patients. Patients classified as low risk or intermediate risk have a favorable prognosis, with survival rates exceeding 95%. Low-risk and intermediate-risk neuroblastoma usually occur in children younger than 18 months. These tumors commonly have gains of whole chromosomes and are hyperdiploid when examined by flow cytometry.[1,2]

Sources: 1 · 2

High-risk neuroblastoma patients. The prognosis is more guarded for patients with high-risk neuroblastoma, with a long-term survival rate of less than 50%. High-risk neuroblastoma generally occurs in children older than 18 months and is often metastatic to bone and bone marrow. Segmental chromosome abnormalities (gains or losses) and/or MYCN gene amplification are usually detected in these tumors. They are near diploid or near tetraploid by flow cytometric measurement.[1-7] High-risk tumors generally harbor few exonic variants in cancer-related genes (see the Exonic Variants in Neuroblastoma section).

Sources: 1 · 7

Biological subtypes of high-risk neuroblastoma can be defined by the mostly nonoverlapping genomic alterations listed below:

MYCN amplification.

Structural variants up- or down-stream of TERT, resulting in TERT expression.

ATRX alterations leading to activation of the alternative lengthening of telomere (ALT) pathway.

FOXR2 expression resulting in MYCN stabilization.

CDK4 and MDM2 co-amplification.

The subtypes listed have specific clinical characteristics, as discussed below. Variants in ALK, which occur across the different subtypes of high-risk neuroblastoma, are observed in approximately 15% of cases and are discussed separately.

Key genomic characteristics of high-risk neuroblastoma that are present in most cases of high-risk neuroblastoma are discussed below.

Health professional · Neuroblastoma / Molecular features of neuroblastoma

Segmental chromosomal aberrations (SCAs)

Source: Childhood Cancer Genomics (PDQ®)–Health Professional Version, National Cancer Institute.

Source updated: April 30, 2025. Captured 2026-09-09.

The SCAs frequently observed in neuroblastoma and used when assigning SCA status include losses of or at chromosome arms 1p, 3p, 4p, and 11q and gains of or at chromosome arms 1q, 2p, and 17q.[8] These alterations can be detected by multiple methods, including fluorescence in situ hybridization (FISH), array comparative genomic hybridization (aCGH), and next-generation sequencing (NGS) assays. SCAs are present in most high-risk and/or stage 4 neuroblastoma tumors.[3,4,6,7,9] Among all patients with neuroblastoma, a higher number of chromosome breakpoints (i.e., a higher number of SCAs) correlated with the following:[3-7][Level of evidence C2]

Sources: 8 · 3 · 4 · 6 · 7 · 9 · 3 · 7 · Level of evidence C2

Advanced age at diagnosis.

Advanced stage of disease.

Higher risk of relapse.

Poorer outcome.

Determining the presence of SCAs is potentially clinically useful. Detecting SCAs can help distinguish patients with clinically favorable presentation who are at higher risk of treatment failure. Examples are provided below.

In an analysis of localized, resectable, non-MYCN amplified neuroblastoma, cases from two consecutive European studies and a North American cohort (including International Neuroblastoma Staging System [INSS] stages 1, 2A, and 2B) were analyzed for selected SCAs (namely loss of 1p, 3p, 4p, and 11q and gain of 1q, 2p, and 17q). The study revealed a different prognostic impact of tumor genomics depending on patient age (<18 months vs. >18 months) and stage (1 vs. 2). Patients were treated with surgery alone regardless of a tumor residuum.[10][Level of evidence C1]

Sources: 10 · Level of evidence C1

For patients with stage 1 disease, presence of SCAs was not predictive of relapse and overall survival (OS).

For patients younger than 18 months with stage 2 disease:

Chromosome 1p loss was a risk factor for relapse but not for diminished OS.

Patients with numerical chromosomal aberrations (NCA) and patients with SCAs had similar outcomes.

For patients older than 18 months with stage 2 disease:

SCAs were observed in approximately 50% of patients.

SCAs (especially 11q loss) were independent risk factors for reduced event-free survival (EFS) and OS. The 5-year EFS rate was 48%, compared with 85% (P = .033), respectively, for patients with or without chromosome 11q loss. The 5-year OS rate was 46%, compared with 92% (P = .038), respectively, for patients with or without chromosome 11q loss.

In a study of children older than 12 months who had unresectable primary neuroblastomas without metastases, SCAs were found in most patients. Older children were more likely to have them and to have more SCAs per tumor cell. In children aged 12 to 18 months, the presence of SCAs had a significant effect on EFS but not on OS. However, in children older than 18 months, there was a significant difference in OS between children with SCAs (67%) and children without SCAs (100%), regardless of tumor histology.[7]

Sources: 7

SCAs were also found to be predictive of recurrence in infants with localized unresectable or metastatic neuroblastoma without MYCN gene amplification.[1,2] An analysis of 133 patients (aged ≥18 months) with INSS stage 3 tumors without MYCN amplification demonstrated that SCAs were associated with inferior EFS, and chromosome 11q loss was independently associated with worse OS.[11]

Sources: 1 · 2 · 11

Chromosome 11q loss occurs in approximately 30% of high-risk neuroblastoma cases, but it is uncommonly observed in tumors with MYCN amplification.[3] Chromosome 11q loss is frequently observed in high-risk neuroblastoma cases with either TERT rearrangements or with ALT pathway activation.[12,13] Chromosome 11q loss has also been associated with inferior EFS and poor response to induction therapy in patients with high-risk neuroblastoma, as described below:

Sources: 3 · 12 · 13

In an analysis of intermediate-risk patients in a Children's Oncology Group (COG) study, 11q loss, but not 1p loss, was associated with reduced EFS but not OS (11q loss and no 11q loss: 3-year EFS rates, 68% and 85%, respectively; P = .022; 3-year OS rates, 88% and 94%, respectively; P = .09).[14][Level of evidence B4]

Sources: 14 · Level of evidence B4

In a multivariable analysis of 407 patients from four consecutive COG high-risk trials, 11q loss was shown to be a significant predictor of progressive disease, and was associated with both lower rates of end-induction complete response and lower end-induction partial response.[15][Level of evidence C1]

Sources: 15 · Level of evidence C1

Distal chromosome 6q losses have also been associated with poor outcome. An international collaboration studied 556 patients with high-risk neuroblastoma. Distal 6q losses were found in 6% of patients and were associated with a 10-year survival rate of only 3.4%.[16] A second study confirmed the very poor prognosis of patients with high-risk neuroblastoma who have distal 6q loss. Pooling across both studies, MYCN amplification occurred in only 20% of cases with distal chromosome 6q loss.[17]

Sources: 16 · 17

The same study of 556 patients with high-risk neuroblastoma that identified poor prognosis for patients with distal 6q loss also evaluated amplifications of regions not encompassing the MYCN locus. Regions of non-MYCN amplification were detected in 18% of the patients and were associated with a 10-year survival rate of 5.8%.[16]

Sources: 16

Health professional · Neuroblastoma / Molecular features of neuroblastoma

MYCN gene amplification

Source: Childhood Cancer Genomics (PDQ®)–Health Professional Version, National Cancer Institute.

Source updated: April 30, 2025. Captured 2026-09-09.

MYCN amplification is detected in 16% to 25% of neuroblastoma tumors.[18] Among patients with high-risk neuroblastoma, 40% to 50% of cases show MYCN amplification.[19]

Sources: 18 · 19

In all stages of disease, amplification of the MYCN gene strongly predicts a poorer prognosis, in both time to tumor progression and OS, in almost all multivariate regression analyses of prognostic factors.[1,2] In the ANBL00B1 (NCT00904241) study of 4,832 newly diagnosed patients enrolled between 2007 to 2017, the 5-year EFS and OS rates were 77% and 87%, respectively, for patients whose tumors were MYCN nonamplified (n = 3,647; 81%). In comparison, the 5-year EFS and OS rates were 51% and 57%, respectively, for patients whose tumors were MYCN amplified (n = 827; 19%).[9]

Sources: 1 · 2 · ANBL00B1 (NCT00904241) · 9

Within the localized-tumor MYCN-amplified cohort, patients with hyperdiploid tumors have better outcomes than patients with diploid tumors.[20] However, patients with hyperdiploid tumors with MYCN amplification or any SCAs do relatively poorly, compared with patients with hyperdiploid tumors without MYCN amplification.[3]

Sources: 20 · 3

Most unfavorable clinical and pathobiological features are associated, to some degree, with MYCN amplification. In a multivariable logistic regression analysis of 7,102 patients in the International Neuroblastoma Risk Group (INRG) study, pooled SCAs and gains of 17q were poor prognostic features, even when not associated with MYCN amplification. However, another poor prognostic feature, SCAs at 11q, are almost entirely mutually exclusive of MYCN amplification.[21,22]

Sources: 21 · 22

In a cohort of 6,223 patients from the INRG database with known MYCN status, the OS hazard ratio (HR) associated with MYCN amplification was 6.3 (95% confidence interval [CI], 5.7–7.0; P < .001). The greatest adverse prognostic impact of MYCN amplification for OS was in the youngest patients (aged <18 months: HR, 19.6; aged ≥18 months: HR, 3.0). Patients whose outcome was most impacted by MYCN status were those with otherwise favorable features, including age younger than 18 months, high mitosis-karyorrhexis index, and low ferritin.[23][Level of evidence C1]

Sources: 23 · Level of evidence C1

Intratumoral heterogeneous MYCN amplification (hetMNA) refers to the coexistence of MYCN-amplified cells (as a cluster or as single scattered cells) and non–MYCN-amplified tumor cells. HetMNA has been reported infrequently. It can occur spatially within the tumor as well as between the tumor and the metastasis at the same time or temporally during the disease course. The International Society of Paediatric Oncology Europe Neuroblastoma (SIOPEN) biology group investigated the prognostic significance of this neuroblastoma subtype. Tumor tissue from 99 patients identified as having hetMNA and diagnosed between 1991 and 2015 was analyzed to elucidate the prognostic significance of MYCN-amplified clones in otherwise non-MYCN–amplified neuroblastomas. Patients younger than 18 months showed a better outcome in all stages compared with older patients. The genomic background correlated significantly with relapse frequency and OS. No relapses occurred in cases of only numerical chromosomal aberrations. This study suggests that hetMNA tumors be evaluated in the context of the genomic tumor background in combination with the clinical pattern, including the patient's age and disease stage. Future studies are needed in patients younger than 18 months who have localized disease with hetMNA.[24]

Sources: 24

Health professional · Neuroblastoma / Molecular features of neuroblastoma

Genomic alterations promoting telomere maintenance

Source: Childhood Cancer Genomics (PDQ®)–Health Professional Version, National Cancer Institute.

Source updated: April 30, 2025. Captured 2026-09-09.

Lengthening of telomeres, the tips of chromosomes, promotes cell survival. Telomeres otherwise shorten with each cell replication, eventually resulting in the cell’s inability to replicate. Patients whose tumors lack telomere maintenance mechanisms have an excellent prognosis, while patients whose tumors harbored telomere maintenance mechanisms have a substantially worse prognosis.[25] Low-risk neuroblastoma tumors, as defined by clinical/biological features, have little telomere lengthening activity. Aberrant genetic mechanisms for telomere lengthening have been identified in high-risk neuroblastoma tumors.[25-28] Thus far, the following three mechanisms, which appear to be mutually exclusive, have been described:

Sources: 25 · 25 · 28

MYCN amplification, which is associated with approximately 40% to 50% of high-risk neuroblastoma cases, is sufficient to drive TERT overexpression.[25,26,29]

Sources: 25 · 26 · 29

TERT gene rearrangements are a second method for neuroblastoma to achieve TERT expression. Chromosomal rearrangements, either proximal or distal to the TERT gene, which encodes the catalytic unit of telomerase, occur in approximately 20% to 25% of high-risk neuroblastoma cases and are mutually exclusive with MYCN amplifications and ALT activation.[13,26-28] The rearrangements induce transcriptional upregulation of TERT by juxtaposing the TERT coding sequence with strong enhancer elements. Rearrangements distal to the TERT gene occur less commonly and also lead to TERT expression.

Sources: 13 · 26 · 28

Children whose tumors have TERT rearrangements have a poor prognosis, which is comparable to the prognosis of children whose tumors have MYCN amplification.[28]

Sources: 28

Chromosome 11q loss and chromosome 1q gain are common in patients with TERT rearrangements.

NGS or FISH using break-apart probes may be used to identify TERT rearrangements.[13]

Sources: 13

ALT pathway activation is an additional mechanism of telomere maintenance that is used by neuroblastoma tumors. Approximately 55% to 60% of ALT-positive cases are characterized by deleterious ATRX variants.[30-32] Cases lacking ATRX variants often show low ATRX protein expression.[31]

Sources: 30 · 32 · 31

ALT activation is present in approximately 20% to 25% of newly diagnosed high-risk cases, compared with approximately 5% to 12% of low-risk and intermediate-risk cases.[28,31,32]

Sources: 28 · 31 · 32

Compared with newly diagnosed cases, the proportion of neuroblastoma cases with ALT-positive tumors was higher in a cohort of patients who relapsed (10% vs. 48%, respectively). This finding may reflect the relatively indolent course of tumors with ALT activation after relapse (see below), compared with the clinical course of other tumors after relapse.[31]

Sources: 31

Like cases with TERT rearrangements, chromosome 11q loss is commonly observed in ALT-positive neuroblastoma. Unique to ALT-positive cases is deletion at chromosome 1q42.2.[12,31]

Sources: 12 · 31

Neuroblastoma cases with ALT activation have low TERT expression and can be identified by immunohistochemistry for the ALT-associated promyelocytic nuclear body, by FISH with a telomere probe to visualize telomere ultrabright spots, and by the C-circle assay.[31-33]

Sources: 31 · 33

ALT-positive tumors in pediatric populations rarely present before the age of 18 months and occur almost exclusively in older children (median age at diagnosis, approximately 8 years).[28,31] The proportion of neuroblastoma cases with ATRX variants increases with age into the adolescent and young adult populations.[30]

Sources: 28 · 31 · 30

The prognosis for high-risk patients with ALT activation is as poor as that for patients with MYCN amplification for EFS.[28,31] However, OS is more favorable for patients with ALT activation. The more favorable OS appears to result from a more protracted disease course after relapse, but with long-term survival at 10 to 15 years being as low as that for other patients with high-risk neuroblastoma.[28,31] In one report, EFS and OS for low-risk and intermediate-risk patients with ALT activation were similar to those observed for ALT-positive patients with high-risk disease.[31]

Sources: 28 · 31 · 28 · 31 · 31

Health professional · Neuroblastoma / Molecular features of neuroblastoma

FOXR2 activation

Source: Childhood Cancer Genomics (PDQ®)–Health Professional Version, National Cancer Institute.

Source updated: April 30, 2025. Captured 2026-09-09.

FOXR2 gene expression is observed in approximately 8% of neuroblastoma cases. FOXR2 gene expression is normally absent postnatally, with the exception of male reproductive tissues.[34] FOXR2 expression is also observed in a subset of central nervous system (CNS) primitive neuroectodermal tumors, termed CNS NB-FOXR2.[35] FOXR2 overexpression was virtually mutually exclusive in neuroblastoma tumors with both elevated MYC and MYCN expression. Although MYCN gene expression was not elevated in neuroblastoma with FOXR2 activation, the gene expression profile for the FOXR2 expressing cases closely resembled that of MYCN-amplified neuroblastoma. FOXR2 binds MYCN and appears to stabilize the MYCN protein, leading to high levels of MYCN protein in neuroblastoma with FOXR2 activation. This finding provides an explanation for the similar gene expression profiles for neuroblastoma with FOXR2 activation and neuroblastoma with MYCN amplification.

Sources: 34 · 35

Neuroblastoma with FOXR2 activation is observed at comparable rates in high-risk and non–high-risk cases.[34] Among high-risk cases, outcomes for patients whose tumors showed FOXR2 activation were similar to those for cases with MYCN amplification. In a multivariable analysis, FOXR2 activation was significantly associated with inferior OS, along with INSS stage 4, age 18 months or older, and MYCN amplification.

Sources: 34

Health professional · Neuroblastoma / Molecular features of neuroblastoma

CDK4 and MDM2 amplification

Source: Childhood Cancer Genomics (PDQ®)–Health Professional Version, National Cancer Institute.

Source updated: April 30, 2025. Captured 2026-09-09.

CDK4 and MDM2 amplification are observed together in 1% to 2% of neuroblastoma cases, and these cases have distinctive biological and clinical features:[36,37]

Sources: 36 · 37

Neuroblastoma with chromosome 12q amplification typically has discrete amplicons involving 12q13–14, which includes CDK4, and 12q15, which includes MDM2 and FRS2 (encoding the gene for fibroblast growth factor receptor substrate 2).

The primary tumors of most cases with CDK4 or MDM2 amplification were associated with the adrenal gland, although some renal primary tumors were also observed.

Lung metastases, which are infrequent in neuroblastoma, were observed in 9 of 13 cases with CDK4 or MDM2 amplification that presented with metastatic disease.

Most patients with CDK4 or MDM2 amplification did not have MYCN amplification, although MYCN amplification was present in approximately 25% of cases.

Outcome for patients with CDK4 or MDM2 amplification is poor. In one experience, only two of six patients with localized disease showed long-term survival, and nine of ten patients with metastatic disease died.[37] Another report described only one of eight patients with CDK4 or MDM2 amplification as a long-term survivor.[36] A third report described three patients with localized disease, all of whom subsequently died of their disease.[38]

Sources: 37 · 36 · 38

Health professional · Neuroblastoma / Molecular features of neuroblastoma

Exonic variants in neuroblastoma (including ALK variants and amplification)

Source: Childhood Cancer Genomics (PDQ®)–Health Professional Version, National Cancer Institute.

Source updated: April 30, 2025. Captured 2026-09-09.

Compared with adult cancers, pediatric neuroblastoma tumors show a low number of variants per genome that affect protein sequence (10–20 per genome).[39] The most common gene variant is ALK, which is altered in approximately 10% of patients (see below). Other genes with even lower frequencies of variants include ATRX, PTPN11, ARID1A, and ARID1B.[26,27,30,40-43] As shown in Figure 9, most neuroblastoma cases lack variants in genes that are altered in a recurrent manner.

Sources: 39 · 26 · 27 · 30 · 40 · 43

The ALK gene provides instructions for making a cell surface receptor tyrosine kinase, expressed at significant levels only in developing embryonic and neonatal brains. ALK is the exonic variant found most commonly in neuroblastoma. Germline pathogenic variants in ALK have been identified as the major cause of hereditary neuroblastoma. Somatically acquired ALK-activating exonic variants are also found as oncogenic drivers in neuroblastoma.[42]

Sources: 42

Two large cohort studies examined the clinical correlates and prognostic significance of ALK alterations. One study from the COG examined ALK status in 1,596 diagnostic neuroblastoma samples across all risk groups.[42] Another study from SIOPEN evaluated 1,092 patients with high-risk neuroblastoma.[44]

Sources: 42 · 44

ALK tyrosine kinase domain variants occurred primarily at three hot spots (F1174, R1275, and F1245 positions), with 10% to 15% of variants occurring at other kinase domain positions.

In the COG cohort, the frequency of ALK variants was 10% in the high-risk neuroblastoma group, 8% in the intermediate-risk neuroblastoma group, and 6% in the low-risk neuroblastoma group.

In the SIOPEN high-risk population, ALK variants were divided into clonal (>20% variant allele frequency [VAF]) and subclonal (0.1%–20% VAF). Clonal ALK variants were detected in 10% of cases, and subclonal variants were found in 3.9% of patients. A total of 13.9% of the cases had an ALK variant.

ALK variants were found at higher rates in patients with MYCN-amplified tumors compared with those without MYCN amplification: 10.9% versus 7.2%, respectively, for the COG cohort and 14% versus 6.5%, respectively, for the SIOPEN cohort (for clonal ALK variants).

For patients with high-risk neuroblastoma, the ALK amplification was observed in approximately 4% of cases in both the COG and the SIOPEN cohorts. ALK amplification occurred almost exclusively in cases that also had MYCN amplification.

ALK alterations were associated with inferior prognoses for patients with high-risk neuroblastoma in both the COG and the SIOPEN studies:

In the SIOPEN cohort, a statistically significant difference in OS was observed between cases with ALK amplification (ALKa) or clonal ALK variant (ALKm) versus subclonal ALKm or no ALK alterations (5-year OS rate: ALKa, 26% [95% CI, 10%–47%]; clonal ALKm, 33% [95% CI, 21%–44%]; subclonal ALKm, 48% [95% CI, 26%–67%]; and no alteration, 51% [95% CI, 46%–55%], respectively; P = .001). In a multivariate model, ALK amplification (HR, 2.38; P = .004) and clonal ALK variant (HR, 1.77; P = .001) were independent predictors of poor outcome.

In the COG high-risk neuroblastoma population, inferior prognoses, similar to those seen in the SIOPEN cohort, were observed for cases with ALK variants and ALK amplifications.

In a study that compared the genomic data of primary diagnostic neuroblastomas originating in the adrenal gland (n = 646) with that of neuroblastomas originating in the thoracic sympathetic ganglia (n = 118), 16% of thoracic tumors harbored ALK variants.[45]

Sources: 45

Small-molecule ALK kinase inhibitors such as lorlatinib (added to conventional therapy) are being tested in patients with recurrent ALK-altered neuroblastoma (NCT03107988) and in patients with newly diagnosed high-risk neuroblastoma with activated ALK (COG ANBL1531).[42] For more information, see the sections on Treatment of High-Risk Neuroblastoma and Treatment of Recurrent or Refractory Neuroblastoma in Neuroblastoma Treatment.

Sources: NCT03107988 · ANBL1531 · 42 · Treatment of High-Risk Neuroblastoma · Treatment of Recurrent or Refractory Neuroblastoma

Health professional · Neuroblastoma / Molecular features of neuroblastoma / Exonic variants in neuroblastoma (including ALK variants and amplification)

Genomic evolution of exonic variants

Source: Childhood Cancer Genomics (PDQ®)–Health Professional Version, National Cancer Institute.

Source updated: April 30, 2025. Captured 2026-09-09.

There are limited data regarding the genomic evolution of exonic variants from diagnosis to relapse for neuroblastoma. Whole-genome sequencing was applied to 23 paired diagnostic and relapsed neuroblastoma tumor samples to define somatic genetic alterations associated with relapse,[46] while a second study evaluated 16 paired diagnostic and relapsed specimens.[47] Both studies identified an increased number of variants in the relapsed samples compared with the samples at diagnosis. This has been confirmed in a study of neuroblastoma tumor samples sent for NGS.[48]

Sources: 46 · 47 · 48

In the first study, an increased incidence of variants in genes associated with RAS-MAPK signaling was found in tumors at relapse compared with tumors from the same patient at diagnosis; 15 of 23 relapse samples contained somatic variants in genes involved in this pathway, and each variant was consistent with pathway activation.[46] In addition, three relapse samples showed structural alterations involving MAPK pathway genes consistent with pathway activation, so aberrations in this pathway were detected in 18 of 23 (78%) relapse samples. Aberrations were found in ALK (n = 10), NF1 (n = 2), and one each in NRAS, KRAS, HRAS, BRAF, PTPN11, and FGFR1. Even with deep sequencing, 7 of the 18 alterations were not detectable in the primary tumor, highlighting the evolution of variants presumably leading to relapse and the importance of genomic evaluations of tissues obtained at relapse.

Sources: 46

In the second study, ALK variants were not observed in either diagnostic or relapse specimens, but relapse-specific recurrent single-nucleotide variants were observed in 11 genes, including the putative CHD5 neuroblastoma tumor suppressor gene located at chromosome 1p36.[47]

Sources: 47

A third retrospective variant-sequencing study used data from Foundation Medicine to compare tumor samples from patients with newly diagnosed neuroblastoma with tumor samples from patients with refractory and relapsed neuroblastoma. The study found a higher percentage of variants that were targetable with current drugs in the relapsed and refractory group.[48]

Sources: 48

A fourth study evaluated the frequency of ALK alterations at diagnosis and relapse. There were significantly higher rates of ALK variants at relapse than at diagnosis (17.7% at relapse vs. 10.5% at diagnosis). The rate of ALK amplifications did not differ between diagnosis and relapse.[49]

Sources: 49

Given the widespread metastatic nature of high-risk and relapsed neuroblastoma, use of circulating tumor DNA (ctDNA) technologies may reveal additional genomic alterations not found in conventional tumor biopsies. Moreover, these approaches have demonstrated the ability to detect resistant variants in patients with neuroblastoma who were treated with ALK inhibitors.[50][Level of evidence C1] In one analysis of serial ctDNA samples from patients treated with lorlatinib, ALK VAF tracked with disease burden in most but not all patients.[51] In subsets of patients who progressed while taking lorlatinib, second compound variants in ALK or variants in other genes, including RAS pathway genes and TP53, have been reported.[51,52]

Sources: 50 · Level of evidence C1 · 51 · 51 · 52

In a deep-sequencing study, 276 neuroblastoma samples (comprised of all stages and from patients of all ages at diagnosis) underwent very deep (33,000X) sequencing of just two amplified ALK variant hot spots, which revealed 4.8% clonal variants and an additional 5% subclonal variants. This finding suggests that subclonal ALK gene variants are common.[53] Thus, deep sequencing can reveal the presence of variants in tiny subsets of neuroblastoma tumor cells that may be able to survive during treatment and grow to constitute a relapse.

Sources: 53

Health professional · Neuroblastoma / Molecular features of neuroblastoma

Additional biological factors associated with prognosis

Source: Childhood Cancer Genomics (PDQ®)–Health Professional Version, National Cancer Institute.

Source updated: April 30, 2025. Captured 2026-09-09.

Health professional · Neuroblastoma / Molecular features of neuroblastoma / Additional biological factors associated with prognosis

MYC and MYCN expression

Source: Childhood Cancer Genomics (PDQ®)–Health Professional Version, National Cancer Institute.

Source updated: April 30, 2025. Captured 2026-09-09.

Immunostaining for MYC and MYCN proteins on a restricted subset of 357 undifferentiated/poorly differentiated neuroblastoma tumors demonstrated that elevated MYC/MYCN protein expression is prognostically significant.[54] Sixty-eight tumors (19%) highly expressed the MYCN protein, and 81 were MYCN amplified. Thirty-nine tumors (10.9%) expressed MYC highly and were mutually exclusive of high MYCN expression. In the MYC-expressing tumors, MYC or MYCN gene amplification was not seen. SCAs were not examined in this study.[54]

Sources: 54 · 54

Patients with favorable-histology tumors without high MYC/MYCN expression had favorable survival (3-year EFS rate, 89.7% ± 5.5%; 3-year OS rate, 97% ± 3.2%).

Patients with undifferentiated or poorly differentiated histology tumors without MYC/MYCN expression had a 3-year EFS rate of 63.1% (± 13.6%) and a 3-year OS rate of 83.5% (± 9.4%).

The 3-year EFS rates in patients with MYCN amplification, high MYCN expression, and high MYC expression were 48.1% (± 11.5%), 46.2% (± 12%), and 43.4% (± 23.1%), respectively. OS rates were 65.8% (± 11.1%), 63.2% (± 12.1%), and 63.5% (± 19.2%), respectively.

Additionally, when high expression of MYC and MYCN proteins underwent multivariate analysis with other prognostic factors, including MYC/MYCN gene amplification, high MYC and MYCN protein expression was independent of other prognostic markers.

For information about the treatment of neuroblastoma, see Neuroblastoma Treatment.

Sources: Neuroblastoma Treatment

Health professional

Retinoblastoma

Source: Childhood Cancer Genomics (PDQ®)–Health Professional Version, National Cancer Institute.

Source updated: April 30, 2025. Captured 2026-09-09.

Health professional · Retinoblastoma

Heritable Retinoblastoma

Source: Childhood Cancer Genomics (PDQ®)–Health Professional Version, National Cancer Institute.

Source updated: April 30, 2025. Captured 2026-09-09.

Heritable retinoblastoma is defined by the presence of a germline pathogenic variant of the RB1 gene. This germline pathogenic variant may have been inherited from an affected progenitor (25% of cases) or may have occurred in a germ cell before conception or in utero during early embryogenesis in patients with sporadic disease (75% of cases). The presence of positive family history or bilateral or multifocal disease is suggestive of heritable disease.

Heritable retinoblastoma may manifest as unilateral or bilateral disease. The penetrance of the RB1 variant (laterality, age at diagnosis, and number of tumors) is probably dependent on concurrent genetic modifiers such as MDM2 and MDM4 polymorphisms.[1,2] All children with bilateral disease and approximately 15% of patients with unilateral disease are presumed to have the heritable form, even though only 25% have an affected parent. In a series of 482 patients with unilateral retinoblastoma, germline pathogenic variants were identified in 33% of infants younger than 12 months, 6% of children aged 12 to 24 months, and 7% of children aged 24 to 39 months. The highest incidence of germline retinoblastoma was in patients younger than 1 year compared with patients older than 1 year (odds ratio, 2.96).[3][Level of evidence C2]

Sources: 1 · 2 · 3 · Level of evidence C2

Children with heritable retinoblastoma tend to be diagnosed at a younger age than children with the nonheritable form of the disease.[4]

Sources: 4

Health professional · Retinoblastoma

Nonheritable Retinoblastoma

Source: Childhood Cancer Genomics (PDQ®)–Health Professional Version, National Cancer Institute.

Source updated: April 30, 2025. Captured 2026-09-09.

The genomic landscape of retinoblastoma is driven by alterations in RB1 that lead to biallelic inactivation.[5,6] A rare cause of RB1 inactivation is chromothripsis, which may be difficult to detect by conventional methods.[7]

Sources: 5 · 6 · 7

Recurrent changes in genes other than RB1 are uncommon in retinoblastoma but do occur. Variants or deletions of BCOR and amplification of MYCN are the most frequently reported events.[5-10] A study of 1,068 unilateral nonfamilial retinoblastoma tumors reported that 2% to 3% of tumors lacked evidence of RB1 loss and approximately one-half of these cases without evidence of RB1 loss showed MYCN amplification.[6] However, MYCN amplification is also observed in retinoblastoma tumors that have RB1 alterations, suggesting that inactivation of RB1 by a variant or an inactive retinoblastoma protein is a requirement for the development of retinoblastoma, independent of MYCN amplification.[11]

Sources: 5 · 10 · 6 · 11

For information about the treatment of retinoblastoma, see Retinoblastoma Treatment.

Sources: Retinoblastoma Treatment

Health professional

Kidney Tumors

Source: Childhood Cancer Genomics (PDQ®)–Health Professional Version, National Cancer Institute.

Source updated: April 30, 2025. Captured 2026-09-09.

Health professional · Kidney Tumors

Wilms Tumor

Source: Childhood Cancer Genomics (PDQ®)–Health Professional Version, National Cancer Institute.

Source updated: April 30, 2025. Captured 2026-09-09.

Health professional · Kidney Tumors / Wilms Tumor

Molecular Features of Wilms Tumor

Source: Childhood Cancer Genomics (PDQ®)–Health Professional Version, National Cancer Institute.

Source updated: April 30, 2025. Captured 2026-09-09.

A Wilms tumor may arise during embryogenesis on the background of an otherwise genomically normal kidney, or it may arise from nongermline somatic genetic precursor lesions residing in histologically and functionally normal kidney tissue. Hypermethylation of H19, a known component of a subset of Wilms tumors, is a very common genetic abnormality found in these normal-appearing areas of precursor lesions.[1]

Sources: 1

One study performed genome-wide sequencing, mRNA and miRNA expression, DNA copy number, and methylation analysis on 117 Wilms tumors, followed by targeted sequencing of 651 Wilms tumors.[2] The tumors were selected for either favorable histology (FH) Wilms that had relapsed or those with diffuse anaplasia. The study showed the following:[2]

Sources: 2 · 2

Wilms tumors commonly arise through more than one genetic event.

Wilms tumors show differences in gene expression and methylation patterns with different genetic aberrations.

Wilms tumors have a large number of candidate driver genes, most of which are altered in less than 5% of Wilms tumors.

Wilms tumors have recurrent variants in genes with common functions, with most involved in either early renal development or epigenetic regulation (e.g., chromatin modifications, transcription elongation, and miRNA).

Approximately one-third of Wilms tumor cases involve variants in WT1, CTNNB1, or AMER1 (WTX).[3,4] Another subset of Wilms tumor cases results from variants in miRNA processing genes (miRNAPG), including DROSHA, DGCR8, DICER1, and XPO5.[5-8] Other genes critical for early renal development that are recurrently altered in Wilms tumor include SIX1 and SIX2 (transcription factors that play key roles in early renal development),[5,6] EP300, CREBBP, and MYCN.[2] Of the variants in Wilms tumors, 30% to 50% appear to converge on the process of transcriptional elongation in renal development and include the genes MLLT1, BCOR, MAP3K4, BRD7, and HDAC4.[2] Anaplastic Wilms tumor is characterized by the presence of TP53 variants.

Sources: 3 · 4 · 5 · 8 · 5 · 6 · 2 · 2

Elevated rates of Wilms tumor are observed in patients with a number of genetic disorders, including WAGR (Wilms tumor, aniridia, genitourinary abnormalities, and range of developmental delays) syndrome (WAGR spectrum), Beckwith-Wiedemann syndrome, hemihypertrophy, Denys-Drash syndrome, and Perlman syndrome.[9] Other genetic causes that have been observed in familial Wilms tumor cases include germline pathogenic variants in REST and CTR9.[10,11]

Sources: 9 · 10 · 11

The genomic and genetic characteristics of Wilms tumor are summarized below.

Health professional · Kidney Tumors / Wilms Tumor / Molecular Features of Wilms Tumor

WT1 gene

Source: Childhood Cancer Genomics (PDQ®)–Health Professional Version, National Cancer Institute.

Source updated: April 30, 2025. Captured 2026-09-09.

The WT1 gene is located on the short arm of chromosome 11 (11p13). WT1 is a transcription factor that is required for normal genitourinary development and is important for differentiation of the renal blastema.[12] WT1 variants are observed in 10% to 20% of cases of sporadic Wilms tumor.[3,12,13]

Sources: 12 · 3 · 12 · 13

Wilms tumor with a WT1 variant is characterized by the following:

Evidence of WNT pathway activation by activating variants in the CTNNB1 gene is common.[13-15]

Sources: 13 · 15

Loss of heterozygosity (LOH) at 11p15 is commonly observed, as paternal uniparental disomy for chromosome 11 represents a common mechanism for losing the remaining normal WT1 allele.[13,16]

Sources: 13 · 16

Nephrogenic rests are benign foci of embryonal kidney cells that abnormally persist into postnatal life. Intralobar nephrogenic rests occur in approximately 20% of Wilms tumor cases. They are observed at high rates in cases with genetic syndromes that have WT1 variants such as WAGR and Denys-Drash syndromes.[17] Intralobar nephrogenic rests are also observed in cases with sporadic WT1 and MLLT1 variants.[18,19]

Sources: 17 · 18 · 19

WT1 germline pathogenic variants are uncommon (2%–4%) in nonsyndromic Wilms tumor.[20,21]

Sources: 20 · 21

WT1 variants and 11p15 LOH were associated with relapse in patients with very low-risk Wilms tumor in one study of 56 patients who did not receive chemotherapy.[22] These findings need validation but may provide biomarkers for stratifying patients in the future.

Sources: 22

Germline WT1 pathogenic variants are more common in children with Wilms tumor and one of the following:

WAGR syndrome, Denys-Drash syndrome,[23] or Frasier syndrome.[24]

Sources: 23 · 24

Genitourinary anomalies, including hypospadias and cryptorchidism.

Bilateral Wilms tumor.

Unilateral Wilms tumor with nephrogenic rests in the contralateral kidney.

Stromal and rhabdomyomatous differentiation.

Germline WT1 pathogenic single nucleotide variants produce genetic syndromes that are characterized by nephropathy, 46XY disorder of sex development, and varying risks of Wilms tumor.[25,26] Syndromic conditions with germline WT1 pathogenic variants include WAGR syndrome, Denys-Drash syndrome,[23] and Frasier syndrome.[24]

Sources: 25 · 26 · 23 · 24

WAGR syndrome. Children with WAGR syndrome are at high risk (approximately 50%) of developing Wilms tumor.[27] WAGR syndrome results from deletions at chromosome 11p13 that involve a set of contiguous genes that include the WT1 and PAX6 genes. Inactivating variants or deletions in the PAX6 gene lead to aniridia, while deletion of WT1 confers the increased risk of Wilms tumor. Loss of the LMO2 gene has been associated with a more frequent development of Wilms tumor in patients with congenital aniridia and WAGR-region deletions.[28][Level of evidence C1] Sporadic aniridia in which WT1 is not deleted is not associated with increased risk of Wilms tumor. Accordingly, children with familial aniridia, generally occurring for many generations, and without renal abnormalities, have a normal WT1 gene and are not at an increased risk of Wilms tumor.[29,30] Wilms tumor in children with WAGR syndrome is characterized by an excess of bilateral disease, intralobar nephrogenic rests, early age at diagnosis, and stromal-predominant histology in FH tumors.[31] The intellectual disability in WAGR syndrome may be secondary to deletion of other genes, including SLC1A2 or BDNF.[32]

Sources: 27 · 28 · Level of evidence C1 · 29 · 30 · 31 · 32

Denys-Drash syndrome. This syndrome is characterized by nephrotic syndrome caused by diffuse mesangial sclerosis, XY pseudohermaphroditism, and increased risk of Wilms tumor (>90%). WT1 variants in Denys-Drash syndrome are most often missense variants in exons 8 and 9, which code for the DNA binding region of WT1.[23]

Sources: 23

Frasier syndrome. This syndrome is characterized by progressive nephropathy caused by focal segmental glomerulosclerosis, gonadoblastoma, and XY pseudohermaphroditism.WT1 variants in Frasier syndrome typically occur in intron 9 at the KT site, and create an alternative splicing variant, thereby preventing production of the usually more abundant WT1 +KTS isoform.[33]

Sources: 33

Studies evaluating genotype/phenotype correlations of WT1 variants have shown that the risk of Wilms tumor is highest for truncating variants (14 of 17 cases, 82%) and lower for missense variants (27 of 67 cases, 42%). The risk is lowest for KTS splice site variants (1 of 27 cases, 4%).[25,26] Bilateral Wilms tumor was more common in cases with WT1-truncating variants (9 of 14 cases) than in cases with WT1 missense variants (3 of 27 cases).[25,26] These genomic studies confirm previous estimates of elevated risk of Wilms tumor for children with Denys-Drash syndrome and low risk of Wilms tumor for children with Frasier syndrome.

Sources: 25 · 26 · 25 · 26

Health professional · Kidney Tumors / Wilms Tumor / Molecular Features of Wilms Tumor

CTNNB1 gene

Source: Childhood Cancer Genomics (PDQ®)–Health Professional Version, National Cancer Institute.

Source updated: April 30, 2025. Captured 2026-09-09.

CTNNB1 is one of the most commonly altered genes in Wilms tumor, reported to occur in 15% of patients with Wilms tumor.[2,4,13,15,34] These CTNNB1 variants result in activation of the WNT pathway, which plays a prominent role in the developing kidney.[35] CTNNB1 variants commonly occur with WT1 variants, and most cases of Wilms tumor with WT1 variants have a concurrent CTNNB1 variant.[13,15,34] Activation of beta-catenin in the presence of intact WT1 protein appears to be inadequate to promote tumor development because CTNNB1 variants are rarely found in the absence of a WT1 or AMER1 variant, except when associated with a MLLT1 variant.[4,36] CTNNB1 variants appear to be late events in Wilms tumor development because they are found in tumors but not in nephrogenic rests.[18]

Sources: 2 · 4 · 13 · 15 · 34 · 35 · 13 · 15 · 34 · 4 · 36 · 18

Health professional · Kidney Tumors / Wilms Tumor / Molecular Features of Wilms Tumor

AMER1 (WTX) gene on the X chromosome

Source: Childhood Cancer Genomics (PDQ®)–Health Professional Version, National Cancer Institute.

Source updated: April 30, 2025. Captured 2026-09-09.

AMER1 is located on the X chromosome at Xq11.1. It is altered in 15% to 20% of Wilms tumor cases.[3,4,13,37,38] Germline pathogenic variants in AMER1 cause an X-linked sclerosing bone dysplasia, osteopathia striata congenita with cranial sclerosis (MIM300373).[39] Despite having germline AMER1 pathogenic variants, individuals with osteopathia striata congenita are not predisposed to tumor development.[39] The AMER1 protein appears to be involved in both the degradation of beta-catenin and in the intracellular distribution of APC protein.[36,40] AMER1 is most commonly altered by deletions involving part or all of the AMER1 gene, with deleterious single nucleotide variants occurring less commonly.[3,13,37] Most Wilms tumor cases with AMER1 alterations have epigenetic 11p15 abnormalities.[13]

Sources: 3 · 4 · 13 · 37 · 38 · MIM300373 · 39 · 39 · 36 · 40 · 3 · 13 · 37 · 13

AMER1 alterations are equally distributed between males and females, and AMER1 inactivation has no apparent effect on clinical presentation or prognosis.[3]

Sources: 3

Health professional · Kidney Tumors / Wilms Tumor / Molecular Features of Wilms Tumor

Imprinting cluster regions (ICRs) on chromosome 11p15 (WT2) and Beckwith-Wiedemann syndrome

Source: Childhood Cancer Genomics (PDQ®)–Health Professional Version, National Cancer Institute.

Source updated: April 30, 2025. Captured 2026-09-09.

A second Wilms tumor locus, WT2, maps to an imprinted region of chromosome 11p15.5. When it is a germline pathogenic variant, it causes Beckwith-Wiedemann syndrome. About 3% of children with Wilms tumor have germline epigenetic or genetic changes at the 11p15.5 growth regulatory locus without any clinical manifestations of overgrowth. Like children with Beckwith-Wiedemann syndrome, these children have an increased incidence of bilateral Wilms tumor or familial Wilms tumor.[32]

Sources: 32

Approximately one-fifth of patients with Beckwith-Wiedemann syndrome who develop Wilms tumor present with bilateral disease, and metachronous bilateral disease is also observed.[29,41,42] The prevalence of Beckwith-Wiedemann syndrome is about 1% among children with Wilms tumor reported to the National Wilms Tumor Study (NWTS).[42,43]

Sources: 29 · 41 · 42 · 42 · 43

Approximately 80% of patients with Beckwith-Wiedemann syndrome have a molecular defect of the 11p15 domain.[44] Various molecular mechanisms underlying Beckwith-Wiedemann syndrome have been identified. Some of these abnormalities are genetic (germline pathogenic variants of the maternal allele of CDKN1C, paternal uniparental isodisomy of 11p15, or duplication of part of the 11p15 domain) but are more frequently epigenetic (loss of methylation of the maternal ICR2 [CDKN1C and KCNQ1OT1 genes] or gain of methylation of the maternal ICR1 [IGF2 and H19 genes]).[32,45]

Sources: 44 · 32 · 45

Several candidate genes at the WT2 locus comprise the two independent imprinted domains: IGF2 and H19; and CDKN1C and KCNQ1OT1.[45] LOH, which exclusively affects the maternal chromosome, has the effect of upregulating paternally active genes and silencing maternally active ones. A loss or switch of the imprint for genes (change in methylation status) in this region has also been frequently observed and results in the same functional aberrations.[32,44,45]

Sources: 45 · 32 · 44 · 45

A relationship between epigenotype and phenotype has been shown in Beckwith-Wiedemann syndrome, with a different rate of cancer in Beckwith-Wiedemann syndrome according to the type of alteration of the 11p15 region.[46]

Sources: 46

The following four main molecular subtypes of Beckwith-Wiedemann syndrome are characterized by specific genotype-phenotype correlations:

ICR1 gain of methylation (ICR1-GoM). Five percent to 10% of cases are caused by telomeric ICR1-GoM, which causes both biallelic expression of the IGF2 gene (normally expressed by the paternal allele only) and reduced expression of the oncosuppressor H19 gene. The incidence of Wilms tumor is 22.8%.[47]

Sources: 47

ICR2 loss of methylation (ICR2-LoM). Fifty percent of cases with Beckwith-Wiedemann syndrome are caused by ICR2-LoM, resulting in reduced expression of the CDKN1C gene, normally expressed by the maternal chromosome only. Tumor incidence is very low (2.5%).[47]

Sources: 47

Uniparental disomy (UPD). Altered expression at both imprinted gene clusters is observed in mosaic UPD of chromosome 11p15.5, accounting for 20% to 25% of the cases. The incidence of Wilms tumor is 6.2%, followed by hepatoblastoma (4.7%) and adrenal carcinoma (1.5%).[47] Fewer than 1% of cases with Beckwith-Wiedemann syndrome are caused by chromosomal rearrangements involving the 11p15 region.

Sources: 47

CDKN1C variants. Maternally inheritable CDKN1C loss-of-function variants account for approximately 5% of the cases. This type is associated with a 4.3% incidence of neuroblastoma.[47]

Sources: 47

Other tumors such as neuroblastoma or hepatoblastoma were reported in patients with paternal 11p15 isodisomy.[48-50] For patients with Beckwith-Wiedemann syndrome, the relative risk of developing hepatoblastoma is 2,280 times that of the general population.[42]

Sources: 48 · 50 · 42

Loss of imprinting or gene methylation is rarely found at other loci, supporting the specificity of loss of imprinting at 11p15.5.[51] Interestingly, Wilms tumor in Japanese and East Asian children, which occurs at a lower incidence than in White children, is not associated with either nephrogenic rests or IGF2 loss of imprinting.[52]

Sources: 51 · 52

Health professional · Kidney Tumors / Wilms Tumor / Molecular Features of Wilms Tumor

Other genes and chromosomal alterations

Source: Childhood Cancer Genomics (PDQ®)–Health Professional Version, National Cancer Institute.

Source updated: April 30, 2025. Captured 2026-09-09.

Additional genes and chromosomal alterations that have been implicated in the pathogenesis and biology of Wilms tumor include the following:

1q. Gain of chromosome 1q is associated with an inferior outcome and is the single most powerful predictor of outcome.[53,54] Gain of chromosome 1q is one of the most common cytogenetic abnormalities in Wilms tumor and is observed in approximately 30% of tumors. In an analysis of FH Wilms tumor from 1,114 patients from NWTS-5 (COG-Q9401/NCT00002611), 28% of the tumors displayed 1q gain.[53] One study included a cohort of FH Wilms tumor that was enriched for patients who relapsed. The study found that the prevalence of 1q gain was higher in the relapsed Wilms tumor specimens (75%) than in the matched primary samples (47%).[55] The increased prevalence of 1q gain at relapse supports its association with poor prognosis and disease progression.

Sources: 53 · 54 · NWTS-5 (COG-Q9401/NCT00002611) · 53 · 55

The 8-year event-free survival (EFS) rate was 77% for patients with 1q gain and 90% for those lacking 1q gain (P < .001). Within each disease stage, 1q gain was associated with inferior EFS.

The 8-year overall survival (OS) rate was 88% for those with 1q gain and 96% for those lacking 1q gain (P < .001). OS was significantly inferior in cases with stage I disease (P < .0015) and stage IV disease (P = .011).

Similar results were reported in the International Society of Paediatric Oncology (SIOP) WT 2001 study of 586 children with Wilms tumor.[54]

Sources: 54

16q and 1p. Additional tumor-suppressor or tumor-progression genes may lie on chromosomes 16q and 1p, as evidenced by LOH for these regions in 17% and 11% of Wilms tumor cases, respectively.[56]These conflicting results may arise from the greater prognostic significance of 1q gain described above. LOH of 16q and 1p loses significance as independent prognostic markers in the presence of 1q gain. However, in the absence of 1q gain, LOH of 16q and 1p retains their adverse prognostic impact.[53] The LOH of 16q and 1p appears to arise from complex chromosomal events that result in 1q LOH or 1q gain. The change in 1q appears to be the critical tumorigenic genetic event.[59]

Sources: 56 · 53 · 59

In large NWTS studies, patients with tumor-specific loss of these loci had significantly worse relapse-free survival and OS rates. Combined loss of 1p and 16q are criteria used to select FH Wilms tumor patients for more aggressive therapy in the current Children's Oncology Group (COG) study. However, a U.K. study of more than 400 patients found no significant association between 1p deletion and poor prognosis, but a poor prognosis was associated with 16q LOH.[57]

Sources: 57

An Italian study of 125 patients, using treatment quite similar to that in the COG study, found significantly worse prognosis in those with 1p deletions but not 16q deletions.[58]

Sources: 58

miRNAPG. Variants in selected miRNAPG are observed in approximately 20% of Wilms tumor cases and appear to perpetuate the progenitor state.[2,5-8] The products of these genes direct the maturation of miRNAs from the initial pre-miRNA transcripts to functional cytoplasmic miRNAs (see Figure 10).[60] The most commonly altered miRNAPG is DROSHA, with a recurrent variant (E1147K) affecting a metal-binding residue of the RNase IIIb domain, representing about 80% of DROSHA-altered tumors. Other miRNAPG that are altered in Wilms tumor include DGCR8, DICER1, TARBP2, DIS3L2, and XPO5. These variants are generally mutually exclusive, and they appear to be deleterious and result in impaired expression of tumor-suppressing miRNAs. A striking sex bias was noted for patients with variants in DGCR8 (located on chromosome 22q11), with 38 of 43 cases (88%) arising in girls.[5,6]Germline pathogenic variants in miRNAPG are observed for DICER1 and DIS3L2, with variants in the former causing DICER1 syndrome and variants in the latter causing Perlman syndrome.

Sources: 2 · 5 · 8 · 60 · 5 · 6

DICER1 syndrome is typically caused by inherited truncating variants in DICER1, with tumor formation following acquisition of a missense variant in a domain of the remaining allele of DICER1 (the RNase IIIb domain) responsible for processing miRNAs derived from the 5p arms of pre-miRNAs.[61] Tumors associated with DICER1 syndrome include pleuropulmonary blastoma, cystic nephroma, ovarian sex cord–stromal tumors, multinodular goiter, and embryonal rhabdomyosarcoma.[61] Wilms tumor is an uncommon presentation of the DICER1 syndrome. In one study, three families with DICER1 syndrome included children with Wilms tumor, with two of the Wilms tumor cases showing the typical second DICER1 variant in the RNase IIIb domain.[62] Another study identified DICER1 variants in 2 of 48 familial Wilms tumor families.[63] Large sequencing studies of Wilms tumor cohorts have also observed occasional cases with DICER1 variants.[6,7]

Sources: 61 · 61 · 62 · 63 · 6 · 7

Perlman syndrome is a rare autosomal recessive overgrowth disorder caused by variants in DIS3L2, which encodes a ribonuclease that is responsible for degrading pre-let-7 miRNA.[64,65] Heterozygous germline DIS3L2 pathogenic inactivations are also associated with Wilms tumor development.[66] Patients with Perlman syndrome have a poor prognosis, with a high neonatal mortality rate. In a survey of published cases of Perlman syndrome (N = 28), in infants who survived beyond the neonatal period, approximately two-thirds developed Wilms tumor, and all patients showed developmental delay. Fetal macrosomia, ascites, and polyhydramnios are frequent manifestations.[67]

Sources: 64 · 65 · 66 · 67

SIX1 and SIX2.SIX1 and SIX2 are highly homologous transcription factors that play key roles in early renal development and are expressed in the metanephric mesenchyme, where they maintain the mesenchymal progenitor population. In patients with Wilms tumors, the frequency of SIX1 variants is 3% to 4%, and the frequency of SIX2 variants is 1% to 3%.[5,6]MLLT1. Approximately 4% of Wilms tumor cases have variants in the highly conserved YEATS domain of MLLT1 (ENL), a gene known to be involved in transcriptional elongation by RNA polymerase II during early development.[19] The altered MLLT1 protein shows altered binding to acetylated histone tails. Patients with MLLT1-altered tumors present at a younger age and have a high prevalence of precursor intralobar nephrogenic rests, supporting a model whereby activating MLLT1 variants early in renal development result in the development of Wilms tumor.

Sources: 5 · 6 · 19

Virtually all SIX1 and SIX2 variants are in exon 1 and result in a glutamine-to-arginine variant at position 177 (Q177R).

Variants in WT1, AMER1, and CTNNB1 are infrequent in cases with SIX1, SIX2, or miRNAPG variants. Conversely, SIX1 or SIX2 variants and miRNAPG variants tend to occur together.

In Wilms tumor, SIX1 and SIX2 variants are associated with the high-risk blastemal subtype and the presence of undifferentiated blastema in chemotherapy-naïve samples.

In a study of 82 cases of FH Wilms tumor, SIX1 Q177R hotspot variants were identified at a higher rate in tumor specimens at relapse (11 cases; 13.4%) than in those at diagnosis (4%). For 45 cases that had both diagnostic and relapse specimens, there were 6 cases with SIX1 Q177R at relapse, 3 of which did not have SIX1 Q177R at diagnosis. This finding suggests that this variant is not required for tumor development in some individuals with Wilms tumor.[55]

Sources: 55

TP53 (tumor suppressor gene). Most anaplastic Wilms tumor cases show variants in the TP53 tumor suppressor gene.[68-70] TP53 may be useful as an unfavorable prognostic marker.[68,69] In a study of 118 prospectively identified patients with diffuse anaplastic Wilms tumor registered on the NWTS-5 trial, 57 patients (48%) demonstrated TP53 variants, 13 patients (11%) demonstrated TP53 segmental copy number loss without variants, and 48 patients (41%) lacked both (wild-type TP53 [wtTP53]). All TP53 variants were detected by sequencing alone. Patients with stage III or stage IV disease with wtTP53 had a significantly lower relapse rate and mortality rate than did patients with TP53 abnormalities (P = .00006 and P = .00007, respectively). The TP53 status had no effect on patients with stage I or stage II tumors.[71]

Sources: 68 · 70 · 68 · 69 · 71

In-depth analysis of a subset of 39 patients with diffuse anaplastic Wilms tumor showed that 7 patients (18%) were wtTP53. These wtTP53 tumors demonstrated gene expression evidence of p53 pathway activation. Retrospective pathology review of wtTP53 tumors revealed no or very low volume of anaplasia in six of seven tumors. These data support the key role of TP53 loss in the development of anaplasia in Wilms tumor and support its significant clinical influence in patients who have residual anaplastic disease after surgery.[71]

Sources: 71

FBXW7.FBXW7, a ubiquitin ligase component, is an established tumor suppressor gene that has been identified as recurrently altered at low rates in Wilms tumor and other malignancies. Variants of this gene have been associated with epithelial-type tumor histology.[72]; [73][Level of evidence C1]

Sources: 72 · 73 · Level of evidence C1

TRIM28.TRIM28 encodes a multidomain protein involved in the regulation of many cellular processes and is an autosomal dominant Wilms tumor predisposition gene. TRIM28 accounts for about 8% of familial Wilms tumor and 2% of unselected Wilms tumor.[74-77]; [73][Level of evidence C1]

Sources: 74 · 77 · 73 · Level of evidence C1

A strong association between TRIM28 variants and epithelial Wilms tumor has been observed, and most individuals with a TRIM28 variant have a Wilms tumor of predominantly epithelial histology.[74-76]; [73][Level of evidence C1]

Sources: 74 · 76 · 73 · Level of evidence C1

In a cohort of 91 affected individuals from 49 families with Wilms tumor pedigrees, 33 individuals were identified as having constitutional cancer-predisposing variants, 21 of whom had a variant in TRIM28. There was a strong parent-of-origin effect, with all ten evaluable cases having inherited variants that were maternally transmitted.[73][Level of evidence C1]

Sources: 73 · Level of evidence C1

Most TRIM28-altered cases have either frameshift, nonsense, or splice-site variants in one allele combined with LOH in the second allele, leading to loss of TRIM28 protein expression in the tumor. Immunohistochemistry staining for loss of TRIM28 protein expression can be used to identify most patients whose tumors have TRIM28 variants.[77]

Sources: 77

9q22.3 microdeletion syndrome. Patients with 9q22.3 microdeletion syndrome have an increased risk of Wilms tumor.[78] The chromosomal region with germline pathogenic deletion includes PTCH1, the gene that is altered in Gorlin syndrome (nevoid basal cell carcinoma syndrome associated with osteosarcoma). 9q22.3 microdeletion syndrome is characterized by the clinical findings of Gorlin syndrome, as well as developmental delay and/or intellectual disability, metopic craniosynostosis, obstructive hydrocephalus, prenatal and postnatal macrosomia, and seizures. Five patients who presented with Wilms tumor in the context of a constitutional 9q22.3 microdeletion have been reported.[78-80]

Sources: 78 · 78 · 80

MYCN. Genomic alterations involving the MYCN network (e.g., MYCN, MAX, MGA, NONO) have been reported to occur in 25% to 30% of Wilms tumor cases.[55] Specific genomic alterations associated with the MYCN network include the following:

Sources: 55

MYCN copy number gain was observed in approximately 13% of Wilms tumor cases. MYCN gain was more common in anaplastic cases (7 of 23 cases, 30%) than in nonanaplastic cases (11.2%), and it was associated with poorer relapse-free survival (RFS) and overall survival, independent of histology.[81] MYCN tandem duplication was reported in 11 of 82 (13%) FH Wilms tumor specimens from relapse.[55]

Sources: 81 · 55

Germline pathogenic copy number gain at MYCN has been reported in a bilateral Wilms tumor case,[81] and germline MYCN pathogenic duplication was also reported for a child with prenatal bilateral nephroblastomatosis and a family history of nephroblastoma.[82]

Sources: 81 · 82

Variants at codon 44 (p.P44L) of MYCN are observed in approximately 3% to 4% of Wilms tumor cases at diagnosis [81,83] and in 8.5% of cases at relapse.[55] In a study of 810 Wilms tumor cases, 24 (3%) had MYCN P44L hotspot variants. RFS was significantly lower (68.6%) in patients with P44L variants than in patients with wild-type MYCN status (87.1%).[83]

Sources: 81 · 83 · 55 · 83

The MYCN interacting protein MAX was altered at codon 60 (R60Q) in 7 of 782 Wilms tumor cases (0.9%).[83] RFS was significantly lower in patients with the MAX R60Q hotspot variant than in patients with wild-type MAX status.

Sources: 83

CTR9. Inactivating CTR9 germline pathogenic variants were identified in 4 of 36 familial Wilms tumor pedigrees.[11,84] CTR9, which is located at chromosome 11p15.3, is a key component of the polymerase-associated factor 1 complex (PAF1c), which has multiple roles in RNA polymerase II regulation and is implicated in embryonic organogenesis and maintenance of embryonic stem cell pluripotency.

Sources: 11 · 84

REST. Inactivating germline pathogenic variants in REST (encoding RE1-silencing transcription factor) were identified in four familial Wilms tumor pedigrees.[10] REST is a transcriptional repressor that functions in cellular differentiation and embryonic development. Most REST variants clustered within the portion of REST encoding the DNA-binding domain, and functional analyses showed that these variants compromise REST transcriptional repression. When screened for REST variants, 9 of 519 individuals with Wilms tumor who had no history of relatives with the disease tested positive for the variant; some had parents who also tested positive.[10] These observations indicate that REST is a Wilms tumor predisposition gene associated with approximately 2% of Wilms tumor.

Sources: 10 · 10

Figure 11 summarizes the genomic landscape of a selected cohort of Wilms tumor patients selected because they experienced relapse despite showing FH.[19] The 75 FH Wilms tumor cases were clustered by unsupervised analysis of gene expression data, resulting in six clusters. Five of six MLLT1-altered tumors with available gene expression data were in cluster 3, and two were accompanied by CTNNB1 variants. This cluster also contained four tumors with a variant or small segment deletion of WT1, all of which also had either a variant of CTNNB1 or small segment deletion or variant of AMER1. It also contained a substantial number of tumors with retention of imprinting of 11p15 (including all MLLT1-altered tumors). The miRNAPG-altered cases clustered together and were mutually exclusive with both MLLT1 and with WT1-, AMER1-, or CTNNB1-altered cases.

Sources: 19

Health professional · Kidney Tumors / Wilms Tumor / Molecular Features of Wilms Tumor

Genomic alterations in Wilms tumor at relapse

Source: Childhood Cancer Genomics (PDQ®)–Health Professional Version, National Cancer Institute.

Source updated: April 30, 2025. Captured 2026-09-09.

Wilms tumor at relapse appears to maintain most of the genomic alterations present at diagnosis, although there may be changes in the prevalence of alterations in specific genes between diagnosis and relapse.[55] A study from the Children’s Oncology Group presented whole-genome sequencing (WGS) data on relapse tumor specimens from 51 patients and corresponding diagnostic specimens from 45 of these patients. For an additional 31 patients who had relapse specimens available, a targeted sequencing panel was applied. Key findings included the following:

Sources: 55

The prevalence of 1q gain in relapsed Wilms tumor specimens (75%) was higher than that observed for tumors at diagnosis (47%).[55] The increased prevalence of 1q gain at relapse is consistent with its association with poor prognosis and disease progression.

Sources: 55

SIX1 Q177R hotspot variants were identified at a higher rate in tumor specimens at relapse (11 of 82 cases; 13.4%) than in those at diagnosis (4%).[55] For 45 cases with both diagnostic and relapse specimens, there were 6 cases with SIX1 Q177R at relapse, 3 of which did not have SIX1 Q177R at diagnosis. This is consistent with SIX1 Q177R not being an early tumorigenesis event in some cases.[55]

Sources: 55 · 55

Genomic alterations in genes associated with the MYCN network were present in approximately 30% of Wilms tumor cases at relapse.[55] The most common MYCN network alterations were MYCN tandem duplication (13%) and MYCN P44L hotspot variants (11%).

Sources: 55

Recurrent and refractory Wilms tumors from 56 pediatric patients underwent tumor sequencing in the National Cancer Institute–Children's Oncology Group (NCI-COG) Pediatric MATCH trial. This process revealed genomic alterations that were considered actionable for treatment in MATCH study arms in 6 of 56 tumors (10.7%). BRCA2 variants were found in 2 of 56 tumors (3.6%).[85]

Sources: 85

Health professional · Kidney Tumors / Wilms Tumor / Molecular Features of Wilms Tumor

Genomic alterations in adults with Wilms tumor

Source: Childhood Cancer Genomics (PDQ®)–Health Professional Version, National Cancer Institute.

Source updated: April 30, 2025. Captured 2026-09-09.

Wilms tumor in patients older than 16 years is rare, with an incidence rate of less than 0.2 cases per 1 million people per year.[86] As a result, there are limited data available describing the genomic alterations that are observed in adults with Wilms tumor.

Sources: 86

A study of 14 patients with a Wilms tumor diagnosis who were older than 16 years (range, 17–46 years; median age, 31 years) evaluated exonic variants for 1,425 cancer-related genes.[87]

Sources: 87

Five patients (36%) harbored BRAF V600E variants.[87] While BRAF V600E variants are extremely uncommon in pediatric Wilms tumor, they are present in 90% of metanephric adenomas of the kidney, a typically benign condition arising almost exclusively in adults.[88]

Sources: 87 · 88

All five adult cases of Wilms tumor with BRAF V600E had better-differentiated areas identical to metanephric adenoma adjacent to areas consistent in appearance with epithelial Wilms tumor.

Two of the five cases with BRAF V600E variants had TERT promoter variants in addition to BRAF variants.

ASXL1 variants were observed in 4 of 14 cases, including 1 of 5 cases with BRAF V600E variants and 3 of 9 cases without BRAF V600E variants. ASXL1 variants are not common in pediatric Wilms tumor (approximately 2% of cases).[2]

Sources: 2

For the nine tumors that did not have BRAF variants, some had genomic alterations associated with Wilms tumor in children (e.g., 1q gain and variants in WT1 [n = 2]).

Another report described renal tumors that had histological overlap between metanephric adenoma and epithelial Wilms tumor.[89] While most epithelial Wilms tumors (five of nine) with areas resembling metanephric adenoma were negative for BRAF V600E variants, four cases were positive for the BRAF V600E variant. Two of the cases with BRAF V600E variants occurred in children (aged 3 years and 6 years), and the other two cases occurred in adults.

Sources: 89

For information about the treatment of Wilms tumor, see Wilms Tumor and Other Childhood Kidney Tumors Treatment.

Sources: Wilms Tumor and Other Childhood Kidney Tumors Treatment

Health professional · Kidney Tumors

Renal Cell Carcinoma

Source: Childhood Cancer Genomics (PDQ®)–Health Professional Version, National Cancer Institute.

Source updated: April 30, 2025. Captured 2026-09-09.

Health professional · Kidney Tumors / Renal Cell Carcinoma

Molecular features of renal cell carcinoma

Source: Childhood Cancer Genomics (PDQ®)–Health Professional Version, National Cancer Institute.

Source updated: April 30, 2025. Captured 2026-09-09.

Translocation-positive carcinomas of the kidney are recognized as a distinct form of renal cell carcinoma (RCC) and may be the most common form of RCC in children, accounting for 40% to 50% of pediatric RCC.[90]; [91][Level of evidence C1] In a Children's Oncology Group (COG) prospective clinical trial of 120 childhood and adolescent patients with RCC, nearly one-half of patients had translocation-positive RCC.[92,93] These carcinomas are characterized by translocations involving the TFE3 gene located on Xp11.2. The TFE3 gene may partner with one of the following genes:

Sources: 90 · 91 · Level of evidence C1 · 92 · 93

ASPSCR in t(X;17)(p11.2;q25).

PRCC in t(X;1)(p11.2;q21).

SFPQ in t(X;1)(p11.2;p34).

NONO in inv(X;p11.2;q12).

CLTC in t(X;17)(p11;q23).

VCP in t(x;9)(p11.23;p13.3).[94]

Sources: 94

In a single-institution investigation, molecular data from 22 patients with translocation-positive RCCs were pooled with previously published data. Investigators found that certain copy-number variations were associated with disease aggressiveness in patients with translocation-positive RCCs. Tumors bearing 9p loss, 17q gain, or a genetically high burden of copy-number variations were associated with poor survival in these patients. Three pediatric patients who had an indolent disease course were included in the study and were found to have lower copy-number burdens, which supports the less-aggressive disease course in these patients, as compared with adult patients.[95][Level of evidence C1]

Sources: 95 · Level of evidence C1

Another less-common translocation subtype, t(6;11)(p21;q12), involving a TFEB gene fusion, induces overexpression of TFEB. The translocations involving TFE3 and TFEB induce overexpression of these proteins, which can be identified by immunohistochemistry.[96]

Sources: 96

Previous exposure to chemotherapy is the only known risk factor for the development of Xp11 translocation RCCs. In one study, the postchemotherapy interval ranged from 4 to 13 years. All reported patients received either a DNA topoisomerase II inhibitor or an alkylating agent.[97,98]

Sources: 97 · 98

Controversy exists as to the biological behavior of translocation RCC in children and young adults. Whereas some series have suggested a good prognosis when translocation-positive RCC is treated with surgery alone despite presenting at a more advanced stage (III/IV), a meta-analysis reported that these patients have poorer outcomes.[99-101] The outcomes for these patients are being studied in the ongoing COG AREN03B2 (NCT00898365) biology and classification study. Vascular endothelial growth factor receptor–targeted therapies and mammalian target of rapamycin (mTOR) inhibitors seem to be active in Xp11 translocation metastatic RCC.[102] Recurrences have been reported 20 to 30 years after initial resection of the translocation-associated RCC.[103]

Sources: 99 · 101 · AREN03B2 (NCT00898365) · 102 · 103

Diagnosis of Xp11 translocation RCC needs to be confirmed by a molecular genetic approach, rather than using TFE3 immunohistochemistry alone, because reported cases have lacked the translocation.

There is a rare subset of RCC cases that is positive for TFE3 and lack a TFE3 translocation, showing an ALK translocation instead. This subset of cases represents a newly recognized subgroup within RCC that is estimated to involve 15% to 20% of unclassified pediatric RCC. In the eight reported cases in children aged 6 to 16 years, the following was observed:[104-107]

Sources: 104 · 107

ALK was fused to VCL in a t(2;10)(p23;q22) translocation (n = 3). The VCL translocation cases all occurred in children with the sickle cell trait, whereas none of the TPM3 translocation cases did.

ALK was fused to TPM3 (n = 3).

ALK was fused to HOOK1 on 1p32 (n = 1).

t(1;2) translocation fusing ALK and TPM3 (n = 1).

For information about the treatment of renal cell carcinoma, see Wilms Tumor and Other Childhood Kidney Tumors Treatment.

Sources: Wilms Tumor and Other Childhood Kidney Tumors Treatment

Health professional · Kidney Tumors

Rhabdoid Tumors of the Kidney

Source: Childhood Cancer Genomics (PDQ®)–Health Professional Version, National Cancer Institute.

Source updated: April 30, 2025. Captured 2026-09-09.

Health professional · Kidney Tumors / Rhabdoid Tumors of the Kidney

Molecular features of rhabdoid tumors of the kidney

Source: Childhood Cancer Genomics (PDQ®)–Health Professional Version, National Cancer Institute.

Source updated: April 30, 2025. Captured 2026-09-09.

Independent of their anatomical locations, rhabdoid tumors have a common genetic abnormality—loss of function of the SMARCB1 gene located at chromosome 22q11.2 (>95% of tumors).[108] The following text refers to rhabdoid tumors without regard to their primary site. SMARCB1 encodes a component of the SWItch/Sucrose Non-Fermentable (SWI/SNF) chromatin remodeling complex that has an important role in controlling gene transcription.[109,110] Loss of function occurs by deletions that lead to loss of part or all of the SMARCB1 gene and by variants that are commonly frameshift or nonsense variants that lead to premature truncation of the SMARCB1 protein.[108,110] A common pathway for achieving complete loss of SMARCB1 function is the combination of a SMARCB1 variant or partial/complete gene deletion for one SMARCB1 allele in conjunction with uniparental disomy for the chromosomal region containing SMARCB1 with loss of part or all of the parental chromosome that has a wild-type SMARCB1 allele.[111] A small percentage of rhabdoid tumors are caused by alterations in SMARCA4, which is the primary ATPase in the SWI/SNF complex.[112,113] Exome sequencing of 35 cases of rhabdoid tumor identified a very low variant rate, with no genes having recurring variants other than SMARCB1, which appeared to contribute to tumorigenesis.[114]

Sources: 108 · 109 · 110 · 108 · 110 · 111 · 112 · 113 · 114

Germline pathogenic variants of SMARCB1 have been documented in patients with one or more primary tumors of the brain and/or kidney, consistent with a genetic predisposition to the development of rhabdoid tumors.[115,116] Approximately one-third of patients with rhabdoid tumors have germline SMARCB1 pathogenic variants.[110,117] In most cases, the variants are de novo and not inherited. The median age at diagnosis of children with rhabdoid tumors and a germline pathogenic variant or deletion is younger (6 months) than that of children with apparently sporadic disease (18 months).[118] Early-onset, multifocal disease and familial cases with the presence of SMARCB1 pathogenic variants strongly support the possibility of rhabdoid tumor predisposition syndrome type 1.

Sources: 115 · 116 · 110 · 117 · 118

In a study of 100 patients with rhabdoid tumors of the brain, kidney, or soft tissues, 35 were found to have a germline SMARCB1 pathogenic variant. These variants included single nucleotide and frameshift variants, intragenic deletions and duplications, and larger deletions. Nine cases demonstrated parent-to-child transmission of an altered copy of SMARCB1. In eight of the nine cases, one or more family members were also diagnosed with rhabdoid tumor or schwannoma. Two of the eight families presented with multiple affected children, consistent with gonadal mosaicism.[110] It appears that patients with germline pathogenic variants may have the worst prognosis.[119,120]

Sources: 110 · 119 · 120

Rarely, extracranial rhabdoid tumors can harbor the alternative inactivation of SMARCA4 instead of SMARCB1.[112,113,121] In a series of 12 patients diagnosed with extracranial rhabdoid tumors with SMARCA4 inactivation, 4 cases occurred in the kidney.[122] All four cases had germline pathogenic variants of SMARCA4. The cases of SMARCA4 inactivation were comparable to the extracranial rhabdoid tumors with SMARCB1 inactivation on a clinical, pathological, and genomic level. Using DNA methylation and transcriptomics-based tumor classification, the extracranial rhabdoid tumors with SMARCA4 inactivation display molecular features intermediate between small cell carcinoma of the ovary, hypercalcemic type (driven by SMARCA4 alterations), and extracranial rhabdoid tumors with SMARCB1 inactivations. Extracranial rhabdoid tumors with SMARCA4 inactivation display concomitant lack of SMARCA4 (BRG1) and SMARCA2 (BRM) expression at the protein level, similar to what is seen in small cell carcinoma of the ovary, hypercalcemic type. These results help to expand the similarities and differences between these three tumor types within the rhabdoid tumor spectrum.[122] For more information about SMARCA4, in the context of genetic predisposition, visit Rhabdoid Tumor Predisposition Syndrome Type 2.

Sources: 112 · 113 · 121 · 122 · 122 · Rhabdoid Tumor Predisposition Syndrome Type 2

For information about the treatment of rhabdoid tumor of the kidney, see Wilms Tumor and Other Childhood Kidney Tumors Treatment.

Sources: Wilms Tumor and Other Childhood Kidney Tumors Treatment

Health professional · Kidney Tumors

Clear Cell Sarcoma of the Kidney

Source: Childhood Cancer Genomics (PDQ®)–Health Professional Version, National Cancer Institute.

Source updated: April 30, 2025. Captured 2026-09-09.

Health professional · Kidney Tumors / Clear Cell Sarcoma of the Kidney

Molecular features of clear cell sarcoma of the kidney

Source: Childhood Cancer Genomics (PDQ®)–Health Professional Version, National Cancer Institute.

Source updated: April 30, 2025. Captured 2026-09-09.

The molecular background of clear cell sarcoma of the kidney is poorly understood because of its rarity and lack of experimental models. However, several molecular features of clear cell sarcoma of the kidney have been described, including the following:

Internal tandem duplications in exon 15 of the BCOR gene (BCL6 corepressor) have been reported in 90% of cases of clear cell sarcoma of the kidney, with a smaller subset harboring YWHAE::NUTM2B, YWHAE::NUTM2E, or BCOR::CCNB3 gene fusions.[123-128] All of these genetic abnormalities result in a transcriptional signature characterized by high BCOR mRNA expression.[129]

Sources: 123 · 128 · 129

Diffuse strong immunoreactivity for BCOR is highly sensitive and specific for the diagnosis of clear cell sarcoma of the kidney. One series evaluated 79 neoplasms, including Wilms tumors, congenital mesoblastic nephromas, clear cell sarcoma of the kidney, metanephric stromal tumors, rhabdoid tumors of the kidney, renal primitive neuroectodermal tumor (PNET), and sclerosing epithelioid fibrosarcomas. All of the clear cell sarcoma of the kidney samples that were tested demonstrated diffuse, strong nuclear labeling for BCOR. Most of the other pediatric renal neoplasms were completely negative for BCOR.[130]

Sources: 130

For information about the treatment of clear cell tumor of the kidney, see Wilms Tumor and Other Childhood Kidney Tumors Treatment.

Sources: Wilms Tumor and Other Childhood Kidney Tumors Treatment

Health professional

Melanoma

Source: Childhood Cancer Genomics (PDQ®)–Health Professional Version, National Cancer Institute.

Source updated: April 30, 2025. Captured 2026-09-09.

For information about the genomics of childhood melanoma, see the Molecular Features section in Childhood Melanoma Treatment.

Sources: Molecular Features

For information about the treatment of childhood melanoma, see Childhood Melanoma Treatment.

Sources: Childhood Melanoma Treatment

Health professional

Thyroid Cancer

Source: Childhood Cancer Genomics (PDQ®)–Health Professional Version, National Cancer Institute.

Source updated: April 30, 2025. Captured 2026-09-09.

For information about the genomics of childhood thyroid cancer, see the sections on Histology and Molecular Features of Differentiated Thyroid Cancer and Histology and Molecular Features of Medullary Thyroid Cancer in Childhood Thyroid Cancer Treatment.

Sources: Histology and Molecular Features of Differentiated Thyroid Cancer · Histology and Molecular Features of Medullary Thyroid Cancer

For information about the treatment of childhood thyroid cancer, see Childhood Thyroid Cancer Treatment.

Sources: Childhood Thyroid Cancer Treatment

Health professional

Multiple Endocrine Neoplasia Syndromes

Source: Childhood Cancer Genomics (PDQ®)–Health Professional Version, National Cancer Institute.

Source updated: April 30, 2025. Captured 2026-09-09.

For information about the genomics of childhood multiple endocrine neoplasia (MEN) syndromes, see the Clinical Presentation, Molecular Features, and Diagnostic Evaluation section in Childhood Multiple Endocrine Neoplasia (MEN) Syndromes Treatment.

Sources: Clinical Presentation, Molecular Features, and Diagnostic Evaluation

For information about the treatment of childhood MEN syndromes, see Childhood Multiple Endocrine Neoplasia (MEN) Syndromes Treatment.

Sources: Childhood Multiple Endocrine Neoplasia (MEN) Syndromes Treatment

Studies

Medical Research Council (MRC) Working Party on Leukaemia in Children UK National Acute Lymphoblastic Leukaemia (ALL) Trial: UKALL 2003

NCT00222612 · UNKNOWN · phase4

Acute Lymphoblastic Leukemia

ClinicalTrials.gov record

Biomarkers in Tumor Tissue Samples From Patients With Newly Diagnosed Neuroblastoma or Ganglioneuroblastoma

NCT00904241 · COMPLETED · Phase not reported

Ganglioneuroblastoma, Localized Resectable Neuroblastoma, Localized Unresectable Neuroblastoma, Regional Neuroblastoma, Stage 4 Neuroblastoma, Stage 4S Neuroblastoma

ClinicalTrials.gov record

Hyperfractionated Versus Conventionally Fractionated Radiotherapy in Standard Risk Medulloblastoma (PNET4)

NCT01351870 · COMPLETED · phase3

Medulloblastoma

ClinicalTrials.gov record

NANT 2015-02: A Phase 1 Study of Lorlatinib (PF-06463922)

NCT03107988 · COMPLETED · phase1

Neuroblastoma

ClinicalTrials.gov record

Testing the Addition of 131I-MIBG or Lorlatinib to Intensive Therapy in People With High-Risk Neuroblastoma (NBL)

NCT03126916 · RECRUITING · phase3

Ganglioneuroblastoma, Ganglioneuroblastoma, Nodular, Neuroblastoma

ClinicalTrials.gov record

A Study to Compare Standard Chemotherapy to Therapy With CPX-351 and/or Gilteritinib for Patients With Newly Diagnosed AML With or Without FLT3 Mutations

NCT04293562 · RECRUITING · phase3

Acute Myeloid Leukemia

ClinicalTrials.gov record

Study of Adults With Low Growth Hormone Who Survived Childhood Cancer Where Treatment Caused Low Bone Density

NCT00145704 · TERMINATED · na

Osteopenia

ClinicalTrials.gov record

Peer i-Coaching for Activated Self-Management Optimization in Adolescents and Young Adults With Chronic Conditions

NCT03938324 · COMPLETED · na

Sickle Cell Disease, Chronic Kidney Diseases, Systemic Lupus Erythematosus, Childhood Cancer, Inflammatory Bowel Diseases, Stem Cell Transplant, Organ Transplant, Diabetes...

ClinicalTrials.gov record