Molecular features of myelodysplastic neoplasms (MDS)

Compared with MDS in adults, pediatric MDS is associated with a distinctive constellation of genetic alterations. In adults, MDS often evolves from clonal hematopoiesis and is characterized by variants in TET2, DNMT3A, DDX41 and TP53. In contrast, variants in these genes are rare in pediatric MDS, while variants in GATA2, SAMD9, SAMD9L, ETV6, SETBP1, ASXL1, and RAS/MAPK pathway genes are observed in subsets of children with MDS.[412,413]

A report of the genomic landscape of pediatric MDS described the results of whole-exome sequencing for 32 pediatric patients with primary MDS and targeted sequencing for another 14 cases.[412] These 46 cases were equally divided between childhood MDS with low blasts (cMDS-LB) (previously called refractory cytopenia of childhood) and childhood MDS with increased blasts (cMDS-IB) (previously called MDS with excess blasts [MDS-EB)]). The results from the report include the following:

A second report described the application of a targeted sequencing panel of 105 genes to 50 pediatric patients with MDS (cMDS-LB = 31 and cMDS-IB = 19) and was enriched for cases with monosomy 7 (48%).[412,413] SAMD9 and SAMD9L were not included in the gene panel. The second report described the following results:

Patients with germline GATA2 pathogenic variants, in addition to MDS, show a wide range of hematopoietic and immune defects as well as nonhematopoietic manifestations.[414] The former defects include monocytopenia with susceptibility to atypical mycobacterial infection and DCML deficiency (loss of dendritic cells, monocytes, and B and natural killer lymphoid cells). The resulting immunodeficiency leads to increased susceptibility to warts, severe viral infections, mycobacterial infections, fungal infections, and human papillomavirus–related cancers. The nonhematopoietic manifestations include deafness and lymphedema.

Germline GATA2 pathogenic variants were studied in 426 pediatric patients with primary MDS and 82 cases with secondary MDS who were enrolled in consecutive studies of the European Working Group of MDS in Childhood (EWOG-MDS).[415] The study had the following results:

SAMD9 and SAMD9L germline pathogenic variants are both associated with pediatric MDS cases in which there is an additional loss of all or part of chromosome 7.[417,418]

In 2016, SAMD9 was identified as the cause of the MIRAGE syndrome (myelodysplasia, infection, restriction of growth, adrenal hypoplasia, genital phenotypes, and enteropathy), which is associated with early-onset MDS with monosomy 7.[419] Subsequently, variants in SAMD9L were identified in patients with ataxia pancytopenia syndrome (ATXPC; OMIM 159550). SAMD9 and SAMD9L variants were also identified as the cause of the myelodysplasia and leukemia syndrome with monosomy 7 (MLSM7; OMIM 252270),[420] a syndrome first identified in phenotypically normal siblings who developed MDS or AML associated with monosomy 7 during childhood.[421]

The presence of an isolated monosomy 7 is the most common cytogenetic abnormality, although it does not appear to portend a poor prognosis, compared with its presence in overt AML. However, the presence of monosomy 7 in combination with other cytogenetic abnormalities is associated with a poor prognosis.[422,423] The relatively common abnormalities of -Y, 20q-, and 5q- in adults with MDS are rare in childhood MDS. The presence of cytogenetic abnormalities that are found in AML (t(8;21)(q22;q22.1), inv(16)(p13.1;q22) or t(16;16)(p13.1;q22), and APL with PML::RARA gene fusions) defines disease that should be treated as AML and not MDS, regardless of blast percentage. The World Health Organization (WHO) notes that whether this should also apply to other recurring genetic abnormalities remains controversial.[424]

For information about the treatment of childhood MDS, see Childhood Myelodysplastic Neoplasms Treatment.