Molecular features of rhabdoid tumors of the kidney

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]

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.

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]

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.

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