Rhabdoid Tumor Predisposition Syndrome via the SMARCB1 Gene

Rhabdoid tumors are rare aggressive tumors found in children. These tumors are histologically confirmed by having large cells with eccentrically located nuclei and abundant, eosinophilic cytoplasm (Beckwith et al. Cancer 41:1937–48, 1978); however the histology is heterogeneous and misclassification can occur . Originally rhabdoid tumors were found in the kidney and thought to be a variant of Wilms tumor (rhabdoid tumors of the kidney -RTK). It is now known to be more aggressive kidney cancer. Whereas the overall survival rate for Wilms tumors exceeds 85%, the survival rate for renal malignant rhabdoid tumors is only 20-25%. Moreover, rhabdoid tumors have since been found in the liver, soft tissue, lung, skin, heart and the central nervous system (CNS). Approximately,10-15% of patients with malignant rhabdoid tumors have synchronous or metachronous brain tumors. In the CNS, where rhabdoid tumors are termed AT/RT (atypical teratoid, rhabdoid tumor), the most affected area is in the cerebellum. Germline mutations in the SMARCB1 gene (also known as INI1 and hSNF5) are causative for Rhabdoid Tumor Predisposition Syndrome. Patients with germline SMARCB1 mutations have earlier-onset presentation versus sporadic rhabdoid tumors (6 months vs. 18 months) (Bourdeaut et al. Clin Cancer Res 17:31-38, 2011). SMARCB1 mutations may also predispose an individual for late-onset indolent schwannomas, a condition presenting with two or more benign tumors of the nerve sheath (Teplick et al. Eur J Pediatr 170:285–294, 2011).

Rhabdoid Tumor Predisposition Syndrome is an autosomal dominant disorder with incomplete penetrance caused by mutations in the SMARCB1 gene (Schneppenheim et al. Am J Hum Genet 86, 279–284, 2010) . Most mutations appear to be de novo, and gonadal mosaicism has been reported (Bourdeaut et al. Clin Cancer Res 17:31-38, 2011). SMARCB1 is a tumor suppressor that functions as a member of the human ATP-dependent SWI/SNF complex, which has a role in epigenetic modification by regulating gene transcription and DNA repair (Reisman et al. Oncogene 28:1653–1668, 2009). Germline SMARCB1 mutations include missense, nonsense, splicing, regulatory, small and large deletions and duplications (Human Gene Mutation Database). Strong genotype-phenotypes do not exist, but splicing mutations and missense mutations have been found more predominantly in familial schwannomatosis, whereas truncating mutations are more frequently observed in individuals with rhabdoids (Bourdeaut et al. Clin Cancer Res 17:31-38, 2011).

Germline mutations in the SMARCB1 gene have been found in 23-60% of individuals with rhabdoid tumors, with increased rates observed at an earlier ages of diagnosis (i.e. <6 months) (Bourdeaut et al. Clin Cancer Res 17:31-38, 2011).

Clinical sensitivity for germline deletions and duplications of the SMARCB1 gene for familial and sporadic rhabdoid tumors is approximately 30% (11/35), with the majority of these being deletions (Eaton et al. Pediatr Blood Cancer 56(1): 7-15, 2011).

This test provides full coverage of all coding exons of the SMARCB1 gene, plus ~10 bases of flanking noncoding DNA. We define full coverage as >20X NGS reads or Sanger sequencing.