Germline Nonsense Mutation and Somatic Inactivation of SMARCA4/BRG1 in a Family with Rhabdoid Tumor Predisposition Syndrome

Abstract

Rhabdoid tumors of early infancy are highly aggressive with consequent poor prognosis. Most cases show inactivation of the SMARCB1 (also known as INI1 and hSNF5) tumor suppressor, a core member of the ATP-dependent SWI/SNF chromatin-remodeling complex. Familial cases, described as rhabdoid tumor predisposition syndrome (RTPS), have been linked to heterozygous SMARCB1 germline mutations. We identified inactivation of another member of the SWI/SNF chromatin-remodeling complex, its ATPase subunit SMARCA4 (also known as BRG1), due to a SMARCA4/BRG1 germline mutation and loss of heterozygosity by uniparental disomy in the tumor cells of two sisters with rhabdoid tumors lacking SMARCB1 mutations. SMARCA4 is thus a second member of the SWI/SNF complex involved in cancer predisposition. Its general involvement in other tumor entities remains to be established.

Cancer Surveillance in Gorlin Syndrome and Rhabdoid Tumor Predisposition Syndrome

“…RTs are frequently fatal, but in rare cases, RTs can present in families, and relatives of patients may develop RTs or other tumors (32)(33)(34). Indeed, SMARCB1 mutation carriers may be at risk for developing other tumors, including schwannomas, malignant peripheral nerve sheath tumors, cribriform neuroepithelial tumors, meningiomas, and other rare tumors (Table 2; refs.…”

Germline nonsense-mutations of the SMARCB1 gene in Russian patients with rhabdoid renal tumors

“…Опухоли могут развиваться как спорадические вслед-ствие соматических мутаций, а могут быть проявлени-ем синдрома предрасположенности к развитию рабдо-идных опухолей (rhabdoid tumor predisposition syndrome, RTPS). В настоящее время выделяют 2 типа синдрома: 1-й тип (RTPS1, OMIM: 609322) обусловлен наличием герминальных мутаций в гене SMARCB1; 2-й тип, зна-чительно более редкий (RTPS2, OMIM: 613325), харак-теризуется мутациями в гене SMARCA4 [5,6]. Доля RTPS1 среди ЗРО всех локализаций составляет 30 % [7,8].…”

Aberrant chromatin remodeling in gynecological cancer (Review)

“…In SCCOHT, germline mutations have been revealed in one allele of SMARCA4, and expression is deleted due to an inactivating germline mutation and frameshift and nonsense mutations in the other allele (26,(45)(46)(47). Rhabdoid tumors that develop in organs other than the ovary, including the kidney and brain, have germline and somatic expression of SMARCA4 (48). Immunostaining for the expression of SMARCA4 in tumor tissues of patients with lung cancer revealed downregulation of SMARCA4 in no patients with squamous cell carcinoma, in 10% with adenocarcinoma, in 31.3% with large cell carcinoma and in 36.4% with pleomorphic carcinoma (49), and somatic mutation and deletion of SMARCA4 are present in these types of cancer (26).…”