Rhabdoid Tumor Predisposition Syndrome 2

A number sign (#) is used with this entry because rhabdoid tumor predisposition syndrome-2 (RTPS2) is caused by heterozygous germline mutation in the SMARCA4 gene (603254) on chromosome 19p13.

Rhabdoid tumor predisposition syndrome-2 is an autosomal dominant cancer predisposition syndrome characterized by the onset in infancy, childhood, or young adulthood of various poorly differentiated tumors. Classically, tumors that arise in the central nervous system are referred to as atypical teratoid/rhabdoid tumors, whereas those arising in the kidney or other extracranial sites are referred to as malignant rhabdoid tumors. Tumors may also present as small cell carcinoma of the ovary, hypercalcemic type (SCCOHT), also known as malignant rhabdoid tumor of the ovary (MRTO). All of these tumors are highly aggressive and often fatal (summary by Foulkes et al., 2014).

See also RTPS1 (609322), which is caused by mutation in the SMARCB1 gene (601607) on chromosome 22q11.

Poremba et al. (1993) reported a 27-year-old pregnant woman who was found to have an ovarian mass diagnosed as an immature teratoma. The female fetus showed hydrocephalus due to an intracranial tumor also diagnosed as an immature teratoma, with histologic features similar to the mother's tumor. The infant died at age 9 weeks. Analysis of polymorphic markers indicated that the 2 tumors arose independently in the mother and fetus, suggesting a genetic basis for cancer predisposition in this family. By genetic reanalysis of the mother and daughter reported by Poremba et al. (1993), Witkowski et al. (2013) determined that the tumor in both patients was a malignant rhabdoid tumor, consistent with a diagnosis of RTPS2 (see MOLECULAR GENETICS).

Longy et al. (1996) reported a family in which 3 sisters developed SCCOHT between ages 14 and 28 years. Despite treatment, each had an aggressive tumor with recurrence that resulted in death within several months. Longy et al. (1996) suggested that this represented a distinct category of familial ovarian cancer that is distinguished from ovarian epithelial tumors.

Martinez-Borges et al. (2009) reported an 11-year-old Caucasian girl who presented with SCCOHT. The family history was significant for fatal SCCOHT in the mother at age 24 years and in the mother's monozygotic twin sister at age 26 years.

Schneppenheim et al. (2010) reported 2 German sisters with highly aggressive malignant embryonal tumors of the brain. At age 8 months, the first girl was found to have a mass originating from the right cerebellopontine angle involving the brainstem. She died a few weeks later. Her sister presented at 7 months of age with increased abdominal circumference and pain. Although imaging studies suggested a stage IV Wilms tumor (194070) with metastases to the lungs and mediastinum, neuropathologic analysis showed a rhabdoid tumor. She died at 18 months of distant and local disease. Neuropathology of both tumors showed a SMARCB1-expressive atypical teratoid/rhabdoid tumor.

By candidate gene sequencing in 2 German sisters with early-onset fatal rhabdoid tumors, Schneppenheim et al. (2010) identified a heterozygous germline truncating mutation in the SMARCA4 gene (R1189X; 603254.0001). The girls' unaffected father was heterozygous for the germline R1189X mutation, indicating reduced penetrance. Analysis of tumor tissue showed complete loss of SMARCA4 expression and loss of heterozygosity at the SMARCA4 locus. SNP array analysis indicated that partial uniparental disomy of the paternal allele was the cause of LOH in the tumors. Schneppenheim et al. (2010) noted both SMARCA4 and the tumor suppressor SMARCB1 are members of the ATP-dependent SWI/SNF chromatin-remodeling complex.

Kupryjanczyk et al. (2013) identified 2 somatic truncating mutations in the SMARCA4 gene in 2 small cell ovarian carcinoma hypercalcemic type tumors (SCCOHT) from 2 unrelated individuals. The SMARCA4 gene was chosen for study after histologic analysis showed a resemblance to atypical teratoid/rhabdoid tumors. Some elements of germ cell tumors, such as immature teratoma and yolk sac tumor, were observed in both tumors. Immunohistochemical staining was positive for SMARCA1, but negative for SMARCA4. Kupryjanczyk et al. (2013) concluded that SCCOHT is related to malignant rhabdoid tumor.

In a mother and daughter with RTPS2, Witkowski et al. (2013) identified a germline heterozygous truncating mutation in the SMARCA4 gene (W1178X; 603254.0008). The patients were originally reported by Poremba et al. (1993) as having immature teratomas. Witkowski et al. (2013) used whole-exome sequencing and Sanger sequencing to identify the mutation, which arose de novo in the mother. Tumor tissue from both patients also carried a somatic truncating mutation in the SMARCA4 gene, consistent with the '2-hit' hypothesis of tumorigenesis.

In affected members of 4 unrelated families with RTPS2 presenting as SCCOHT, Witkowski et al. (2014) identified 4 different germline heterozygous mutations in the SMARCA4 gene (603254.0009-603254.0012). The mutations in the first 3 families were found by whole-exome sequencing and resulted in complete loss of the SMARCA4 protein. Tumor tissue, when available, showed either a somatic inactivating SMARCA4 mutation or loss of heterozygosity at the SMARCA4 locus. Whole-exome or Sanger sequencing identified at least 1 germline or somatic SMARCA4 mutation in 24 of 26 additional cases of SCCOHT as well as in the BIN-67 cell line. Six of 12 apparently nonfamilial cases for which nontumor tissue was available carried a deleterious germline SMARCA4 mutation, indicating that hereditary cases are more common than previously thought. Immunohistochemical studies showed loss of SMARCA4 expression in 38 of 43 SCCOHT tumors; 3 of those that retained SMARCA4 expression were later recategorized as non-SCCOHT. Witkowski et al. (2014) concluded that SCCOHT falls within the category of extracranial rhabdoid tumors, to which it is more similar than to other types of ovarian carcinoma.

Jelinic et al. (2014) identified biallelic inactivating somatic mutations in the SMARCA4 gene in 100% of 12 SCCOHT samples. The mutations were found by exome sequencing of 279 cancer-related genes in these tumors and were confirmed by Sanger sequencing. The findings were consistent with SMARCA4 being a tumor suppressor gene.

Using whole-exome or whole-genome sequencing, Ramos et al. (2014) identified somatic inactivating mutations in the SMARCA4 gene in 6 of 9 SCCOHT tumors and in the SCCOHT cell line BIN-67. Two tumors carried 2 mutations each, indicating biallelic inactivation. Immunohistochemical studies showed that all tumor samples with a SMARCA4 mutation lacked SMARCA4 protein expression. Loss of SMARCA4 was highly specific to SCCOHT; SMARCA4 protein loss was found in only 0.4% (2 of 485) of primary ovarian epithelial, sex cord stromal, and germ cell tumors. The findings indicated that loss of normal SWI/SNF complex function may represent a key tumorigenic step in SCCOHT formation.