Constitutional mutations of the hSNF5/INI1 gene predispose to a variety ofcancers

Biallelic, truncating mutations of the hSNF5/INI1 gene have recently been d ocumented in malignant rhabdoid tumor (MRT), one of the most aggressive hum an cancers. This finding suggests that hSNF5/INI1 is a new tumor-suppressor gene for which germline mutations might predispose to cancer. We now repor t the presence of loss-of-function mutations of this gene in the constituti onal DNA from affected members but not from healthy relatives in cancer-pro ne families. Furthermore, a constitutional mutation is documented in a pati ent with two successive primary cancers. In agreement with the two-hit mode l, the wild-type hSNF5/INI1 allele is deleted in the tumor DNA from mutatio n carriers. In all tested cases, DNA from parents demonstrated normal hSNF5 /INI1 sequences, therefore indicating the de novo occurrence of the mutatio n, which was shown to involve the maternal allele in one case and the pater nal allele in two other cases. These data indicate that constitutional muta tion of the hSNF5/INI1 gene defines a new hereditary syndrome predisposing to renal or extrarenal MRT and to a variety of tumors of the CNS, including choroid plexus carcinoma, medulloblastoma, and central primitive neuroecto dermal tumor. This condition, which we propose to term "rhabdoid predisposi tion syndrome," may account for previous observations of familial and multi focal cases of the aforementioned tumor types. It could also provide the mo lecular basis for cases of Li-Fraumeni syndrome without p53 germline mutati ons.