Haploinsufficiency of Snf5 (integrase interactor 1) predisposes to malignant rhabdoid tumors in mice

Malignant rhabdoid tumor (MRT) is an aggressive, highly lethal cancer of yo ung children. Tumors occur in various locations, including kidney, brain, a nd soft tissues. Despite intensive therapy, 80% of affected children die, o ften within 1 year of diagnosis. The majority of MRT samples and cell lines have sustained biallelic inactivating mutations of the hSNF5 (integrase in teractor 1) gene, suggesting that hSNF5 may act as a tumor suppressor. We s ought to examine the role of Snf5 in development and cancer in a murine mod el. Here we report that Snf5 is widely expressed during embryogenesis with focal areas of high-level expression in the mandibular portion of the first branchial arch and central nervous system. Homozygous knockout of Snf5 res ults in embryonic lethality by embryonic day 7, whereas heterozygous mice a re born at the expected frequency and appear normal. However, beginning as early as 5 weeks of age, heterozygous mice develop tumors consistent with M RT, The majority of tumors arise in soft tissues derived from the first bra nchial arch. Our findings constitute persuasive genetic evidence that Snf5, a core member of the Swi/Snf chromatin-remodeling complex, functions as a tumor suppressor gene, and, moreover, Snf5 heterozygotes provide a murine m odel of this lethal pediatric cancer.