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Tumor-Specific Cooperation of Retinoblastoma Protein Family and Snf5 Inactivation

Departments of ¹ Pathology and Laboratory Medicine, ² Genetics, and ³ Pediatrics and ⁴ UNC Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina; ⁵ Department of Pathology, Brigham and Women's Hospital; ⁶ Department of Pediatric Oncology, Dana-Farber Cancer Institute, Children's Hospital Boston and Harvard University, Boston, Massachusetts

Requests for reprints: Bernard E. Weissman, UNC Lineberger Comprehensive Cancer Center, University of North Carolina, CB#7259, Room 32-048, Chapel Hill, NC 27514. Phone: 919-966-7533; Fax: 919-966-9673; E-mail: weissman{at}med.unc.edu.

Malignant rhabdoid tumors (MRT) are rare aggressive cancers that occur in young children. Seventy-five percent of sporadic MRTs harbor inactivating SNF5 mutations, and mice heterozygous for an Snf5-null allele develop MRTs with partial penetrance. The diagnosis of choroid plexus carcinomas (CPC) in addition to MRTs in families with a single mutant SNF5 allele prompted us to assess the role of SNF5 loss in CPC in genetically engineered mice. With high frequency, TgT₁₂₁ mice develop CPCs that are initiated by inactivation of retinoblastoma protein (pRb) and related proteins p107 and p130. However, CPC penetrance and latency were not significantly affected by Snf5 heterozygosity, consistent with recent evidence that CPCs in SNF5 families were, in many cases, misdiagnosed MRTs. Surprisingly, although the CPC phenotype was unaffected, TgT₁₂₁;Snf5^+/– mice developed MRTs with increased penetrance and decreased latency compared with TgT₁₂₁;Snf5^+/+ littermates. MRTs expressed the T₁₂₁ protein with a concomitant increase in mitotic activity. The predominant appearance of TgT₁₂₁;Snf5^+/– MRTs in the spinal cord led to the discovery that these tumors likely arose from a subset of spinal cord neural progenitor cells expressing T₁₂₁ rather than from transdifferentiation of CPC. Significantly, the target cell type(s) for MRT is unknown. Hence, this study not only shows that pRb_f and SNF5 inactivation cooperate to induce MRTs but also provides new insight into the MRT target population. [Cancer Res 2007;67(7):3002–9]