Inherited heterozygous BRCA2 mutations predispose carriers to tissue-specific cancers, but somatic deletion of the wild-type allele is considered essential for carcinogenesis. We find in a murine model of familial pancreatic cancer that germline heterozygosity for a pathogenic Brca2 truncation suffices to promote pancreatic ductal adenocarcinomas (PDACs) driven by KrasG12D, irrespective of Trp53 status. Unexpectedly, tumor cells retain a functional Brca2 allele. Correspondingly, three out of four PDACs from patients inheriting BRCA2999del5 did not exhibit loss-of-heterozygosity (LOH). Three tumors from these patients displaying LOH were acinar carcinomas, which also developed only in mice with biallelic Brca2 inactivation. We suggest a revised model for tumor suppression by BRCA2 with implications for the therapeutic strategy targeting BRCA2 mutant cancer cells. © 2010 Elsevier Inc.
CITATION STYLE
Skoulidis, F., Cassidy, L. D., Pisupati, V., Jonasson, J. G., Bjarnason, H., Eyfjord, J. E., … Venkitaraman, A. R. (2010). Germline Brca2 Heterozygosity Promotes KrasG12D -Driven carcinogenesis in a murine model of familial pancreatic cancer. Cancer Cell, 18(5), 499–509. https://doi.org/10.1016/j.ccr.2010.10.015
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