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Cancer Cell. 2010 Nov 16;18(5):499-509. doi: 10.1016/j.ccr.2010.10.015. Epub 2010 Nov 4.

Germline Brca2 heterozygosity promotes Kras(G12D) -driven carcinogenesis in a murine model of familial pancreatic cancer.

Author information

1
Department of Oncology and the Medical Research Council Cancer Cell Unit, University of Cambridge, Hills Road, Cambridge CB2 0XZ, UK.

Abstract

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 Kras(G12D), irrespective of Trp53 status. Unexpectedly, tumor cells retain a functional Brca2 allele. Correspondingly, three out of four PDACs from patients inheriting BRCA2(999del5) 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.

PMID:
21056012
DOI:
10.1016/j.ccr.2010.10.015
[Indexed for MEDLINE]
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