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

Cancer Cell 2010 Nov 4;18(5):499-509. Epub 2010 Nov 4.

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

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.

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ccr.2010.10.015DOI Listing
November 2010
13 Reads
23.523 Impact Factor

Publication Analysis

Top Keywords

familial pancreatic
8
pancreatic cancer
8
model familial
8
murine model
8
brca2
6
allele correspondingly
4
brca2 allele
4
brca2 truncation
4
truncation suffices
4
functional brca2
4
correspondingly three
4
three pdacs
4
brca2999del5 exhibit
4
inheriting brca2999del5
4
patients inheriting
4
pdacs patients
4
retain functional
4
suffices promote
4
pdacs driven
4
krasg12d irrespective
4

Similar Publications