期刊
CANCER CELL
卷 18, 期 5, 页码 499-509出版社
CELL PRESS
DOI: 10.1016/j.ccr.2010.10.015
关键词
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资金
- Medical Research Council (MRC)
- Onassis Foundation
- Cancer Research UK
- MRC [G0700651, G0600332, MC_U105359877, G9900064] Funding Source: UKRI
- Medical Research Council [G9900064, G0600332, MC_U105359877, G0700651] Funding Source: researchfish
- National Institute for Health Research [CL-2008-14-003] Funding Source: researchfish
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.
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