Author/Authors :
Skoulidis، نويسنده , , Ferdinandos and Cassidy، نويسنده , , Liam D. and Pisupati، نويسنده , , Venkat and Jonasson، نويسنده , , Jon G. and Bjarnason، نويسنده , , Hordur and Eyfjord، نويسنده , , Jorunn E. and Karreth، نويسنده , , Florian A. and Lim، نويسنده , , Michael and Barber، نويسنده , , Lorraine M. and Clatworthy، نويسنده , , Susan A. and Davies، نويسنده , , Susan E. and Olive، نويسنده , , Kenneth P. and Tuveson، نويسنده , , David A. and Venkitaraman، نويسنده , , Ashok R.، نويسنده ,
Abstract :
Summary
ted 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.
