Germline Brca2 heterozygosity promotes Kras(G12D) -driven carcinogenesis in a murine model of familial pancreatic cancer.
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.
Department of Oncology and the Medical Research Council Cancer Cell Unit, University of Cambridge, Hills Road, Cambridge CB2 0XZ, UK.
Ferdinandos
F
Skoulidis
Liam D
LD
Cassidy
Venkat
V
Pisupati
Jon G
JG
Jonasson
Hordur
H
Bjarnason
Jorunn E
JE
Eyfjord
Florian A
FA
Karreth
Michael
M
Lim
Lorraine M
LM
Barber
Susan A
SA
Clatworthy
Susan E
SE
Davies
Kenneth P
KP
Olive
David A
DA
Tuveson
Ashok R
AR
Venkitaraman
D000483:Alleles; D000818:Animals; D024682:BRCA2 Protein / Q000235:genetics*; D021441:Carcinoma, Pancreatic Ductal / Q000235:genetics* / Q000473:pathology; D045744:Cell Line, Tumor; D018389:Codon, Nonsense; D004195:Disease Models, Animal; D020868:Gene Silencing; D024522:Genes, BRCA2; D018095:Germ-Line Mutation; D006579:Heterozygote; D019656:Loss of Heterozygosity; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D010190:Pancreatic Neoplasms / Q000235:genetics* / Q000473:pathology; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics* / Q000502:physiology; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism
D024682:BRCA2 Protein; D018389:Codon, Nonsense; D016159:Tumor Suppressor Protein p53; C495971:Hras protein, mouse; D016283:Proto-Oncogene Proteins p21(ras)