Germline Brca2 Heterozygosity Promotes KrasG12D -Driven carcinogenesis in a murine model of familial pancreatic cancer

Ferdinandos Skoulidis; Liam D. Cassidy; Venkat Pisupati; Jon G. Jonasson; Hordur Bjarnason; Jorunn E. Eyfjord; Florian A. Karreth; Michael Lim; Lorraine M. Barber; Susan A. Clatworthy; Susan E. Davies; Kenneth P. Olive; David A. Tuveson; Ashok R. Venkitaraman

doi:10.1016/j.ccr.2010.10.015

Germline Brca2 Heterozygosity Promotes Kras^G12D -Driven carcinogenesis in a murine model of familial pancreatic cancer

Ferdinandos Skoulidis, Liam D. Cassidy, Venkat Pisupati, Jon G. Jonasson, Hordur Bjarnason, Jorunn E. Eyfjord, Florian A. Karreth, Michael Lim, Lorraine M. Barber, Susan A. Clatworthy, Susan E. Davies, Kenneth P. Olive, David A. Tuveson, Ashok R. Venkitaraman

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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.

Original language	English (US)
Pages (from-to)	499-509
Number of pages	11
Journal	Cancer cell
Volume	18
Issue number	5
DOIs	https://doi.org/10.1016/j.ccr.2010.10.015
State	Published - Nov 16 2010
Externally published	Yes

ASJC Scopus subject areas

Oncology
Cell Biology
Cancer Research

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Skoulidis, F., Cassidy, L. D., Pisupati, V., Jonasson, J. G., Bjarnason, H., Eyfjord, J. E., Karreth, F. A., Lim, M., Barber, L. M., Clatworthy, S. A., Davies, S. E., Olive, K. P., Tuveson, D. A., & Venkitaraman, A. R. (2010). Germline Brca2 Heterozygosity Promotes Kras^G12D -Driven carcinogenesis in a murine model of familial pancreatic cancer. Cancer cell, 18(5), 499-509. https://doi.org/10.1016/j.ccr.2010.10.015

Skoulidis, F, Cassidy, LD, Pisupati, V, Jonasson, JG, Bjarnason, H, Eyfjord, JE, Karreth, FA, Lim, M, Barber, LM, Clatworthy, SA, Davies, SE, Olive, KP, Tuveson, DA & Venkitaraman, AR 2010, 'Germline Brca2 Heterozygosity Promotes Kras^G12D -Driven carcinogenesis in a murine model of familial pancreatic cancer', Cancer cell, vol. 18, no. 5, pp. 499-509. https://doi.org/10.1016/j.ccr.2010.10.015

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title = "Germline Brca2 Heterozygosity Promotes KrasG12D -Driven carcinogenesis in a murine model of familial pancreatic cancer",

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 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.",

author = "Ferdinandos Skoulidis and Cassidy, {Liam D.} and Venkat Pisupati and Jonasson, {Jon G.} and Hordur Bjarnason and Eyfjord, {Jorunn E.} and Karreth, {Florian A.} and Michael Lim and Barber, {Lorraine M.} and Clatworthy, {Susan A.} and Davies, {Susan E.} and Olive, {Kenneth P.} and Tuveson, {David A.} and Venkitaraman, {Ashok R.}",

note = "Funding Information: We thank the past and present members of the Venkitaraman and Tuveson laboratories for helpful comments. We thank Jos Jonkers and Anton Berns (Netherlands Cancer Institute) for the Brca2 F11/WT mouse strain, and Lewis A. Chodosh (University of Pennsylvania) for the rabbit polyclonal antibody against the N terminus of murine Brca2. F.S. was supported in A.R.V.'s laboratory by studentships from the Medical Research Council (MRC) and Onassis Foundation, and subsequently by a Cancer Research UK Clinical Research Training Fellowship. L.D.C. was supported by a Cancer Research UK Molecular Pathology of Cancer studentship in A.R.V.'s laboratory. Work in A.R.V.'s laboratory is supported by the MRC. The authors declare no competing financial interests. ",

year = "2010",

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doi = "10.1016/j.ccr.2010.10.015",

language = "English (US)",

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AU - Skoulidis, Ferdinandos

AU - Cassidy, Liam D.

AU - Pisupati, Venkat

AU - Jonasson, Jon G.

AU - Bjarnason, Hordur

AU - Eyfjord, Jorunn E.

AU - Karreth, Florian A.

AU - Lim, Michael

AU - Barber, Lorraine M.

AU - Clatworthy, Susan A.

AU - Davies, Susan E.

AU - Olive, Kenneth P.

AU - Tuveson, David A.

AU - Venkitaraman, Ashok R.

N1 - Funding Information: We thank the past and present members of the Venkitaraman and Tuveson laboratories for helpful comments. We thank Jos Jonkers and Anton Berns (Netherlands Cancer Institute) for the Brca2 F11/WT mouse strain, and Lewis A. Chodosh (University of Pennsylvania) for the rabbit polyclonal antibody against the N terminus of murine Brca2. F.S. was supported in A.R.V.'s laboratory by studentships from the Medical Research Council (MRC) and Onassis Foundation, and subsequently by a Cancer Research UK Clinical Research Training Fellowship. L.D.C. was supported by a Cancer Research UK Molecular Pathology of Cancer studentship in A.R.V.'s laboratory. Work in A.R.V.'s laboratory is supported by the MRC. The authors declare no competing financial interests.

PY - 2010/11/16

Y1 - 2010/11/16

N2 - 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 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.

AB - 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 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.

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Germline Brca2 Heterozygosity Promotes Kras^G12D -Driven carcinogenesis in a murine model of familial pancreatic cancer

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