Germline BRCA2 mutations drive prostate cancers with distinct evolutionary trajectories

RA Taylor; M Fraser; J Livingstone; SMG Espiritu; H Thorne; V Huang; W Lo; YJ Shiah; TN Yamaguchi; A Sliwinski; S Horsburgh; A Meng; LE Heisler; N Yu; F Yousif; M Papargiris; MG Lawrence; L Timms; DG Murphy; M Frydenberg; JF Hopkins; D Bolton; D Clouston; JD McPherson; T Van Der Kwast; PC Boutros; GP Risbridger; RG Bristow

Journal article

Germline BRCA2 mutations drive prostate cancers with distinct evolutionary trajectories

RA Taylor, M Fraser, J Livingstone, SMG Espiritu, H Thorne, V Huang, W Lo, YJ Shiah, TN Yamaguchi, A Sliwinski, S Horsburgh, A Meng, LE Heisler, N Yu, F Yousif, M Papargiris, MG Lawrence, L Timms, DG Murphy, M Frydenberg Show all

Nature Communications | NATURE PUBLISHING GROUP | Published : 2017

DOI: 10.1038/ncomms13671

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Abstract

Germline mutations in the BRCA2 tumour suppressor are associated with both an increased lifetime risk of developing prostate cancer (PCa) and increased risk of aggressive disease. To understand this aggression, here we profile the genomes and methylomes of localized PCa from 14 carriers of deleterious germline BRCA2 mutations (BRCA2-mutant PCa). We show that BRCA2-mutant PCa harbour increased genomic instability and a mutational profile that more closely resembles metastastic than localized disease. BRCA2-mutant PCa shows genomic and epigenomic dysregulation of the MED12L/MED12 axis, which is frequently dysregulated in metastatic castration-resistant prostate cancer (mCRPC). This dysregulati..

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University of Melbourne Researchers

Renea Taylor Author

Mitchell Lawrence Author

Declan Murphy Author

Damien Bolton Author

Grants

Awarded by National Breast Cancer Foundation

Funding Acknowledgements

The authors thank all members of the Boutros, Risbridger and Bristow labs for helpful suggestions, and Eveline Niedermayr, all the kConFab research nurses and staff, the heads and staff of the Family Cancer Clinics, and the many families who contribute to kConFab. The results described here are in part based upon data generated by the TCGA Research Network: http://cancergenome.nih.gov/. This study was conducted with the support of Movember funds through Prostate Cancer Canada and with the additional support of the Ontario Institute for Cancer Research, funded by the Government of Ontario. This study was conducted with the support of the Ontario Institute for Cancer Research to PCB through funding provided by the Government of Ontario. This work was supported by Prostate Cancer Canada and is proudly funded by the Movember Foundation-Grant #RS2014-01 to PCB. PCB was supported by a Terry Fox Research Institute New Investigator Award and a CIHR New Investigator Award. This project was supported by Genome Canada through a Large-Scale Applied Project contract to PCB and Drs. Ryan Morin and Sohrab P. Shah. The authors gratefully thank the Princess Margaret Cancer Centre Foundation and Radiation Medicine Program Academic Enrichment Fund for support (to R.G.B.). R.G.B. is a recipient of a Canadian Cancer Society Research Scientist Award. This study was supported with funds from National Health and Medical Research Council of Australia (NHMRC ID APP1077799), Victorian State Government Cancer Agency Program Grant (Prostate Translational Research in Victoria Collaboration; CAPTIV) and TissuPath. R.A.T. was supported by Victorian Cancer Agency Fellowship. G.P.R. was supported by NHMRC Fellowships (IDs: 1002648 & 1102752). MGL was supported by a NHMRC Fellowship (1035721) and Movember Young Investigator Grant from the Prostate Cancer Foundation of Australia. kConFab is supported by a grant from the National Breast Cancer Foundation, and previously by the National Health and Medical Research Council, the Queensland Cancer Fund, the Cancer Councils of New South Wales, Victoria, Tasmania and South Australia and the Cancer Foundation of Western Australia.