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Genomic Hallmarks of Localized, Non-indolent Prostate Cancer.

Prostate tumours are highly variable in their response to therapies, but clinically available prognostic factors can explain only a fraction of this heterogeneity. Here we analysed 200 whole-genome sequences and 277 additional whole-exome sequences from localized, non-indolent prostate tumours with similar clinical risk profiles, and carried out RNA and methylation analyses in a subset.  These tumours had a paucity of clinically actionable single nucleotide variants, unlike those seen in metastatic disease. Rather, a significant proportion of tumours harboured recurrent non-coding aberrations, large-scale genomic rearrangements, and alterations in which an inversion repressed transcription within its boundaries. Local hypermutation events were frequent and correlated with specific genomic profiles. Numerous molecular aberrations were prognostic for disease recurrence, including several DNA methylation events, and a signature comprised of these aberrations outperformed well-described prognostic biomarkers. We suggest that intensified treatment of genomically aggressive localized prostate cancer may improve cure rates.

Nature. 2017 Jan 9 [Epub ahead of print]

Fraser M1, Sabelnykova VY2, Yamaguchi TN2, Heisler LE2, Livingstone J2, Huang V2, Shiah YJ2, Yousif F2, Lin X2, Masella AP2, Fox NS2,3, Xie M2, Prokopec SD2, Berlin A4, Lalonde E2,3, Ahmed M1, Trudel D5, Luo X2, Beck TA2, Meng A1, Zhang J1, D'Costa A2, Denroche RE2, Kong H2, Espiritu SM2, Chua ML4, Wong A6, Chong T6, Sam M6, Johns J6, Timms L6, Buchner NB6, Orain M7, Picard V8, Hovington H8, Murison A1, Kron K1, Harding NJ2, P'ng C2, Houlahan KE2, Chu KC2, Lo B2, Nguyen F2, Li CH2,3, Sun RX2,9, de Borja R2, Cooper CI2, Hopkins JF2, Govind SK2, Fung C2, Waggott D2, Green J2, Haider S2, Chan-Seng-Yue MA2, Jung E2, Wang Z2, Bergeron A8, Dal Pra A4, Lacombe L8, Collins CC10,11, Sahinalp C12, Lupien M1,3, Fleshner NE13, He HH1,3, Fradet Y8, Tetu B7, van der Kwast T5, McPherson JD3,6, Bristow RG1,3,4, Boutros PC2,3,9

1. Princess Margaret Cancer Centre, University Health Network, Toronto, Canada
2. Informatics & Biocomputing Program, Ontario Institute for Cancer Research, Toronto, Canada
3. Department of Medical Biophysics, University of Toronto, Toronto, Canada
4. Department of Radiation Oncology, University of Toronto, Toronto, Canada
5. Department of Pathology and Laboratory Medicine, Toronto General Hospital/University Health Network, Toronto, Canada
6. Genome Technologies Program, Ontario Institute for Cancer Research, Toronto, Canada
7. Department of Pathology and Research Centre of CHU de Québec-Université Laval. Québec City, Canada
8. Division of Urology and Research Centre of CHU de Québec-Université Laval, Québec City, Canada
9. Department of Pharmacology &Toxicology, University of Toronto, Toronto, Canada
10. Department of Urologic Sciences, University of British Columbia, Vancouver, Canada
11. Vancouver Prostate Centre, Vancouver, Canada
12. School of Computing Science, Simon Fraser University, Burnaby, Canada
13. Division of Urology, Princess Margaret Cancer Centre/University Health Network, Toronto, Canada

PubMed https://www.ncbi.nlm.nih.gov/pubmed/28068672