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.

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Fraser M, Sabelnykova VY, Yamaguchi TN, Heisler LE, Livingstone J, Huang V, Shiah YJ, Yousif F, Lin X, Masella AP, Fox NS, Xie M, Prokopec SD, Berlin A, Lalonde E, Ahmed M, Trudel D, Luo X, Beck TA, Meng A, Zhang J, D'Costa A, Denroche RE, Kong H, Espiritu SM, Chua ML, Wong A, Chong T, Sam M, Johns J, Timms L, Buchner NB, Orain M, Picard V, Hovington H, Murison A, Kron K, Harding NJ, P'ng C, Houlahan KE, Chu KC, Lo B, Nguyen F, Li CH, Sun RX, de Borja R, Cooper CI, Hopkins JF, Govind SK, Fung C, Waggott D, Green J, Haider S, Chan-Seng-Yue MA, Jung E, Wang Z, Bergeron A, Dal Pra A, Lacombe L, Collins CC, Sahinalp C, Lupien M, Fleshner NE, He HH, Fradet Y, Tetu B, van der Kwast T, McPherson JD, Bristow RG, Boutros PC