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The long tail of oncogenic drivers in prostate cancer.

ABSTRACT: Comprehensive genomic characterization of prostate cancer has identified recurrent alterations in genes involved in androgen signaling, DNA repair, and PI3K signaling, among others. However, larger and uniform genomic analysis may identify additional recurrently mutated genes at lower frequencies. Here we aggregate and uniformly analyze exome sequencing data from 1,013 prostate cancers. We identify and validate a new class of E26 transformation-specific (ETS)-fusion-negative tumors defined by mutations in epigenetic regulators, as well as alterations in pathways not previously implicated in prostate cancer, such as the spliceosome pathway. We find that the incidence of significantly mutated genes (SMGs) follows a long-tail distribution, with many genes mutated in less than 3% of cases. We identify a total of 97 SMGs, including 70 not previously implicated in prostate cancer, such as the ubiquitin ligase CUL3 and the transcription factor SPEN. Finally, comparing primary and metastatic prostate cancer identifies a set of genomic markers that may inform risk stratification.

SUBMITTER: Armenia J

PROVIDER: S-EPMC6107367 | biostudies-literature | 2018 May

REPOSITORIES: biostudies-literature

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The long tail of oncogenic drivers in prostate cancer.

Armenia Joshua J Wankowicz Stephanie A M SAM Liu David D Gao Jianjiong J Kundra Ritika R Reznik Ed E Chatila Walid K WK Chakravarty Debyani D Han G Celine GC Coleman Ilsa I Montgomery Bruce B Pritchard Colin C Morrissey Colm C Barbieri Christopher E CE Beltran Himisha H Sboner Andrea A Zafeiriou Zafeiris Z Miranda Susana S Bielski Craig M CM Penson Alexander V AV Tolonen Charlotte C Huang Franklin W FW Robinson Dan D Wu Yi Mi YM Lonigro Robert R Garraway Levi A LA Demichelis Francesca F Kantoff Philip W PW Taplin Mary-Ellen ME Abida Wassim W Taylor Barry S BS Scher Howard I HI Nelson Peter S PS de Bono Johann S JS Rubin Mark A MA Sawyers Charles L CL Chinnaiyan Arul M AM Schultz Nikolaus N Van Allen Eliezer M EM

Nature genetics 20180402 5

Comprehensive genomic characterization of prostate cancer has identified recurrent alterations in genes involved in androgen signaling, DNA repair, and PI3K signaling, among others. However, larger and uniform genomic analysis may identify additional recurrently mutated genes at lower frequencies. Here we aggregate and uniformly analyze exome sequencing data from 1,013 prostate cancers. We identify and validate a new class of E26 transformation-specific (ETS)-fusion-negative tumors defined by mu ...[more]

PMID: 29610475

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Project description:BackgroundAfrican ancestry is a significant risk factor for advanced prostate cancer (PCa). Mortality rates in sub-Saharan Africa are 2.5-fold greater than global averages. However, the region has largely been excluded from the benefits of whole genome interrogation studies. Additionally, while structural variation (SV) is highly prevalent, PCa genomic studies are still biased towards small variant interrogation.MethodsUsing whole genome sequencing and best practice workflows, we performed a comprehensive analysis of SVs for 180 (predominantly Gleason score ≥ 8) prostate tumours derived from 115 African, 61 European and four ancestrally admixed patients. We investigated the landscape and relationship of somatic SVs in driving ethnic disparity (African versus European), with a focus on African men from southern Africa.ResultsDuplication events showed the greatest ethnic disparity, with a 1.6- (relative frequency) to 2.5-fold (count) increase in African-derived tumours. Furthermore, we found duplication events to be associated with CDK12 inactivation and MYC copy number gain, and deletion events associated with SPOP mutation. Overall, African-derived tumours were 2-fold more likely to present with a hyper-SV subtype. In addition to hyper-duplication and deletion subtypes, we describe a new hyper-translocation subtype. While we confirm a lower TMPRSS2-ERG fusion-positive rate in tumours from African cases (10% versus 33%), novel African-specific PCa ETS family member and TMPRSS2 fusion partners were identified, including LINC01525, FBXO7, GTF3C2, NTNG1 and YPEL5. Notably, we found 74 somatic SV hotspots impacting 18 new candidate driver genes, with CADM2, LSAMP, PTPRD, PDE4D and PACRG having therapeutic implications for African patients.ConclusionsIn this first African-inclusive SV study for high-risk PCa, we demonstrate the power of SV interrogation for the identification of novel subtypes, oncogenic drivers and therapeutic targets. Identifying a novel spectrum of SVs in tumours derived from African patients provides a mechanism that may contribute, at least in part, to the observed ethnic disparity in advanced PCa presentation in men of African ancestry.

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The long tail of oncogenic drivers in prostate cancer.

Publications

The long tail of oncogenic drivers in prostate cancer.

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