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• W2904355372 abstract "•Clock-like mutation process attributed to APOBEC3 mediates earliest mutations in PC•Identification of four molecular subgroups that stratifies intermediate-risk disease•Rearrangements at the ESRP1 locus associated with aggressive and proliferative cancer•Development of method to predict clinical trajectories of PC from DNA sequencing data Identifying the earliest somatic changes in prostate cancer can give important insights into tumor evolution and aids in stratifying high- from low-risk disease. We integrated whole genome, transcriptome and methylome analysis of early-onset prostate cancers (diagnosis ≤55 years). Characterization across 292 prostate cancer genomes revealed age-related genomic alterations and a clock-like enzymatic-driven mutational process contributing to the earliest mutations in prostate cancer patients. Our integrative analysis identified four molecular subgroups, including a particularly aggressive subgroup with recurrent duplications associated with increased expression of ESRP1, which we validate in 12,000 tissue microarray tumors. Finally, we combined the patterns of molecular co-occurrence and risk-based subgroup information to deconvolve the molecular and clinical trajectories of prostate cancer from single patient samples. Identifying the earliest somatic changes in prostate cancer can give important insights into tumor evolution and aids in stratifying high- from low-risk disease. We integrated whole genome, transcriptome and methylome analysis of early-onset prostate cancers (diagnosis ≤55 years). Characterization across 292 prostate cancer genomes revealed age-related genomic alterations and a clock-like enzymatic-driven mutational process contributing to the earliest mutations in prostate cancer patients. Our integrative analysis identified four molecular subgroups, including a particularly aggressive subgroup with recurrent duplications associated with increased expression of ESRP1, which we validate in 12,000 tissue microarray tumors. Finally, we combined the patterns of molecular co-occurrence and risk-based subgroup information to deconvolve the molecular and clinical trajectories of prostate cancer from single patient samples. We used a set of tumors diagnosed early in life and thus harboring the earliest molecular lesions detectable in prostate cancer which led us to identify an APOBEC-driven clock-like mutational process driving the earliest somatic mutations in prostate cancer. We identified somatic alterations of ESRP1, a molecular driver of the disease with a particular value in the pre-operation setting where biomarkers are desperately needed. By integrating DNA methylation and RNA expression data from tumors diagnosed with early-onset, we identified four robust subgroups that readily stratify patients into high- and low-risk groups. We combined our cohort of early-onset patients and identified risk-stratification groups to develop a framework to predict the temporal and clinical outcome order of somatic alterations. One of the biggest unmet clinical needs in prostate cancer (PC) is to stratify clinically indolent from aggressive types, particularly in patients diagnosed at young age. Molecular markers have shown promise in risk stratification, but the utility is complicated by the heterogeneous natural history. Primary localized PC develops over decades (Pound et al., 1999Pound C.R. Partin A.W. Eisenberger M.A. Chan D.W. Pearson J.D. Walsh P.C. Natural history of progression after PSA elevation following radical prostatectomy.JAMA. 1999; 281: 1591-1597Crossref PubMed Scopus (2709) Google Scholar), with a typical late age-of-onset (median 66 years of age, seer.cancer.gov). Prior studies have revealed a remarkable inter- and intra-tumor heterogeneity in PC (Boutros et al., 2015Boutros P.C. Fraser M. Harding N.J. de Borja R. Trudel D. Lalonde E. Meng A. Hennings-Yeomans P.H. McPherson A. Sabelnykova V.Y. et al.Spatial genomic heterogeneity within localized, multifocal prostate cancer.Nat. Genet. 2015; 47: 736-745Crossref PubMed Scopus (328) Google Scholar, TCGA, 2015TCGA The molecular taxonomy of primary prostate cancer.Cell. 2015; 163: 1011-1025Abstract Full Text Full Text PDF PubMed Scopus (1860) Google Scholar) associated with poor outcome in primary localized PC (Espiritu et al., 2018Espiritu S.M.G. Liu L.Y. Rubanova Y. Bhandari V. Holgersen E.M. Szyca L.M. Fox N.S. Chua M.L.K. Yamaguchi T.N. Heisler L.E. et al.The evolutionary landscape of localized prostate cancers drives clinical aggression.Cell. 2018; 173: 1003-1013.e15Abstract Full Text Full Text PDF PubMed Scopus (131) Google Scholar). Prior focus on elderly, late-onset patients has hindered the identification of the earliest genomic alterations, which could aid in identifying the evolutionary paths and clinical outcome of PC. One of the earliest molecular alterations in PC are ETS fusions involving the fusion of androgen receptor (AR) responsive promoters and members of the ETS transcription factor (TF) family genes, most notably the TMPRSS2-ERG fusion (Tomlins et al., 2005Tomlins S.A. Rhodes D.R. Perner S. Dhanasekaran S.M. Mehra R. Sun X.-W. Varambally S. Cao X. Tchinda J. Kuefer R. et al.Recurrent fusion of TMPRSS2 and ETS transcription factor genes in prostate cancer.Science. 2005; 310: 644-648Crossref PubMed Scopus (3115) Google Scholar) present in 50% of all PC and exhibiting an elevated occurrence in early-onset PC (EOPC) (Tomlins et al., 2005Tomlins S.A. Rhodes D.R. Perner S. Dhanasekaran S.M. Mehra R. Sun X.-W. Varambally S. Cao X. Tchinda J. Kuefer R. et al.Recurrent fusion of TMPRSS2 and ETS transcription factor genes in prostate cancer.Science. 2005; 310: 644-648Crossref PubMed Scopus (3115) Google Scholar, Weischenfeldt et al., 2013Weischenfeldt J. Simon R. Feuerbach L. Schlangen K. Weichenhan D. Minner S. Wuttig D. Warnatz H.J. Stehr H. Rausch T. et al.Integrative genomic analyses reveal an androgen-driven somatic alteration landscape in early-onset prostate cancer.Cancer Cell. 2013; 23: 159-170Abstract Full Text Full Text PDF PubMed Scopus (267) Google Scholar). PC has relatively few somatic point mutations but has frequent genomic structural variants (SVs), several of which are associated with clinical outcome, including disruption or loss of PTEN, TP53, NKX3-1, and MAP3K7 (Kluth et al., 2013Kluth M. Hesse J. Heinl A. Krohn A. Steurer S. Sirma H. Simon R. Mayer P.-S. Schumacher U. Grupp K. et al.Genomic deletion of MAP3K7 at 6q12-22 is associated with early PSA recurrence in prostate cancer and absence of TMPRSS2:ERG fusions.Mod. Pathol. 2013; 26: 975-983Crossref PubMed Scopus (120) Google Scholar, Taylor et al., 2010Taylor B.S. Schultz N. Hieronymus H. Gopalan A. Xiao Y. Carver B.S. Arora V.K. Kaushik P. Cerami E. Reva B. et al.Integrative genomic profiling of human prostate cancer.Cancer Cell. 2010; 18: 11-22Abstract Full Text Full Text PDF PubMed Scopus (2742) Google Scholar, TCGA, 2015TCGA The molecular taxonomy of primary prostate cancer.Cell. 2015; 163: 1011-1025Abstract Full Text Full Text PDF PubMed Scopus (1860) Google Scholar). Identifying the molecular evolution and clinical trajectories of PC requires analysis of the earliest somatic mutation events. A particular relevant subset of PC are early detected cancers associated with EOPC (Pritchard et al., 2016Pritchard C.C. Mateo J. Walsh M.F. De Sarkar N. Abida W. Beltran H. Garofalo A. Gulati R. Carreira S. Eeles R. et al.Inherited DNA-repair gene mutations in men with metastatic prostate cancer.N. Engl. J. Med. 2016; 375: 443-453Crossref PubMed Scopus (950) Google Scholar, Weischenfeldt and Korbel, 2017Weischenfeldt J. Korbel J.O. Genomes of early onset prostate cancer.Curr. Opin. Urol. 2017; 27: 481-487Crossref PubMed Scopus (8) Google Scholar, Weischenfeldt et al., 2013Weischenfeldt J. Simon R. Feuerbach L. Schlangen K. Weichenhan D. Minner S. Wuttig D. Warnatz H.J. Stehr H. Rausch T. et al.Integrative genomic analyses reveal an androgen-driven somatic alteration landscape in early-onset prostate cancer.Cancer Cell. 2013; 23: 159-170Abstract Full Text Full Text PDF PubMed Scopus (267) Google Scholar), here defined as patients with an age-at-diagnosis at 55 and below, who are likely to develop a severe disease course and eventually require radical treatment. Studies in EOPC, furthermore, offer insights into early mutational processes and evolutionary trajectories of PC. We applied uniform and comprehensive genomics-based profiling of 292 PC cases (including 203 EOPCs) (Table S1; Figures 1 and S1A). Profiling included whole genome sequencing (WGS) of tumors and matched peripheral blood from 184 EOPC patients and 85 late-onset (LOPC) patients, methylomes (450k methylome arrays) in 203 EOPC tumors and 45 LOPC tumors and mRNA sequencing (mRNA-seq) of 96 EOPC samples. Established somatic and germline variant calling pipelines were used to identify single-nucleotide variants (SNVs), short insertions and deletions (InDels), and SVs. Genome-wide analysis of somatic SNVs revealed an expected lower average number of SNVs per Mb in EOPC (median = 0.47, interquartile range = 0.49) compared with LOPC (median = 0.53) (Fraser et al., 2017Fraser M. Sabelnykova V.Y. Yamaguchi T.N. Heisler L.E. Livingstone J. Huang V. Shiah Y.-J. Yousif F. Lin X. Masella A.P. et al.Genomic hallmarks of localized, non-indolent prostate cancer.Nature. 2017; 541: 359-364Crossref PubMed Scopus (363) Google Scholar). TP53 was the most frequently affected gene by nonsynonymous SNVs in the EOPC cohort (6%). SVs often involve recurrent fusion gene formation or loss of tumor-suppressor genes in PC (Fraser et al., 2017Fraser M. Sabelnykova V.Y. Yamaguchi T.N. Heisler L.E. Livingstone J. Huang V. Shiah Y.-J. Yousif F. Lin X. Masella A.P. et al.Genomic hallmarks of localized, non-indolent prostate cancer.Nature. 2017; 541: 359-364Crossref PubMed Scopus (363) Google Scholar, Taylor et al., 2010Taylor B.S. Schultz N. Hieronymus H. Gopalan A. Xiao Y. Carver B.S. Arora V.K. Kaushik P. Cerami E. Reva B. et al.Integrative genomic profiling of human prostate cancer.Cancer Cell. 2010; 18: 11-22Abstract Full Text Full Text PDF PubMed Scopus (2742) Google Scholar, TCGA, 2015TCGA The molecular taxonomy of primary prostate cancer.Cell. 2015; 163: 1011-1025Abstract Full Text Full Text PDF PubMed Scopus (1860) Google Scholar). We confirmed previous findings, namely an increased number of SNVs and SVs with age (p < 0.001) (Figures S1B and S1C). We identified recurrent genomic altered loci (RGA), as breakpoint peak regions at minimum 5% recurrence (Figures 1A and 1B). Our analysis revealed 70% of the EOPC tumor genomes carrying an SV associated with formation of an ETS fusion gene (Figure S1D). The second- and third-most frequently altered loci in EOPC were at chromosome 8p (centered at NKX3-1, 37%) and 3p14 (centered at FOXP1, 30%). We identified PTEN as the gene with the highest rate of biallelic inactivation (12 samples) across the cohort, followed by TP53 (8 samples). Despite being more often affected by SVs, neither NKX3-1 nor FOXP1 underwent recurrent biallelic inactivation, corroborating earlier suggestions of haploinsufficient tumor-suppressive roles of these genes (Locke et al., 2012Locke J.A. Zafarana G. Ishkanian A.S. Milosevic M. Thoms J. Have C.L. Malloff C.A. Lam W.L. Squire J.A. Pintilie M. et al.NKX3.1 haploinsufficiency is prognostic for prostate cancer relapse following surgery or image-guided radiotherapy.Clin. Cancer Res. 2012; 18: 308-316Crossref PubMed Scopus (40) Google Scholar, Myers et al., 2017Myers A. du Souich C. Yang C.L. Borovik L. Mwenifumbo J. Rupps R. Study C. Lehman A. Boerkoel C.F. FOXP1 haploinsufficiency: phenotypes beyond behavior and intellectual disability?.Am. J. Med. Genet. A. 2017; 173: 3172-3181Crossref PubMed Scopus (16) Google Scholar). To identify RGAs associated with age-of-onset, we performed a parallel analysis of LOPC genomes, which revealed similar affected loci but with a more uniform pattern, distinct from that of EOPC (Figures S1D and S1E). LOPC displayed an overall higher proportion of RGAs affected by genomic losses compared with a higher rate of balanced breaks in EOPC (p < 1 × 10−7 and p < 1 × 10−4, Fisher's exact test). Moreover, EOPC exhibited a more monoclonal architecture compared with LOPC (66% and 53%, respectively, Figures 1C and S1F), suggesting that EOPC tend to be primarily associated with a clonal origin, potentially due to the shorter life-span compared with LOPC. The epigenetic landscape is often altered during cancer progression and impacts on where DNA double-strand breaks occur (Aryee et al., 2013Aryee M.J. Liu W. Engelmann J.C. Nuhn P. Gurel M. Haffner M.C. Esopi D. Irizarry R.A. Getzenberg R.H. Nelson W.G. et al.DNA methylation alterations exhibit intraindividual stability and interindividual heterogeneity in prostate cancer metastases.Sci. Transl. Med. 2013; 5: 169ra10Crossref PubMed Scopus (208) Google Scholar, Urbanucci et al., 2017Urbanucci A. Barfeld S.J. Kytölä V. Itkonen H.M. Coleman I.M. Vodák D. Sjöblom L. Sheng X. Tolonen T. Minner S. et al.Androgen receptor deregulation drives bromodomain-mediated chromatin alterations in prostate cancer.Cell Rep. 2017; 19: 2045-2059Abstract Full Text Full Text PDF PubMed Scopus (73) Google Scholar). We previously showed that breakpoints in EOPC genomes occur more often in the vicinity of AR-binding sites (Weischenfeldt et al., 2013Weischenfeldt J. Simon R. Feuerbach L. Schlangen K. Weichenhan D. Minner S. Wuttig D. Warnatz H.J. Stehr H. Rausch T. et al.Integrative genomic analyses reveal an androgen-driven somatic alteration landscape in early-onset prostate cancer.Cancer Cell. 2013; 23: 159-170Abstract Full Text Full Text PDF PubMed Scopus (267) Google Scholar). This raises the possibility that age-associated altered chromatin states impact on breakpoint occurrence. We therefore examined genomic breakpoints from EOPC tumors in relation to specific chromatin regions (Taberlay et al., 2014Taberlay P.C. Statham A.L. Kelly T.K. Clark S.J. Jones P.A. Reconfiguration of nucleosome-depleted regions at distal regulatory elements accompanies DNA methylation of enhancers and insulators in cancer.Genome Res. 2014; 24: 1421-1432Crossref PubMed Scopus (139) Google Scholar). This revealed a significant enrichment of breakpoints in EOPC near open chromatin, active enhancers, TF binding, and actively transcribed regions (Figures S1G and S1H). Active enhancers are associated with long-range promoter-enhancer DNA-DNA chromatin loops, which can increase the likelihood of SV formation between normally distant loci (Chen et al., 2018Chen H. Li C. Peng X. Zhou Z. Weinstein J.N. Liang H. Cancer Genome Atlas Research NetworkA pan-cancer analysis of enhancer expression in nearly 9000 patient samples.Cell. 2018; 173: 386-399.e12Abstract Full Text Full Text PDF PubMed Scopus (152) Google Scholar). We integrated publicly available Hi-C data, which revealed significant correlation between breakpoints and both the number of chromatin loops and H3K27ac peaks (p < 0.0001 both, Spearman’s rho = 0.23 and 0.18, respectively) in EOPC, but to a lesser extent in LOPC (p < 0.0001 both, Spearman’s rho = 0.11 and 0.06 for Hi-C and H3K27ac, respectively, Figure 1D), suggesting that the chromatin state and long-range interactions partake in shaping the SV landscape in EOPC (Figure 1E). We identified two RGAs in EOPC located at 13q22 (27%) and 8q22 (17%) (Figures 2A and 2B ). The minimal overlap peak region at 13q22 centered on KLF5, encoding a transcriptional activator involved in repressing cell proliferation (Xing et al., 2014Xing C. Ci X. Sun X. Fu X. Zhang Z. Dong E.N. Hao Z.-Z. Dong J.-T. Klf5 deletion promotes Pten deletion-initiated luminal-type mouse prostate tumors through multiple oncogenic signaling pathways.Neoplasia. 2014; 16: 883-899Abstract Full Text Full Text PDF PubMed Scopus (24) Google Scholar). Loss of 13q22 was associated with decreased KLF5 mRNA level as well as a global increase in SV and SNV burden (Figures 2C and S2A). We additionally identified a subset of tumors that displayed a marked reduction in KLF5 expression and a differentially methylated CpG site (q = 0.002, t test) proximal to the KLF5 promoter in a CpG island shore that was inversely correlated with KLF5 mRNA level (Spearman’s rho = −0.523, q = 0.0038, CpG no. 18 in Figures 2D and S2B). A recent study in mouse embryonic stem cells identified a set of KLF5 targets, including the ubiquitin ligase gene Spop, which was significantly downregulated in response to KLF5 knockdown (Parisi et al., 2010Parisi S. Cozzuto L. Tarantino C. Passaro F. Ciriello S. Aloia L. Antonini D. De Simone V. Pastore L. Russo T. Direct targets of Klf5 transcription factor contribute to the maintenance of mouse embryonic stem cell undifferentiated state.BMC Biol. 2010; 8: 128Crossref PubMed Scopus (41) Google Scholar). Chromatin immunoprecipitation sequencing data showed binding of KLF5 at the SPOP promoter (Yan et al., 2013Yan J. Enge M. Whitington T. Dave K. Liu J. Sur I. Schmierer B. Jolma A. Kivioja T. Taipale M. et al.Transcription factor binding in human cells occurs in dense clusters formed around cohesin anchor sites.Cell. 2013; 154: 801-813Abstract Full Text Full Text PDF PubMed Scopus (241) Google Scholar) and we identified a positive correlation between KLF5 and SPOP mRNA levels in our PC cohort (Figures 2E and S2C) as well as in The Cancer Genome Atlas (TCGA) cohort (p < 1 × 10−4, Spearman’s rho = 0.19), but no association with the SPOP mutation status (Fisher's exact test). A region at 8q22 displayed recurrent genomic duplications centered on ESRP1 (Figure 2B), with the minimal overlapping region residing 33 Mbp away from MYC. ESRP1 encodes an RNA-binding protein involved in epithelial-to-mesenchymal transition (EMT) and RNA splicing (Jeong et al., 2017Jeong H.M. Han J. Lee S.H. Park H.-J. Lee H.J. Choi J.-S. Lee Y.M. Choi Y.-L. Shin Y.K. Kwon M.J. ESRP1 is overexpressed in ovarian cancer and promotes switching from mesenchymal to epithelial phenotype in ovarian cancer cells.Oncogenesis. 2017; 6: e389Crossref PubMed Scopus (48) Google Scholar). Tumors harboring duplications intersecting ESRP1 displayed significantly increased ESRP1 mRNA expression (>1.5-fold, Figure 2F). While several duplications overlapped both ESRP1 and MYC, only ESRP1 displayed a significant increase in mRNA level across the affected samples (Figures 2F and S2D). ESRP1 duplications were significantly associated with elevated Gleason score (GS) (p < 1 × 10−11, chi-square test), in fact, more than any other RGA in the cohort. We therefore pursued immunohistochemistry-based validation in 11,954 tumor specimens on tissue microarrays (Figure 2G), which confirmed a significant correlation between increased GS and pT and ESRP1 staining (Figure S2E). High ESRP1 protein level particularly showed association with high GS (>4+4), tumor stage (pT3b-pT4), number of lymph node metastases and preoperative prostate-specific antigen levels. Increased ESRP1 protein levels correlated with higher proliferation rate irrespective of GS, as measured by Ki67 index labeling (Figure 2H). In addition, ESRP1 protein intensity was associated with adverse outcome, with strong ESRP1 staining correlating with significantly shorter time to biochemical recurrence (BCR) (Figures 2I and S2F). A multivariate analysis revealed ESRP1 to be an independent prognostic marker in four established clinico-pathological parameters and that high ESRP1 expression was associated with shorter BCR irrespective of ERG status (Table S2; Figures S2G and S2H). ESRP1 was particularly discriminative in the biopsy setting, where GS is often underestimated and additional prognostic markers are needed. In summary, we identified recurrent genomic duplications of ESRP1 associated with increased ESRP1 protein expression, higher levels of cell proliferation, and elevated GS and tumor stage, and demonstrated that ESRP1 expression is an independent prognostic biomarker in PC. Mutational signatures can be employed to describe intrinsic and exogenous-mediated mutational processes acting on tumor cells (Alexandrov et al., 2013Alexandrov L.B. Nik-Zainal S. Wedge D.C. Aparicio S.A. Behjati S. Biankin A.V. Bignell G.R. Bolli N. Borg A. Borresen-Dale A.L. et al.Signatures of mutational processes in human cancer.Nature. 2013; 500: 415-421Crossref PubMed Scopus (6263) Google Scholar, Alexandrov et al., 2015Alexandrov L.B. Jones P.H. Wedge D.C. Sale J.E. Campbell P.J. Nik-Zainal S. Stratton M.R. Clock-like mutational processes in human somatic cells.Nat. Genet. 2015; 47: 1402-1407Crossref PubMed Scopus (548) Google Scholar, Nik-Zainal et al., 2016Nik-Zainal S. Davies H. Staaf J. Ramakrishna M. Glodzik D. Zou X. Martincorena I. Alexandrov L.B. Martin S. Wedge D.C. et al.Landscape of somatic mutations in 560 breast cancer whole-genome sequences.Nature. 2016; 534: 47-54Crossref PubMed Scopus (1267) Google Scholar) (Figure 3A). We observed six mutational signatures: two clock-like signatures (1 and 5), two related to DNA repair defects (3 and 6), and two related to APOBEC cytidine deaminase-attributable mutagenesis (2 and 13). Mutational processes were associated to GS, in particular the APOBEC signatures (2 and 13) and the homologous recombination repair-associated signature 3 (Figure 3B). The clock-like mutational signatures 1 and 5 were the predominant signatures across all tumors and both showed significant association with patient age (Figure 3C). Curiously, we also observed clear signs of a clock-like accumulation of APOBEC-associated signature 2 and 13 mutations in PC (Figure 3C), and could further corroborate this finding using a knowledge-based approach that estimates APOBEC mutagenesis in cancer genomes (p = 5.2 × 10−3, Spearman’s rho = 0.17). APOBEC proteins are cytidine deaminases that can act to restrict retroelements during the single-stranded DNA replication cycle, but can also induce mutations in cancer genomes (Roberts et al., 2012Roberts S.A. Sterling J. Thompson C. Harris S. Mav D. Shah R. Klimczak L.J. Kryukov G.V. Malc E. Mieczkowski P.A. et al.Clustered mutations in yeast and in human cancers can arise from damaged long single-strand DNA regions.Mol. Cell. 2012; 46: 424-435Abstract Full Text Full Text PDF PubMed Scopus (301) Google Scholar, Roberts et al., 2013Roberts S.A. Lawrence M.S. Klimczak L.J. Grimm S.A. Fargo D. Stojanov P. Kiezun A. Kryukov G.V. Carter S.L. Saksena G. et al.An APOBEC cytidine deaminase mutagenesis pattern is widespread in human cancers.Nat. Genet. 2013; 45: 970-976Crossref PubMed Scopus (809) Google Scholar). These lesions were previously suggested to be driven by APOBEC3A (A3A) and/or APOBEC3B (A3B) (Swanton et al., 2015Swanton C. McGranahan N. Starrett G.J. Harris R.S. APOBEC enzymes: mutagenic fuel for cancer evolution and heterogeneity.Cancer Discov. 2015; 5: 704-712Crossref PubMed Scopus (301) Google Scholar). APOBEC-associated mutations occasionally arise as clusters of C strand- (or G strand)-coordinated mutational events (C/G clusters)––also termed kataegis events––a mutational phenomenon resulting in localized hypermutation (Nik-Zainal et al., 2012Nik-Zainal S. Alexandrov L.B. Wedge D.C. Van Loo P. Greenman C.D. Raine K. Jones D. Hinton J. Marshall J. Stebbings L.A. et al.Mutational processes molding the genomes of 21 breast cancers.Cell. 2012; 149: 979-993Abstract Full Text Full Text PDF PubMed Scopus (1288) Google Scholar, Roberts et al., 2012Roberts S.A. Sterling J. Thompson C. Harris S. Mav D. Shah R. Klimczak L.J. Kryukov G.V. Malc E. Mieczkowski P.A. et al.Clustered mutations in yeast and in human cancers can arise from damaged long single-strand DNA regions.Mol. Cell. 2012; 46: 424-435Abstract Full Text Full Text PDF PubMed Scopus (301) Google Scholar). Indeed, we observed a strong enrichment of APOBEC mutagenesis at C/G clusters in PC (Figure 3D). We also identified a significant association between patient age and C/G clusters attributable to APOBEC enzymes (Figure S3A), which was primarily attributable to A3B-like mutagenesis at C/G clusters (Figure 3E). To further substantiate the relevance of A3B-like mutagenesis in PC, we genotyped a known ∼30 kb germline APOBEC3B deletion, which results in complete removal of its protein-coding sequence (Middlebrooks et al., 2016Middlebrooks C.D. Banday A.R. Matsuda K. Udquim K.-I. Onabajo O.O. Paquin A. Figueroa J.D. Zhu B. Koutros S. Kubo M. et al.Association of germline variants in the APOBEC3 region with cancer risk and enrichment with APOBEC-signature mutations in tumors.Nat. Genet. 2016; 48: 1330-1338Crossref PubMed Scopus (105) Google Scholar). We observed in germline APOBEC3B deletion carriers; (1) significantly fewer APOBEC-associated signature 2 and 13 mutation, (2) reduced expression levels of A3B in PC, and (3) a significant shift from A3B-like to A3A-like mutagenesis (Figure S3B). These findings thus suggest that A3B-like mutagenesis is active at a basal level in prostate cells, and that this endogenous mutagenic process is responsible for the clock-like accumulation of somatic mutations––including the occurrence of localized hypermutation events––in PC. APOBEC-associated mutations have previously been observed to frequently co-localize with SV breakpoints in cancer (Chan and Gordenin, 2015Chan K. Gordenin D.A. Clusters of multiple mutations: incidence and molecular mechanisms.Annu. Rev. Genet. 2015; 49: 243-267Crossref PubMed Scopus (79) Google Scholar, Roberts et al., 2012Roberts S.A. Sterling J. Thompson C. Harris S. Mav D. Shah R. Klimczak L.J. Kryukov G.V. Malc E. Mieczkowski P.A. et al.Clustered mutations in yeast and in human cancers can arise from damaged long single-strand DNA regions.Mol. Cell. 2012; 46: 424-435Abstract Full Text Full Text PDF PubMed Scopus (301) Google Scholar). We found a strong enrichment of C/G clusters to co-localize with SV breakpoints compared with both non-coordinated mutation clusters and scattered mutations (Figure 3F), with an increase in co-localization frequency between 1 and 10 kb. Several of these APOBEC-associated SV breakpoints resulted in alteration of driver genes in PC, including formation of TMPRSS2-ERG fusion and PTEN, FOXP1, and BRCA2 disruption (Table S2). Our findings demonstrate an age-associated mutational process that involves an endogenous mutagenic enzyme, and suggest that mutations attributable to APOBEC enzymes are likely to contribute to the earliest mutations seen in PC patients. Germline mutations also are likely to contribute to early lesions in PC patients, for example by modulating somatic mutational processes. Germline protein-truncating variants (PTVs) in DNA damage response (DDR) genes including BRCA1, BRCA2, PALB2, ATM, and CHEK2 have previously been associated with poor outcome and increased frequency of PC metastasis (Na et al., 2017Na R. Zheng S.L. Han M. Yu H. Jiang D. Shah S. Ewing C.M. Zhang L. Novakovic K. Petkewicz J. et al.Germline mutations in ATM and BRCA1/2 distinguish risk for lethal and indolent prostate cancer and are associated with early age at death.Eur. Urol. 2017; 71: 740-747Abstract Full Text Full Text PDF PubMed Scopus (201) Google Scholar, Pritchard et al., 2016Pritchard C.C. Mateo J. Walsh M.F. De Sarkar N. Abida W. Beltran H. Garofalo A. Gulati R. Carreira S. Eeles R. et al.Inherited DNA-repair gene mutations in men with metastatic prostate cancer.N. Engl. J. Med. 2016; 375: 443-453Crossref PubMed Scopus (950) Google Scholar). We detected significant associations between germline PTVs in these DDR genes and somatic SVs and SNVs, as well as APOBEC-like signature 2 and the “BRCAness” mutational signature 3 (Figure 4). In summary, we identify three age-associated mutational processes in PC, namely, CpG mutagenesis, signature 5 with unknown etiology, and A3B-associated mutagenesis. Tumor genomes harboring pathogenic germline mutations in genes involved in homologous recombination repair exhibited increased genomic instability. Normal human prostate tissue is composed of basal, luminal, and stromal cells, whereas PC loses basal cells and gains tumor-specific luminal (T-luminal) cells as well as infiltrating immune cells (Bhasin et al., 2015Bhasin J.M. Lee B.H. Matkin L. Taylor M.G. Hu B. Xu Y. Magi-Galluzzi C. Klein E.A. Ting A.H. Methylome-wide sequencing detects DNA hypermethylation distinguishing indolent from aggressive prostate cancer.Cell Rep. 2015; 13: 2135-2146Abstract Full Text Full Text PDF PubMed Scopus (31) Google Scholar). Given that DNA methylation profiles are cell type (ct) specific, we sought to account for differences in ct composition in methylation analyses by using available reference methylomes (Teschendorff and Zheng, 2017Teschendorff A.E. Zheng S.C. Cell-type deconvolution in epigenome-wide association studies: a review and recommendations.Epigenomics. 2017; 9: 757-768Crossref PubMed Scopus (89) Google Scholar). To this end, we acquired additional resected samples from benign prostate hyperplasia cases and PC, and performed fluorescence-activated cell sorting to identify the main cts present in PC (STAR Methods) (Figures 5A and S4A–S4C), which enabled us to identify the ct identity of every methylation site in the PC genome. We found a recurrent shift from basal and luminal cells to T-luminal cells and infiltrating immune cells in high GS tumors (Figures 5B, S4C, and S4D). Given this relevance of T-luminal and immune cell content in identifying high-grade tumors, we combined this information as a Purity-Adjusted Epigenetic Prostate Cancer Index (PEPCI) of tumor aggressiveness (Figures 5A and 5B). We found that high PEPCI was strongly associated with high pT (p < 1 × 10−7, Kruskal-Wallis), high GS (p < 1 × 10−17, Wilcoxon) (Figure 5C) and elevated risk of BCR (log rank p < 0.0001). Moreover, PEPCI was able to stratify intermediate-risk (GS7, especially GS4+3) cases (Figures 5D, S4E, and S4F; Table S3), w" @default.
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