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Genome-wide germline correlates of the epigenetic landscape of prostate cancer.

ABSTRACT: Oncogenesis is driven by germline, environmental and stochastic factors. It is unknown how these interact to produce the molecular phenotypes of tumors. We therefore quantified the influence of germline polymorphisms on the somatic epigenome of 589 localized prostate tumors. Predisposition risk loci influence a tumor's epigenome, uncovering a mechanism for cancer susceptibility. We identified and validated 1,178 loci associated with altered methylation in tumoral but not nonmalignant tissue. These tumor methylation quantitative trait loci influence chromatin structure, as well as RNA and protein abundance. One prominent tumor methylation quantitative trait locus is associated with AKT1 expression and is predictive of relapse after definitive local therapy in both discovery and validation cohorts. These data reveal intricate crosstalk between the germ line and the epigenome of primary tumors, which may help identify germline biomarkers of aggressive disease to aid patient triage and optimize the use of more invasive or expensive diagnostic assays.

SUBMITTER: Houlahan KE

PROVIDER: S-EPMC7418214 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature

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Genome-wide germline correlates of the epigenetic landscape of prostate cancer.

Houlahan Kathleen E KE Shiah Yu-Jia YJ Gusev Alexander A Yuan Jiapei J Ahmed Musaddeque M Shetty Anamay A Ramanand Susmita G SG Yao Cindy Q CQ Bell Connor C O'Connor Edward E Huang Vincent V Fraser Michael M Heisler Lawrence E LE Livingstone Julie J Yamaguchi Takafumi N TN Rouette Alexandre A Foucal Adrien A Espiritu Shadrielle Melijah G SMG Sinha Ankit A Sam Michelle M Timms Lee L Johns Jeremy J Wong Ada A Murison Alex A Orain Michèle M Picard Valérie V Hovington Hélène H Bergeron Alain A Lacombe Louis L Lupien Mathieu M Fradet Yves Y Têtu Bernard B McPherson John D JD Pasaniuc Bogdan B Kislinger Thomas T Chua Melvin L K MLK Pomerantz Mark M MM van der Kwast Theodorus T Freedman Matthew L ML Mani Ram S RS He Housheng H HH Bristow Robert G RG Boutros Paul C PC

Nature medicine 20191007 10

Oncogenesis is driven by germline, environmental and stochastic factors. It is unknown how these interact to produce the molecular phenotypes of tumors. We therefore quantified the influence of germline polymorphisms on the somatic epigenome of 589 localized prostate tumors. Predisposition risk loci influence a tumor's epigenome, uncovering a mechanism for cancer susceptibility. We identified and validated 1,178 loci associated with altered methylation in tumoral but not nonmalignant tissue. The ...[more]

PMID: 31591588

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Project description:Therapeutic approaches targeting proteins on the surface of cancer cells have emerged as an important strategy for precision oncology. To fully capitalize on the potential impact of drugs targeting surface proteins, detailed knowledge about the expression patterns of the target proteins in tumor tissues is required. In castration-resistant prostate cancer (CRPC), agents targeting prostate-specific membrane antigen (PSMA) have demonstrated clinical activity. However, PSMA expression is lost in a significant number of CRPC tumors, and the identification of additional cell surface targets is necessary in order to develop new therapeutic approaches. Here, we performed a comprehensive analysis of the expression and co-expression patterns of trophoblast cell-surface antigen 2 (TROP2), delta-like ligand 3 (DLL3), and carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM5) in CRPC samples from a rapid autopsy cohort. We show that DLL3 and CEACAM5 exhibit the highest expression in neuroendocrine prostate cancer (NEPC), while TROP2 is expressed across different CRPC molecular subtypes, except for NEPC. We observed variable intra-tumoral and inter-tumoral heterogeneity and no dominant metastatic site predilections for TROP2, DLL3, and CEACAM5. We further show that AR amplifications were associated with higher expression of PSMA and TROP2 but lower DLL3 and CEACAM5 levels. Conversely, PSMA and TROP2 expression was lower in RB1-altered tumors. In addition to genomic alterations, we demonstrate a tight correlation between epigenetic states, particularly histone H3 lysine 27 methylation (H3K27me3) at the transcriptional start site and gene body of TACSTD2 (encoding TROP2), DLL3, and CEACAM5, and their respective protein expression in CRPC patient-derived xenografts. Collectively, these findings provide novel insights into the patterns and determinants of expression of TROP2, DLL3, and CEACAM5 with important implications for the clinical development of cell surface targeting agents in CRPC.

Dataset Information

Genome-wide germline correlates of the epigenetic landscape of prostate cancer.

Publications

Genome-wide germline correlates of the epigenetic landscape of prostate cancer.

Similar Datasets

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