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Atlas of prostate cancer heritability in European and African-American men pinpoints tissue-specific regulation.

ABSTRACT: Although genome-wide association studies have identified over 100 risk loci that explain ∼33% of familial risk for prostate cancer (PrCa), their functional effects on risk remain largely unknown. Here we use genotype data from 59,089 men of European and African American ancestries combined with cell-type-specific epigenetic data to build a genomic atlas of single-nucleotide polymorphism (SNP) heritability in PrCa. We find significant differences in heritability between variants in prostate-relevant epigenetic marks defined in normal versus tumour tissue as well as between tissue and cell lines. The majority of SNP heritability lies in regions marked by H3k27 acetylation in prostate adenoc7arcinoma cell line (LNCaP) or by DNaseI hypersensitive sites in cancer cell lines. We find a high degree of similarity between European and African American ancestries suggesting a similar genetic architecture from common variation underlying PrCa risk. Our findings showcase the power of integrating functional annotation with genetic data to understand the genetic basis of PrCa.

SUBMITTER: Gusev A

PROVIDER: S-EPMC4829663 | biostudies-literature | 2016 Apr

REPOSITORIES: biostudies-literature

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Atlas of prostate cancer heritability in European and African-American men pinpoints tissue-specific regulation.

Gusev Alexander A Shi Huwenbo H Kichaev Gleb G Pomerantz Mark M Li Fugen F Long Henry W HW Ingles Sue A SA Kittles Rick A RA Strom Sara S SS Rybicki Benjamin A BA Nemesure Barbara B Isaacs William B WB Zheng Wei W Pettaway Curtis A CA Yeboah Edward D ED Tettey Yao Y Biritwum Richard B RB Adjei Andrew A AA Tay Evelyn E Truelove Ann A Niwa Shelley S Chokkalingam Anand P AP John Esther M EM Murphy Adam B AB Signorello Lisa B LB Carpten John J Leske M Cristina MC Wu Suh-Yuh SY Hennis Anslem J M AJ Neslund-Dudas Christine C Hsing Ann W AW Chu Lisa L Goodman Phyllis J PJ Klein Eric A EA Witte John S JS Casey Graham G Kaggwa Sam S Cook Michael B MB Stram Daniel O DO Blot William J WJ Eeles Rosalind A RA Easton Douglas D Kote-Jarai Zsofia Z Al Olama Ali Amin AA Benlloch Sara S Muir Kenneth K Giles Graham G GG Southey Melissa C MC Fitzgerald Liesel M LM Gronberg Henrik H Wiklund Fredrik F Aly Markus M Henderson Brian E BE Schleutker Johanna J Wahlfors Tiina T Tammela Teuvo L J TL Nordestgaard Børge G BG Key Tim J TJ Travis Ruth C RC Neal David E DE Donovan Jenny L JL Hamdy Freddie C FC Pharoah Paul P Pashayan Nora N Khaw Kay-Tee KT Stanford Janet L JL Thibodeau Stephen N SN McDonnell Shannon K SK Schaid Daniel J DJ Maier Christiane C Vogel Walther W Luedeke Manuel M Herkommer Kathleen K Kibel Adam S AS Cybulski Cezary C Wokolorczyk Dominika D Kluzniak Wojciech W Cannon-Albright Lisa L Teerlink Craig C Brenner Hermann H Dieffenbach Aida K AK Arndt Volker V Park Jong Y JY Sellers Thomas A TA Lin Hui-Yi HY Slavov Chavdar C Kaneva Radka R Mitev Vanio V Batra Jyotsna J Spurdle Amanda A Clements Judith A JA Teixeira Manuel R MR Pandha Hardev H Michael Agnieszka A Paulo Paula P Maia Sofia S Kierzek Andrzej A Conti David V DV Albanes Demetrius D Berg Christine C Berndt Sonja I SI Campa Daniele D Crawford E David ED Diver W Ryan WR Gapstur Susan M SM Gaziano J Michael JM Giovannucci Edward E Hoover Robert R Hunter David J DJ Johansson Mattias M Kraft Peter P Le Marchand Loic L Lindström Sara S Navarro Carmen C Overvad Kim K Riboli Elio E Siddiq Afshan A Stevens Victoria L VL Trichopoulos Dimitrios D Vineis Paolo P Yeager Meredith M Trynka Gosia G Raychaudhuri Soumya S Schumacher Frederick R FR Price Alkes L AL Freedman Matthew L ML Haiman Christopher A CA Pasaniuc Bogdan B

Nature communications 20160407

Although genome-wide association studies have identified over 100 risk loci that explain ∼33% of familial risk for prostate cancer (PrCa), their functional effects on risk remain largely unknown. Here we use genotype data from 59,089 men of European and African American ancestries combined with cell-type-specific epigenetic data to build a genomic atlas of single-nucleotide polymorphism (SNP) heritability in PrCa. We find significant differences in heritability between variants in prostate-relev ...[more]

PMID: 27052111

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Project description:The incidence and mortality rates of prostate cancer are significantly higher in African-American men when compared to European-American men. We tested the hypothesis that differences in tumor biology contribute to this survival health disparity. Using microarray technology, we obtained gene expression profiles of primary prostate tumors resected from 33 African-American and 36 European-American patients. These tumors were matched on clinical parameters. We also evaluated 18 non-tumor prostate tissues from 7 African-American and 11 European-American patients. The resulting datasets were analyzed for expression differences on the gene and pathway level comparing African-American with European-American patients. Our analysis revealed a significant number of genes, e.g., 162 transcripts at a false-discovery rate less than 5%, to be differently expressed between African-American and European-American patients. Using a disease association analysis, we identified a common relationship of these transcripts with autoimmunity and inflammation. These findings were corroborated on the pathway level with numerous differently expressed genes clustering in immune response, stress response, cytokine signaling, and chemotaxis pathways. Furthermore, a two-gene tumor signature was identified that accurately differentiated between African-American and European-American patients. This finding was confirmed in a blinded analysis of a second sample set. In conclusion, the gene expression profiles of prostate tumors indicate prominent differences in tumor immunobiology between African-American and European-American men. The profiles portray the existence of a distinct tumor microenvironment in these two patient groups. Experiment Overall Design: A total of 69 fresh-frozen prostate tumors were obtained from the NCI Cooperative Prostate Cancer Tissue Resource (CPCTR) and the Department of Pathology at the University of Maryland (UMD). All tumors were resected adenocarcinomas that had not received any therapy prior to prostatectomy. The macro-dissected CPCTR tumor specimens (n = 59) were reviewed by a CPCTR-associated pathologist, who confirmed the presence of tumor in the specimens. These tissues were collected between 2002 and 2004 at four different sites, with each site providing tissues from both African-American and European-American patients. Information on race/ethnicity (33 African-Americans and 36 European-Americans) was either extracted from medical records (CPCTR) or obtained through an epidemiological questionnaire in which race/ethnicity was self-reported (UMD). Only one patient, a European-American, was also Hispanic. Surrounding non-tumor prostate tissue was collected from 18 of the recruited patients in this study. Of those, 7 were African-American men and 11 were European-American men. We also isolated total RNA from 10 needle biopsy specimens collected from patients at the National Naval Medical Center (one African-American and 9 European-Americans) that did not have prostate cancer. From those, we prepared two RNA pools, each representing 5 patients. Clinicopathological characteristics of the patients, including age at prostatectomy, histology, Gleason score, pathological stage, PSA at diagnosis, tumor size, extraprostatic extension, margin involvement, and seminal vesicle invasion were obtained from CPCTR. For UMD cases, this information was extracted from the medical and pathology records, if available. Written informed consent was obtained from all donors. Tissue collection and study design were approved by the institutional review boards of the participating institutions.

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Atlas of prostate cancer heritability in European and African-American men pinpoints tissue-specific regulation.

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Atlas of prostate cancer heritability in European and African-American men pinpoints tissue-specific regulation.

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