Journal Article

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

Strom, Sara S., Chokkalingam, Anand P., Schumacher, Frederick R., Murphy, Adam B., Cybulski, Cezary, Mitev, Vanio, Witte, John S., Gusev, Alexander, Klein, Eric A., Trynka, Gosia, Cannon-Albright, Lisa, Carpten, John, Travis, Ruth C., Berg, Christine, Kibel, Adam S., Khaw, Kay-Tee, Teerlink, Craig, Wu, Suh-Yuh, Teixeira, Manuel R., Pettaway, Curtis A., Arndt, Volker, Price, Alkes L., Hamdy, Freddie C., Benlloch, Sara, Kote-Jarai, ZSofia, Schleutker, Johanna, Donovan, Jenny L., Stram, Daniel O., Fitzgerald, Liesel M., Shi, Huwenbo, Clements, Judith A., Maia, Sofia, Chu, Lisa, Kraft, Peter, Niwa, Shelley, Li, Fugen, Gapstur, Susan M., Nemesure, Barbara, Kichaev, Gleb, Ingles, Sue A., Pomerantz, Mark, Giles, Graham G., Berndt, Sonja I., Kittles, Rick A., Thibodeau, Stephen N., Wokolorczyk, Dominika, Kierzek, Andrzej, Park, Jong Y., Stanford, Janet L., Tay, Evelyn, Kaneva, Radka, Conti, David V., Kaggwa, Sam, Hoover, Robert, Leske, M. Cristina, McDonnell, Shannon K., Haiman, Christopher A., Key, Tim J., Long, Henry W., Johansson, Mattias, Henderson, Brian E., Vogel, Walther, Le Marchand, Loic, Kluzniak, Wojciech, N

2016

Overview

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. Over one hundred loci have been identified to be associated with the familial risk of prostate cancer but the functional effects are poorly understood. Here the authors use single-nucleotide variant and epigentic data to show an underlying genetic architecture marked by histone modification.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 631/1647/2217/2138 / 631/208/457 / 692/699/67/589/466 / Acetylation / Atlases as Topic / Black or African American / Cell Line, Tumor / Epigenesis, Genetic / Genetic Loci / Genetic Predisposition to Disease / Genome-Wide Association Study / Histones - genetics / Histones - metabolism / Humanities and Social Sciences / Humans / Inheritance Patterns / Linkage Disequilibrium / Male / multidisciplinary / Polymorphism, Single Nucleotide / Prostate cancer / Prostatic Neoplasms - ethnology / Prostatic Neoplasms - genetics / Prostatic Neoplasms - pathology / Science / Science (multidisciplinary) / White People