title: Whole-exome sequencing of over 4100 men of African ancestry and prostate cancer risk.
abstract: Prostate cancer is the most common non-skin cancer in males, with a ∼1.5-2-fold higher incidence in African American men when compared with whites. Epidemiologic evidence supports a large heritable contribution to prostate cancer, with over 100 susceptibility loci identified to date that can explain ∼33% of the familial risk. To explore the contribution of both rare and common variation in coding regions to prostate cancer risk, we sequenced the exomes of 2165 prostate cancer cases and 2034 controls of African ancestry at a mean coverage of 10.1×. We identified 395 220 coding variants down to 0.05% frequency [57% non-synonymous (NS), 42% synonymous and 1% gain or loss of stop codon or splice site variant] in 16 751 genes with the strongest associations observed in SPARCL1 on 4q22.1 (rs13051, Ala49Asp, OR = 0.78, P = 1.8 × 10(-6)) and PTPRR on 12q15 (rs73341069, Val239Ile, OR = 1.62, P = 2.5 × 10(-5)). In gene-level testing, the two most significant genes were C1orf100 (P = 2.2 × 10(-4)) and GORAB (P = 2.3 × 10(-4)). We did not observe exome-wide significant associations (after correcting for multiple hypothesis testing) in single variant or gene-level testing in the overall case-control or case-case analyses of disease aggressiveness. In this first whole-exome sequencing study of prostate cancer, our findings do not provide strong support for the hypothesis that NS coding variants down to 0.5-1.0% frequency have large effects on prostate cancer risk in men of African ancestry. Higher-coverage sequencing efforts in larger samples will be needed to study rarer variants with smaller effect sizes associated with prostate cancer risk.
authors.affiliation: Department of Preventive Medicine, Keck School of Medicine, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA 90033, USA.
authors.forename: Kristin A
authors.initials: KA
authors.lastname: Rand
authors.affiliation: Department of Genetics, Harvard Medical School, Harvard University, Boston, MA 02115, USA, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
authors.forename: Nadin
authors.initials: N
authors.lastname: Rohland
authors.affiliation: Department of Genetics, Harvard Medical School, Harvard University, Boston, MA 02115, USA, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
authors.forename: Arti
authors.initials: A
authors.lastname: Tandon
authors.affiliation: Department of Preventive Medicine, Keck School of Medicine.
authors.forename: Alex
authors.initials: A
authors.lastname: Stram
authors.affiliation: Department of Preventive Medicine, Keck School of Medicine.
authors.forename: Xin
authors.initials: X
authors.lastname: Sheng
authors.affiliation: Department of Genetics, Harvard Medical School, Harvard University, Boston, MA 02115, USA, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
authors.forename: Ron
authors.initials: R
authors.lastname: Do
authors.affiliation: Bioinformatics Interdepartmental Program, Department of Human Genetics, David Geffen School of Medicine, Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Bogdan
authors.initials: B
authors.lastname: Pasaniuc
authors.affiliation: Department of Genetics, Harvard Medical School, Harvard University, Boston, MA 02115, USA, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
authors.forename: Alex
authors.initials: A
authors.lastname: Allen
authors.affiliation: Department of Genetics, Harvard Medical School, Harvard University, Boston, MA 02115, USA, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
authors.forename: Dominique
authors.initials: D
authors.lastname: Quinque
authors.affiliation: Department of Genetics, Harvard Medical School, Harvard University, Boston, MA 02115, USA, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA, Howard Hughes Medical Institute, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Swapan
authors.initials: S
authors.lastname: Mallick
authors.affiliation: Epidemiology Program, Cancer Research Center, University of Hawaii, Honolulu, HI 96813, USA.
authors.forename: Loic
authors.initials: L
authors.lastname: Le Marchand
authors.affiliation: Department of Surgery.
authors.forename: Sam
authors.initials: S
authors.lastname: Kaggwa
authors.affiliation: School of Public Health, Makerere University College of Health Sciences, Kampala, Uganda and.
authors.forename: Alex
authors.initials: A
authors.lastname: Lubwama
authors.affiliation: Department of Preventive Medicine, Keck School of Medicine, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA 90033, USA.
authors.forename: Daniel O
authors.initials: DO
authors.lastname: Stram
authors.affiliation: School of Public Health, Makerere University College of Health Sciences, Kampala, Uganda and Uro Care, Kampala, Uganda.
authors.forename: Stephen
authors.initials: S
authors.lastname: Watya
authors.affiliation: Department of Preventive Medicine, Keck School of Medicine, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA 90033, USA.
authors.forename: Brian E
authors.initials: BE
authors.lastname: Henderson
authors.affiliation: Department of Preventive Medicine, Keck School of Medicine, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA 90033, USA.
authors.forename: David V
authors.initials: DV
authors.lastname: Conti
authors.affiliation: Department of Genetics, Harvard Medical School, Harvard University, Boston, MA 02115, USA, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA, Howard Hughes Medical Institute, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: David
authors.initials: D
authors.lastname: Reich
authors.affiliation: Department of Preventive Medicine, Keck School of Medicine, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA 90033, USA, haiman@usc.edu.
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Haiman
mesh_terms: D000328:Adult; D000368:Aged; D044383:Black People / Q000235:genetics*; D059472:Exome; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D011471:Prostatic Neoplasms / Q000453:epidemiology / Q000235:genetics*; D012306:Risk; D017422:Sequence Analysis, DNA; D001741:Black or African American