title: Genome-wide testing of putative functional exonic variants in relationship with breast and prostate cancer risk in a multiethnic population.
abstract: Rare variation in protein coding sequence is poorly captured by GWAS arrays and has been hypothesized to contribute to disease heritability. Using the Illumina HumanExome SNP array, we successfully genotyped 191,032 common and rare non-synonymous, splice site, or nonsense variants in a multiethnic sample of 2,984 breast cancer cases, 4,376 prostate cancer cases, and 7,545 controls. In breast cancer, the strongest associations included either SNPs in or gene burden scores for genes LDLRAD1, SLC19A1, FGFBP3, CASP5, MMAB, SLC16A6, and INS-IGF2. In prostate cancer, one of the most associated SNPs was in the gene GPRC6A (rs2274911, Pro91Ser, OR = 0.88, P = 1.3 × 10(-5)) near to a known risk locus for prostate cancer; other suggestive associations were noted in genes such as F13A1, ANXA4, MANSC1, and GP6. For both breast and prostate cancer, several of the most significant associations involving SNPs or gene burden scores (sum of minor alleles) were noted in genes previously reported to be associated with a cancer-related phenotype. However, only one of the associations (rs145889899 in LDLRAD1, p = 2.5 × 10(-7) only seen in African Americans) for overall breast or prostate cancer risk was statistically significant after correcting for multiple comparisons. In addition to breast and prostate cancer, other cancer-related traits were examined (body mass index, PSA level, and alcohol drinking) with a number of known and potentially novel associations described. In general, these findings do not support there being many protein coding variants of moderate to high risk for breast and prostate cancer with odds ratios over a range that is probably required for protein coding variation to play a truly outstanding role in risk heritability. Very large sample sizes will be required to better define the role of rare and less penetrant coding variation in prostate and breast cancer disease genetics.
authors.affiliation: Department of Preventive Medicine, Keck School of Medicine and Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, California, United States of America. haiman@usc.edu
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Haiman
authors.forename: Ying
authors.initials: Y
authors.lastname: Han
authors.forename: Ye
authors.initials: Y
authors.lastname: Feng
authors.forename: Lucy
authors.initials: L
authors.lastname: Xia
authors.forename: Chris
authors.initials: C
authors.lastname: Hsu
authors.forename: Xin
authors.initials: X
authors.lastname: Sheng
authors.forename: Loreall C
authors.initials: LC
authors.lastname: Pooler
authors.forename: Yesha
authors.initials: Y
authors.lastname: Patel
authors.forename: Laurence N
authors.initials: LN
authors.lastname: Kolonel
authors.forename: Erin
authors.initials: E
authors.lastname: Carter
authors.forename: Karen
authors.initials: K
authors.lastname: Park
authors.forename: Loic
authors.initials: L
authors.lastname: Le Marchand
authors.forename: David
authors.initials: D
authors.lastname: Van Den Berg
authors.forename: Brian E
authors.initials: BE
authors.lastname: Henderson
authors.forename: Daniel O
authors.initials: DO
authors.lastname: Stram
mesh_terms: D001741:Black or African American / Q000235:genetics; D000368:Aged; D000483:Alleles; D001213:Asian / Q000235:genetics; D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology; D005091:Exons / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D015810:Linkage Disequilibrium; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000473:pathology; D012307:Risk Factors; D044465:White People
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