Genome-Wide Testing of Putative Functional Exonic Variants in Relationship with Breast and Prostate Cancer Risk in a Multiethnic Population

<div><p>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 <i>LDLRAD1</i>, <i>SLC19A1</i>, <i>FGFBP3</i>, <i>CASP5</i>, <i>MMAB</i>, <i>SLC16A6</i>, and <i>INS-IGF2</i>. In prostate cancer, one of the most associated SNPs was in the gene <i>GPRC6A</i> (rs2274911, <i>Pro91Ser</i>, 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 <i>F13A1</i>, <i>ANXA4</i>, <i>MANSC1</i>, and <i>GP6.</i> 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 <i>LDLRAD1</i>, 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.</p> </div

The Most Significant Associations of Gene Burden of Coding Variants with Prostate Cancer Risk.

<p>The Most Significant Associations of Gene Burden of Coding Variants with Prostate Cancer Risk.</p

The Descriptive Characteristics of the Multiethnic Case-Control Studies of Breast and Prostate Cancer.

<p>The Descriptive Characteristics of the Multiethnic Case-Control Studies of Breast and Prostate Cancer.</p

Number of polymorphic putative functional variants by racial/ethnic group.

<p>Number of polymorphic putative functional variants by racial/ethnic group.</p

The Most Significant Associations of Each Gene's Burden of Coding Variants with Breast Cancer Risk.

<p>The Most Significant Associations of Each Gene's Burden of Coding Variants with Breast Cancer Risk.</p

The Most Significant Associations of Single Coding Variants with Breast Cancer Risk.

a<p>SNP ID from HG19.</p>b<p>Position based on GRCh37.</p>c<p>A1 is minor allele based on the entire multiethnic sample and the tested allele, A2 is the reference allele.</p>d<p>Odds ratio per allele based on the pooled analysis adjusted for age and the first 10 principle components.</p>e<p>MAF is minor allele frequency in controls.</p><p>AA, African Americans; NH, Native Hawaiians; JA, Japanese Americans; LA, Latinos; EA, European Americans; SP, splice-site variant.</p

Minor allele frequency for all variants successfully genotyped using the Illumina Human Exome array.

<p>Minor allele frequency for all variants successfully genotyped using the Illumina Human Exome array.</p

The Most Significant Associations of Single Coding Variants with Prostate Cancer Risk.

a<p>SNP ID from db135.</p>b<p>Position based on GRCh37.</p>c<p>A1 is minor allele based on the entire multiethnic sample and the tested allele, A2 is the reference allele.</p>d<p>Odds ratio per allele based on the pooled analysis adjusted for age and the first 10 principle components.</p>e<p>MAF is minor allele frequency in controls.</p><p>AA, African Americans; NH, Native Hawaiians; JA, Japanese Americans; LA, Latinos; EA, European Americans; SP, splice-site variant.</p

Custom Content Variants Before and After Design.

<p>Custom Content Variants Before and After Design.</p

List of Prioritized Genes by Trait.

<p>List of Prioritized Genes by Trait.</p