Xin Sheng

A common genetic risk factor for colorectal and prostate cancer

Variants on chromosome 8q24 contribute risk for prostate cancer; here, we tested whether they also modulate risk for colorectal cancer. We studied 1,807 affected individuals and 5,511 controls and found that one variant, rs6983267, is also significantly associated with colorectal cancer (odds ratio = 1.22; P = 4.4 × 10−6) and that the apportionment of risk among the variants differs significantly between the two cancers. Comprehensive testing in the region uncovered variants capturing significant additional risk. Our results show that variants at 8q24 have different effects on cancer development that depend on the tissue type.

Genome-wide association study of prostate cancer in men of African ancestry identifies a susceptibility locus at 17q21

In search of common risk alleles for prostate cancer that could contribute to high rates of the disease in men of African ancestry, we conducted a genome-wide association study, with 1,047,986 SNP markers examined in 3,425 African-Americans with prostate cancer (cases) and 3,290 African-American male controls. We followed up the most significant 17 new associations from stage 1 in 1,844 cases and 3,269 controls of African ancestry. We identified a new risk variant on chromosome 17q21 (rs7210100, odds ratio per allele = 1.51, P = 3.4 × 10−13). The frequency of the risk allele is ∼5% in men of African descent, whereas it is rare in other populations (<1%). Further studies are needed to investigate the biological contribution of this allele to prostate cancer risk. These findings emphasize the importance of conducting genome-wide association studies in diverse populations.

Characterizing Genetic Risk at Known Prostate Cancer Susceptibility Loci in African Americans

GWAS of prostate cancer have been remarkably successful in revealing common genetic variants and novel biological pathways that are linked with its etiology. A more complete understanding of inherited susceptibility to prostate cancer in the general population will come from continuing such discovery efforts and from testing known risk alleles in diverse racial and ethnic groups. In this large study of prostate cancer in African American men (3,425 prostate cancer cases and 3,290 controls), we tested 49 risk variants located in 28 genomic regions identified through GWAS in men of European and Asian descent, and we replicated associations (at p≤0.05) with roughly half of these markers. Through fine-mapping, we identified nearby markers in many regions that better define associations in African Americans. At 8q24, we found 9 variants (p≤6×10−4) that best capture risk of prostate cancer in African Americans, many of which are more common in men of African than European descent. The markers found to be associated with risk at each locus improved risk modeling in African Americans (per allele OR = 1.17) over the alleles reported in the original GWAS (OR = 1.08). In summary, in this detailed analysis of the prostate cancer risk loci reported from GWAS, we have validated and improved upon markers of risk in some regions that better define the association with prostate cancer in African Americans. Our findings with variants at 8q24 also reinforce the importance of this region as a major risk locus for prostate cancer in men of African ancestry.

Double-strand break damage and associated DNA repair genes predispose smokers to gene methylation.

Gene promoter hypermethylation in sputum is a promising biomarker for predicting lung cancer. Identifying factors that predispose smokers to methylation of multiple gene promoters in the lung could affect strategies for early detection and chemoprevention. This study evaluated the hypothesis that double-strand break (DSB) repair capacity and sequence variation in genes in this pathway are associated with a high methylation index in a cohort of current and former cancer-free smokers. A 50% reduction in the mean level of DSB repair capacity was seen in lymphocytes from smokers with a high methylation index, defined as three or more of eight genes methylated in sputum, compared with smokers with no genes methylated. The classification accuracy for predicting risk for methylation was 88%. Single nucleotide polymorphisms within the MRE11A, CHEK2, XRCC3, DNA-PKc, and NBN DNA repair genes were highly associated with the methylation index. A 14.5-fold increased odds for high methylation was seen for persons with seven or more risk alleles of these genes. Promoter activity of the MRE11A gene that plays a critical role in recognition of DNA damage and activation of ataxia-telangiectasia mutated was reduced in persons with the risk allele. Collectively, ours is the first population-based study to identify DSB DNA repair capacity and specific genes within this pathway as critical determinants for gene methylation in sputum, which is, in turn, associated with elevated risk for lung cancer.

The contribution of rare variation to prostate cancer heritability

We report targeted sequencing of 63 known prostate cancer risk regions in a multi-ancestry study of 9,237 men and use the data to explore the contribution of low-frequency variation to disease risk. We show that SNPs with minor allele frequencies (MAFs) of 0.1–1% explain a substantial fraction of prostate cancer risk in men of African ancestry. We estimate that these SNPs account for 0.12 (standard error (s.e.) = 0.05) of variance in risk (∼42% of the variance contributed by SNPs with MAF of 0.1–50%). This contribution is much larger than the fraction of neutral variation due to SNPs in this class, implying that natural selection has driven down the frequency of many prostate cancer risk alleles; we estimate the coupling between selection and allelic effects at 0.48 (95% confidence interval [0.19, 0.78]) under the Eyre-Walker model. Our results indicate that rare variants make a disproportionate contribution to genetic risk for prostate cancer and suggest the possibility that rare variants may also have an outsize effect on other common traits.

Genome-wide testing of putative functional exonic variants in relationship with breast and prostate cancer risk in a multiethnic population.

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.

Evaluating genetic risk for prostate cancer among Japanese and Latinos

Background: There have been few genome-wide association studies (GWAS) of prostate cancer among diverse populations. To search for novel prostate cancer risk variants, we conducted GWAS of prostate cancer in Japanese and Latinos. In addition, we tested prostate cancer risk variants and developed genetic risk models of prostate cancer for Japanese and Latinos. Methods: Our first-stage GWAS of prostate cancer included Japanese (cases/controls = 1,033/1,042) and Latino (cases/controls = 1,043/1,057) from the Multiethnic Cohort (MEC). Significant associations from stage I (P < 1.0 × 10−4) were examined in silico in GWAS of prostate cancer (stage II) in Japanese (cases/controls = 1,583/3,386) and Europeans (cases/controls = 1,854/1,894). Results: No novel stage I single-nucleotide polymorphism (SNP) outside of known risk regions reached genome-wide significance. For Japanese, in stage I, the most notable putative novel association was seen with 10 SNPs (P ≤ 8.0 × 10−6) at chromosome 2q33; however, this was not replicated in stage II. For Latinos, the most significant association was observed with rs17023900 at the known 3p12 risk locus (stage I: OR = 1.45; P = 7.01 × 10−5 and stage II: OR = 1.58; P = 3.05 × 10−7). The majority of the established risk variants for prostate cancer, 79% and 88%, were positively associated with prostate cancer in Japanese and Latinos (stage I), respectively. The cumulative effects of these variants significantly influence prostate cancer risk (OR per allele = 1.10; P = 2.71 × 10−25 and OR = 1.07; P = 1.02 × 10−16 for Japanese and Latinos, respectively). Conclusion and Impact: Our GWAS of prostate cancer did not identify novel genome-wide significant variants. However, our findings show that established risk variants for prostate cancer significantly contribute to risk among Japanese and Latinos. Cancer Epidemiol Biomarkers Prev; 21(11); 2048–58. ©2012 AACR.

Genome-wide association study of endometrial cancer in E2C2

Endometrial cancer (EC), a neoplasm of the uterine epithelial lining, is the most common gynecological malignancy in developed countries and the fourth most common cancer among US women. Women with a family history of EC have an increased risk for the disease, suggesting that inherited genetic factors play a role. We conducted a two-stage genome-wide association study of Type I EC. Stage 1 included 5,472 women (2,695 cases and 2,777 controls) of European ancestry from seven studies. We selected independent single-nucleotide polymorphisms (SNPs) that displayed the most significant associations with EC in Stage 1 for replication among 17,948 women (4,382 cases and 13,566 controls) in a multiethnic population (African America, Asian, Latina, Hawaiian and European ancestry), from nine studies. Although no novel variants reached genome-wide significance, we replicated previously identified associations with genetic markers near the HNF1B locus. Our findings suggest that larger studies with specific tumor classification are necessary to identify novel genetic polymorphisms associated with EC susceptibility.

Prostate cancer susceptibility in men of African ancestry at 8q24

The 8q24 region harbors multiple risk variants for distinct cancers, including >8 for prostate cancer. In this study, we conducted fine mapping of the 8q24 risk region (127.8-128.8Mb) in search of novel associations with common and rare variation in 4853 prostate cancer case patients and 4678 control subjects of African ancestry. All statistical tests were two-sided. We identified three independent associations at P values of less than 5.00×10(-8), all of which were replicated in studies from Ghana and Uganda (combined sample = 5869 case patients, 5615 control subjects; rs114798100: risk allele frequency [RAF] = 0.04, per-allele odds ratio [OR] = 2.31, 95% confidence interval [CI] = 2.04 to 2.61, P = 2.38×10(-40); rs72725879: RAF = 0.33, OR = 1.37, 95% CI = 1.30 to 1.45, P = 3.04×10(-27); and rs111906932: RAF = 0.03, OR = 1.79, 95% CI = 1.53 to 2.08, P = 1.39×10(-13)). Risk variants rs114798100 and rs111906923 are only found in men of African ancestry, with rs111906923 representing a novel association signal. The three variants are located within or near a number of prostate cancer-associated long noncoding RNAs (lncRNAs), including PRNCR1, PCAT1, and PCAT2. These findings highlight ancestry-specific risk variation and implicate prostate-specific lncRNAs at the 8q24 prostate cancer susceptibility region.

Screening and association testing of common coding variation in steroid hormone receptor co-activator and co-repressor genes in relation to breast cancer risk: the Multiethnic Cohort

BackgroundOnly a limited number of studies have performed comprehensive investigations of coding variation in relation to breast cancer risk. Given the established role of estrogens in breast cancer, we hypothesized that coding variation in steroid receptor coactivator and corepressor genes may alter inter-individual response to estrogen and serve as markers of breast cancer risk.MethodsWe sequenced the coding exons of 17 genes (EP300, CCND1, NME1, NCOA1, NCOA2, NCOA3, SMARCA4, SMARCA2, CARM1, FOXA1, MPG, NCOR1, NCOR2, CALCOCO1, PRMT1, PPARBP and CREBBP) suggested to influence transcriptional activation by steroid hormone receptors in a multiethnic panel of women with advanced breast cancer (n = 95): African Americans, Latinos, Japanese, Native Hawaiians and European Americans. Association testing of validated coding variants was conducted in a breast cancer case-control study (1,612 invasive cases and 1,961 controls) nested in the Multiethnic Cohort. We used logistic regression to estimate odds ratios for allelic effects in ethnic-pooled analyses as well as in subgroups defined by disease stage and steroid hormone receptor status. We also investigated effect modification by established breast cancer risk factors that are associated with steroid hormone exposure.ResultsWe identified 45 coding variants with frequencies ≥ 1% in any one ethnic group (43 non-synonymous variants). We observed nominally significant positive associations with two coding variants in ethnic-pooled analyses (NCOR2: His52Arg, OR = 1.79; 95% CI, 1.05–3.05; CALCOCO1: Arg12His, OR = 2.29; 95% CI, 1.00–5.26). A small number of variants were associated with risk in disease subgroup analyses and we observed no strong evidence of effect modification by breast cancer risk factors. Based on the large number of statistical tests conducted in this study, the nominally significant associations that we observed may be due to chance, and will need to be confirmed in other studies.ConclusionOur findings suggest that common coding variation in these candidate genes do not make a substantial contribution to breast cancer risk in the general population. Cataloging and testing of coding variants in coactivator and corepressor genes should continue and may serve as a valuable resource for investigations of other hormone-related phenotypes, such as inter-individual response to hormonal therapies used for cancer treatment and prevention.