Genome-wide association studies (GWAS) have revolutionized the field of cancer genetics, but the causal links between increased genetic risk and onset/progression of disease processes remain to be ...identified. Here we report the first step in such an endeavor for prostate cancer. We provide a comprehensive annotation of the 77 known risk loci, based upon highly correlated variants in biologically relevant chromatin annotations--we identified 727 such potentially functional SNPs. We also provide a detailed account of possible protein disruption, microRNA target sequence disruption and regulatory response element disruption of all correlated SNPs at r(2) ≥ 0.88%. 88% of the 727 SNPs fall within putative enhancers, and many alter critical residues in the response elements of transcription factors known to be involved in prostate biology. We define as risk enhancers those regions with enhancer chromatin biofeatures in prostate-derived cell lines with prostate-cancer correlated SNPs. To aid the identification of these enhancers, we performed genomewide ChIP-seq for H3K27-acetylation, a mark of actively engaged enhancers, as well as the transcription factor TCF7L2. We analyzed in depth three variants in risk enhancers, two of which show significantly altered androgen sensitivity in LNCaP cells. This includes rs4907792, that is in linkage disequilibrium (r(2) = 0.91) with an eQTL for NUDT11 (on the X chromosome) in prostate tissue, and rs10486567, the index SNP in intron 3 of the JAZF1 gene on chromosome 7. Rs4907792 is within a critical residue of a strong consensus androgen response element that is interrupted in the protective allele, resulting in a 56% decrease in its androgen sensitivity, whereas rs10486567 affects both NKX3-1 and FOXA-AR motifs where the risk allele results in a 39% increase in basal activity and a 28% fold-increase in androgen stimulated enhancer activity. Identification of such enhancer variants and their potential target genes represents a preliminary step in connecting risk to disease process.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Multiple discrete regions at 8q24 were recently shown to contain alleles that predispose to many cancers including prostate, breast, and colon. These regions are far from any annotated gene and their ...biological activities have been unknown. Here we profiled a 5-megabase chromatin segment encompassing all the risk regions for RNA expression, histone modifications, and locations occupied by RNA polymerase II and androgen receptor (AR). This led to the identification of several transcriptional enhancers, which were verified using reporter assays. Two enhancers in one risk region were occupied by AR and responded to androgen treatment; one contained a single nucleotide polymorphism (rs11986220) that resides within a FoxA1 binding site, with the prostate cancer risk allele facilitating both stronger FoxA1 binding and stronger androgen responsiveness. The study reported here exemplifies an approach that may be applied to any risk-associated allele in non-protein coding regions as it emerges from genome-wide association studies to better understand the genetic predisposition of complex diseases.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Adiposity traits have been associated with risk of many cancers in observational studies, but whether these associations are causal is unclear. Mendelian randomization (MR) uses genetic predictors of ...risk factors as instrumental variables to eliminate reverse causation and reduce confounding bias. We performed MR analyses to assess the possible causal relationship of birthweight, childhood and adult body mass index (BMI), and waist-hip ratio (WHR) on the risks of breast, ovarian, prostate, colorectal and lung cancers.
We tested the association between genetic risk scores and each trait using summary statistics from published genome-wide association studies (GWAS) and from 51 537 cancer cases and 61 600 controls in the Genetic Associations and Mechanisms in Oncology (GAME-ON) Consortium.
We found an inverse association between the genetic score for childhood BMI and risk of breast cancer odds ratio (OR) = 0.71 per standard deviation (s.d.) increase in childhood BMI; 95% confidence interval (CI): 0.60, 0.80; P = 6.5 × 10(-5)). We also found the genetic score for adult BMI to be inversely associated with breast cancer risk (OR = 0.66 per s.d. increase in BMI; 95% CI: 0.57, 0.77; P = 2.5 × 10(-7)), and positively associated with ovarian cancer (OR = 1.35; 95% CI: 1.05, 1.72; P = 0.017), lung cancer (OR = 1.27; 95% CI: 1.09, 1.49; P = 2.9 × 10(-3)) and colorectal cancer (OR = 1.39; 95% CI: 1.06, 1.82, P = 0.016). The inverse association between genetically predicted adult BMI and breast cancer risk remained even after adjusting for directional pleiotropy via MR-Egger regression.
Findings from this study provide additional understandings of the complex relationship between adiposity and cancer risks. Our results for breast and lung cancer are particularly interesting, given previous reports of effect heterogeneity by menopausal status and smoking status.
It has been recently hypothesized that many of the signals detected in genome-wide association studies (GWAS) to T2D and other diseases, despite being observed to common variants, might in fact ...result from causal mutations that are rare. One prediction of this hypothesis is that the allelic associations should be population-specific, as the causal mutations arose after the migrations that established different populations around the world. We selected 19 common variants found to be reproducibly associated to T2D risk in European populations and studied them in a large multiethnic case-control study (6,142 cases and 7,403 controls) among men and women from 5 racial/ethnic groups (European Americans, African Americans, Latinos, Japanese Americans, and Native Hawaiians). In analysis pooled across ethnic groups, the allelic associations were in the same direction as the original report for all 19 variants, and 14 of the 19 were significantly associated with risk. In summing the number of risk alleles for each individual, the per-allele associations were highly statistically significant (P<10(-4)) and similar in all populations (odds ratios 1.09-1.12) except in Japanese Americans the estimated effect per allele was larger than in the other populations (1.20; P(het) = 3.8×10(-4)). We did not observe ethnic differences in the distribution of risk that would explain the increased prevalence of type 2 diabetes in these groups as compared to European Americans. The consistency of allelic associations in diverse racial/ethnic groups is not predicted under the hypothesis of Goldstein regarding "synthetic associations" of rare mutations in T2D.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Background: Healthy dietary patterns have been linked positively with health and longevity. However, prospective studies in diverse populations in the United States addressing dietary patterns and ...mortality are limited. Objective: We assessed the ability of the following 4 diet-quality indexes the Healthy Eating Index-2010 (HEI-2010), the Alternative HEI-2010 (AHEI-2010), the alternate Mediterranean diet score (aMED), and the Dietary Approaches to Stop Hypertension (DASH) to predict the reduction in risk of mortality from all causes, cardiovascular disease (CVD), and cancer. Design: White, African American, Native Hawaiian, Japanese American, and Latino adults (n = 215,782) from the Multiethnic Cohort completed a quantitative food-frequency questionnaire. Scores for each dietary index were computed and divided into quintiles for men and women. Mortality was documented over 13–18 y of follow-up. HRs and 95% CIs were computed by using adjusted Cox models. Results: High HEI-2010, AHEI-2010, aMED, and DASH scores were all inversely associated with risk of mortality from all causes, CVD, and cancer in both men and women (P -trend < 0.0001 for all models). For men, the HEI-2010 was consistently associated with a reduction in risk of mortality for all causes (HR: 0.75; 95% CI: 0.71, 0.79), CVD (HR: 0.74; 95% CI: 0.69, 0.81), and cancer (HR: 0.76; 95% CI: 0.70, 0.83) when lowest and highest quintiles were compared. In women, the AHEI and aMED showed large reductions for all-cause mortality (HR: 0.78; 95% CI: 0.74, 0.82), the AHEI showed large reductions for CVD (HR: 0.76; 95% CI: 0.69, 0.83), and the aMED showed large reductions for cancer (HR: 0.84; 95% CI: 0.76, 0. 92). Conclusion: These results, in a US multiethnic population, suggest that consuming a dietary pattern that achieves a high diet-quality index score is associated with lower risk of mortality from all causes, CVD, and cancer in adult men and women.
An improved model for risk stratification can be useful for guiding public health strategies of breast cancer prevention.
To evaluate combined risk stratification utility of common low penetrant ...single nucleotide polymorphisms (SNPs) and epidemiologic risk factors.
Using a total of 17 171 cases and 19 862 controls sampled from the Breast and Prostate Cancer Cohort Consortium (BPC3) and 5879 women participating in the 2010 National Health Interview Survey, a model for predicting absolute risk of breast cancer was developed combining information on individual level data on epidemiologic risk factors and 24 genotyped SNPs from prospective cohort studies, published estimate of odds ratios for 68 additional SNPs, population incidence rate from the National Cancer Institute-Surveillance, Epidemiology, and End Results Program cancer registry and data on risk factor distribution from nationally representative health survey. The model is used to project the distribution of absolute risk for the population of white women in the United States after adjustment for competing cause of mortality.
Single nucleotide polymorphisms, family history, anthropometric factors, menstrual and/or reproductive factors, and lifestyle factors.
Degree of stratification of absolute risk owing to nonmodifiable (SNPs, family history, height, and some components of menstrual and/or reproductive history) and modifiable factors (body mass index BMI; calculated as weight in kilograms divided by height in meters squared, menopausal hormone therapy MHT, alcohol, and smoking).
The average absolute risk for a 30-year-old white woman in the United States developing invasive breast cancer by age 80 years is 11.3%. A model that includes all risk factors provided a range of average absolute risk from 4.4% to 23.5% for women in the bottom and top deciles of the risk distribution, respectively. For women who were at the lowest and highest deciles of nonmodifiable risks, the 5th and 95th percentile range of the risk distribution associated with 4 modifiable factors was 2.9% to 5.0% and 15.5% to 25.0%, respectively. For women in the highest decile of risk owing to nonmodifiable factors, those who had low BMI, did not drink or smoke, and did not use MHT had risks comparable to an average woman in the general population.
This model for absolute risk of breast cancer including SNPs can provide stratification for the population of white women in the United States. The model can also identify subsets of the population at an elevated risk that would benefit most from risk-reduction strategies based on altering modifiable factors. The effectiveness of this model for individual risk communication needs further investigation.
Genetic factors play an important role in the etiology of both sporadic and familial breast cancer. We aimed to discover novel genetic susceptibility loci for breast cancer. We conducted a four-stage ...genome-wide association study (GWAS) in 19,091 cases and 20,606 controls of East-Asian descent including Chinese, Korean, and Japanese women. After analyzing 690,947 SNPs in 2,918 cases and 2,324 controls, we evaluated 5,365 SNPs for replication in 3,972 cases and 3,852 controls. Ninety-four SNPs were further evaluated in 5,203 cases and 5,138 controls, and finally the top 22 SNPs were investigated in up to 17,423 additional subjects (7,489 cases and 9,934 controls). SNP rs9485372, near the TGF-β activated kinase (TAB2) gene in chromosome 6q25.1, showed a consistent association with breast cancer risk across all four stages, with a P-value of 3.8×10(-12) in the combined analysis of all samples. Adjusted odds ratios (95% confidence intervals) were 0.89 (0.85-0.94) and 0.80 (0.75-0.86) for the A/G and A/A genotypes, respectively, compared with the genotype G/G. SNP rs9383951 (P = 1.9×10(-6) from the combined analysis of all samples), located in intron 5 of the ESR1 gene, and SNP rs7107217 (P = 4.6×10(-7)), located at 11q24.3, also showed a consistent association in each of the four stages. This study provides strong evidence for a novel breast cancer susceptibility locus represented by rs9485372, near the TAB2 gene (6q25.1), and identifies two possible susceptibility loci located in the ESR1 gene and 11q24.3, respectively.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
In a population of almost 184,000 prospectively studied participants, the risk of lung cancer was ascertained according to the level of cigarette smoking and ethnic or racial background. Among those ...who smoked no more than 30 cigarettes per day, the relative risk of lung cancer was highest among African Americans and native Hawaiians, as compared with whites, Hispanics, and Japanese Americans.
Among those who smoked no more than 30 cigarettes per day, the relative risk of lung cancer was highest among African Americans and native Hawaiians, as compared with whites, Hispanics, and Japanese Americans.
The incidence of lung cancer is substantially higher among blacks, Native Hawaiians, and other Polynesians and lower among Japanese Americans and Hispanics than among whites in the United States.
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The vast majority (80 to 90 percent) of these cases are attributable to cigarette smoking. Smoking behavior also varies widely among these ethnic and racial groups. In aggregated population surveys conducted in the United States, the age-adjusted prevalence of cigarette smoking was 30.1 percent among black adults and 27.3 percent among white adults.
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Only 8.0 percent of black smokers, however, were reported to be heavy smokers (smoking at least 25 cigarettes . . .
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.
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DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
A sizable fraction of colorectal cancer (CRC) is expected to be explained by heritable factors, with heritability estimates ranging from 12 to 35% twin and family studies. Genome-wide association ...studies (GWAS) have successfully identified a number of common single-nucleotide polymorphisms (SNPs) associated with CRC risk. Although it has been shown that these CRC susceptibility SNPs only explain a small proportion of the genetic risk, it is not clear how much of the heritability these SNPs explain and how much is left to be detected by other, yet to be identified, common SNPs. Therefore, we estimated the heritability of CRC under different scenarios using Genome-Wide Complex Trait Analysis in the Genetics and Epidemiology of Colorectal Cancer Consortium including 8025 cases and 10 814 controls. We estimated that the heritability explained by known common CRC SNPs identified in GWAS was 0.65% (95% CI:0.3-1%; P = 1.11 × 10-16), whereas the heritability explained by all common SNPs was at least 7.42% (95% CI: 4.71-10.12%; P = 8.13 × 10(-8)), suggesting that many common variants associated with CRC risk remain to be detected. Comparing the heritability explained by the common variants with that from twin and family studies, a fraction of the heritability may be explained by other genetic variants, such as rare variants. In addition, our analysis showed that the gene × smoking interaction explained a significant proportion of the CRC variance (P = 1.26 × 10(-2)). In summary, our results suggest that known CRC SNPs only explain a small proportion of the heritability and more common SNPs have yet to be identified.
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