The association of cigarette smoking with DNA methylation and gene expression in human tissue samples.

Cigarette smoking adversely affects many aspects of human health, and epigenetic responses to smoking may reflect mechanisms that mediate or defend against these effects. Prior studies of smoking and DNA methylation (DNAm), typically measured in leukocytes, have identified numerous smoking-associated regions (e.g., AHRR). To identify smoking-associated DNAm features in typically inaccessible tissues, we generated array-based DNAm data for 916 tissue samples from the GTEx (Genotype-Tissue Expression) project representing 9 tissue types (lung, colon, ovary, prostate, blood, breast, testis, kidney, and muscle). We identified 6,350 smoking-associated CpGs in lung tissue (n = 212) and 2,735 in colon tissue (n = 210), most not reported previously. For all 7 other tissue types (sample sizes 38-153), no clear associations were observed (false discovery rate 0.05), but some tissues showed enrichment for smoking-associated CpGs reported previously. For 1,646 loci (in lung) and 22 (in colon), smoking was associated with both DNAm and local gene expression. For loci detected in both lung and colon (e.g., AHRR, CYP1B1, CYP1A1), top CpGs often differed between tissues, but similar clusters of hyper- or hypomethylated CpGs were observed, with hypomethylation at regulatory elements corresponding to increased expression. For lung tissue, 17 hallmark gene sets were enriched for smoking-associated CpGs, including xenobiotic- and cancer-related gene sets. At least four smoking-associated regions in lung were impacted by lung methylation quantitative trait loci (QTLs) that co-localize with genome-wide association study (GWAS) signals for lung function (FEV1/FVC), suggesting epigenetic alterations can mediate the effects of smoking on lung health. Our multi-tissue approach has identified smoking-associated regions in disease-relevant tissues, including effects that are shared across tissue types.

The Impact of Inherited Genetic Variation on DNA Methylation in Prostate Cancer and Benign Tissues of African American and European American Men.

BACKGROUND: American men of African ancestry (AA) have higher prostate cancer incidence and mortality rates compared with American men of European ancestry (EA). Differences in genetic susceptibility mechanisms may contribute to this disparity. METHODS: To gain insights into the regulatory mechanisms of prostate cancer susceptibility variants, we tested the association between SNPs and DNA methylation (DNAm) at nearby CpG sites across the genome in benign and cancer prostate tissue from 74 AA and 74 EA men. Genome-wide SNP data (from benign tissue) and DNAm were generated using Illumina arrays. RESULTS: Among AA men, we identified 6,298 and 2,641 cis-methylation QTLs (meQTL; FDR of 0.05) in benign and tumor tissue, respectively, with 6,960 and 1,700 detected in EA men. We leveraged genome-wide association study (GWAS) summary statistics to identify previously reported prostate cancer GWAS signals likely to share a common causal variant with a detected meQTL. We identified nine GWAS-meQTL pairs with strong evidence of colocalization (four in EA benign, three in EA tumor, two in AA benign, and three in AA tumor). Among these colocalized GWAS-meQTL pairs, we identified colocalizing expression quantitative trait loci (eQTL) impacting four eGenes with known roles in tumorigenesis. CONCLUSIONS: These findings highlight epigenetic regulatory mechanisms by which prostate cancer-risk SNPs can modify local DNAm and/or gene expression in prostate tissue. IMPACT: Overall, our findings showed general consistency in the meQTL landscape of AA and EA men, but meQTLs often differ by tissue type (normal vs. cancer). Ancestry-based linkage disequilibrium differences and lack of AA representation in GWAS decrease statistical power to detect colocalization for some regions.

Genome-wide association study of prostate-specific antigen levels in 392,522 men identifies new loci and improves cross-ancestry prediction.

We conducted a multi-ancestry genome-wide association study of prostate-specific antigen (PSA) levels in 296,754 men (211,342 European ancestry; 58,236 African ancestry; 23,546 Hispanic/Latino; 3,630 Asian ancestry; 96.5% of participants were from the Million Veteran Program). We identified 318 independent genome-wide significant (p≤5e-8) variants, 184 of which were novel. Most demonstrated evidence of replication in an independent cohort (n=95,768). Meta-analyzing discovery and replication (n=392,522) identified 447 variants, of which a further 111 were novel. Out-of-sample variance in PSA explained by our new polygenic risk score reached 16.9% (95% CI=16.1%-17.8%) in European ancestry, 9.5% (95% CI=7.0%-12.2%) in African ancestry, 18.6% (95% CI=15.8%-21.4%) in Hispanic/Latino, and 15.3% (95% CI=12.7%-18.1%) in Asian ancestry, and lower for higher age. Our study highlights how including proportionally more participants from underrepresented populations improves genetic prediction of PSA levels, with potential to personalize prostate cancer screening.

Sequencing-based fine-mapping and in silico functional characterization of the 10q24.32 arsenic metabolism efficiency locus across multiple arsenic-exposed populations.

Inorganic arsenic is highly toxic and carcinogenic to humans. Exposed individuals vary in their ability to metabolize arsenic, and variability in arsenic metabolism efficiency (AME) is associated with risks of arsenic-related toxicities. Inherited genetic variation in the 10q24.32 region, near the arsenic methyltransferase (AS3MT) gene, is associated with urine-based measures of AME in multiple arsenic-exposed populations. To identify potential causal variants in this region, we applied fine mapping approaches to targeted sequencing data generated for exposed individuals from Bangladeshi, American Indian, and European American populations (n = 2,357, 557, and 648 respectively). We identified three independent association signals for Bangladeshis, two for American Indians, and one for European Americans. The size of the confidence sets for each signal varied from 4 to 85 variants. There was one signal shared across all three populations, represented by the same SNP in American Indians and European Americans (rs191177668) and in strong linkage disequilibrium (LD) with a lead SNP in Bangladesh (rs145537350). Beyond this shared signal, differences in LD patterns, minor allele frequency (MAF) (e.g., rs12573221 ~13% in Bangladesh ~0.2% among American Indians), and/or heterogeneity in effect sizes across populations likely contributed to the apparent population specificity of the additional identified signals. One of our potential causal variants influences AS3MT expression and nearby DNA methylation in numerous GTEx tissue types (with rs4919690 as a likely causal variant). Several SNPs in our confidence sets overlap transcription factor binding sites and cis-regulatory elements (from ENCODE). Taken together, our analyses reveal multiple potential causal variants in the 10q24.32 region influencing AME, including a variant shared across populations, and elucidate potential biological mechanisms underlying the impact of genetic variation on AME.

Somatic loss of the Y chromosome is associated with arsenic exposure among Bangladeshi men.

BACKGROUND: Arsenic exposure increases the risk of several cancers in humans and contributes to genomic instability. Somatic loss of the Y chromosome (LoY) is a potential biomarker of genomic instability and cancer risk. Smoking is associated with LoY, but few other carcinogens have been investigated. We tested the cross-sectional association between arsenic exposure and LoY in leukocytes among genotyped Bangladeshi men (age 20-70 years) from the Health Effects of Arsenic Longitudinal Study. METHODS: We extracted the median of logR-ratios from probes on the Y chromosome (mLRR-chrY) from genotyping arrays (n = 1364) and estimated the percentage of cells with LoY (% LoY) from mLRR-chrY. We evaluated the association between arsenic exposure (measured in drinking water and urine) and LoY using multivariable linear and logistic regression models. The association between LoY and incident arsenic-induced skin lesions was also examined. RESULTS: Ten percent of genotyped men had LoY in at least 5% of cells and % LoY increased with age. Among men randomly selected for genotyping (n = 778), higher arsenic in drinking water, arsenic consumed and urinary arsenic were associated with increased % LoY (P = 0.006, P = 0.06 and P = 0.13, respectively). LoY was associated with increased risk of incident skin lesions (P = 0.008). CONCLUSION: Arsenic exposure was associated with increased LoY, providing additional evidence that arsenic contributes to genomic instability. LoY was associated with developing skin lesions, a risk factor for cancer, suggesting that LoY may be a biomarker of susceptibility in arsenic-exposed populations. The effect of arsenic on somatic events should be further explored in cancer-prone tissue types.

Inherited genetic effects on arsenic metabolism: A comparison of effects on arsenic species measured in urine and in blood.

Inorganic arsenic (iAs) is a carcinogen, and chronic exposure is associated with adverse health outcomes, including cancer and cardiovascular disease. Consumed iAs can undergo two methylation reactions catalyzed by arsenic methyltransferase (AS3MT), producing monomethylated and dimethylated forms of arsenic (MMA and DMA). Methylation of iAs helps facilitate excretion of arsenic in urine, with DMA composing the majority of arsenic species excreted. Past studies have identified genetic variation in the AS3MT (10q24.32) and FTCD (21q22.3) regions associated with arsenic metabolism efficiency (AME), measured as the proportion of each species present in urine (iAs%, MMA%, and DMA%), but their association with arsenic species present in blood has not been examined. We use data from three studies nested within the Health Effects and Longitudinal Study (HEALS)-the Nutritional Influences on Arsenic Toxicity Study, the Folate and Oxidative Stress study, and the Folic Acid and Creatine Trial-to examine the association of previously identified genetic variants with arsenic species in both urine and blood of 334 individuals. We confirm that the genetic variants in AS3MT and FTCD known to effect arsenic species composition in urine (an excreted byproduct of metabolism) have similar effects on arsenic species in blood (a tissue type that directly interacts with many organs, including those prone to arsenic toxicity). This consistency we observe provides further support for the hypothesis the AME SNPs identified to date impact the efficiency of arsenic metabolism and elimination, thereby influencing internal dose of arsenic and the dose delivered to toxicity-prone organs and tissues.

Relative Telomere Length Change in Colorectal Carcinoma and Its Association with Tumor Characteristics, Gene Expression and Microsatellite Instability.

We compared tumor and adjacent normal tissue samples from 165 colorectal carcinoma (CRC) patients to study change in relative telomere length (RTL) and its association with different histological and molecular features. To measure RTL, we used a Luminex-based assay. We observed shorter RTL in the CRC tissue compared to paired normal tissue (RTL 0.722 ± SD 0.277 vs. 0.809 ± SD 0.242, p = 0.00012). This magnitude of RTL shortening (by ~0.08) in tumor tissue is equivalent to RTL shortening seen in human leukocytes over 10 years of aging measured by the same assay. RTL was shorter in cancer tissue, irrespective of age group, gender, tumor pathology, location and microsatellite instability (MSI) status. RTL shortening was more prominent in low-grade CRC and in the presence of microsatellite instability (MSI). In a subset of patients, we also examined differential gene expression of (a) telomere-related genes, (b) genes in selected cancer-related pathways and (c) genes at the genome-wide level in CRC tissues to determine the association between gene expression and RTL changes. RTL shortening in CRC was associated with (a) upregulation of DNA replication genes, cyclin dependent-kinase genes (anti-tumor suppressor) and (b) downregulation of "caspase executor", reducing apoptosis.

The aging epigenome.

A new approach helps to assess the impact of accelerated epigenetic aging on the risk of cancer.

Rare, Protein-Altering Variants in AS3MT and Arsenic Metabolism Efficiency: A Multi-Population Association Study.

BACKGROUND: Common genetic variation in the arsenic methyltransferase (AS3MT) gene region is known to be associated with arsenic metabolism efficiency (AME), measured as the percentage of dimethylarsinic acid (DMA%) in the urine. Rare, protein-altering variants in AS3MT could have even larger effects on AME, but their contribution to AME has not been investigated. OBJECTIVES: We estimated the impact of rare, protein-coding variation in AS3MT on AME using a multi-population approach to facilitate the discovery of population-specific and shared causal rare variants. METHODS: We generated targeted DNA sequencing data for the coding regions of AS3MT for three arsenic-exposed cohorts with existing data on arsenic species measured in urine: Health Effects of Arsenic Longitudinal Study (HEALS, n=2,434), Strong Heart Study (SHS, n=868), and New Hampshire Skin Cancer Study (NHSCS, n=666). We assessed the collective effects of rare (allele frequency <1%), protein-altering AS3MT variants on DMA%, using multiple approaches, including a test of the association between rare allele carrier status (yes/no) and DMA% using linear regression (adjusted for common variants in 10q24.32 region, age, sex, and population structure). RESULTS: We identified 23 carriers of rare-protein-altering AS3MT variant across all cohorts (13 in HEALS and 5 in both SHS and NHSCS), including 6 carriers of predicted loss-of-function variants. DMA% was 6-10% lower in carriers compared with noncarriers in HEALS [ß=-9.4 (95% CI: -13.9, -4.8)], SHS [ß=-6.9 (95% CI: -13.6, -0.2)], and NHSCS [ß=-8.7 (95% CI: -15.6, -2.2)]. In meta-analyses across cohorts, DMA% was 8.7% lower in carriers [ß=-8.7 (95% CI: -11.9, -5.4)]. DISCUSSION: Rare, protein-altering variants in AS3MT were associated with lower mean DMA%, an indicator of reduced AME. Although a small percentage of the population (0.5-0.7%) carry these variants, they are associated with a 6-10% decrease in DMA% that is consistent across multiple ancestral and environmental backgrounds. https://doi.org/10.1289/EHP8152.

Primo: integration of multiple GWAS and omics QTL summary statistics for elucidation of molecular mechanisms of trait-associated SNPs and detection of pleiotropy in complex traits.

To provide a comprehensive mechanistic interpretation of how known trait-associated SNPs affect complex traits, we propose a method, Primo, for integrative analysis of GWAS summary statistics with multiple sets of omics QTL summary statistics from different cellular conditions or studies. Primo examines association patterns of SNPs to complex and omics traits. In gene regions harboring known susceptibility loci, Primo performs conditional association analysis to account for linkage disequilibrium. Primo allows for unknown study heterogeneity and sample correlations. We show two applications using Primo to examine the molecular mechanisms of known susceptibility loci and to detect and interpret pleiotropic effects.

Genetic Determinants of Reduced Arsenic Metabolism Efficiency in the 10q24.32 Region Are Associated With Reduced AS3MT Expression in Multiple Human Tissue Types.

Approximately 140 million people worldwide are exposed to inorganic arsenic through contaminated drinking water. Chronic exposure increases risk for cancers as well as cardiovascular, respiratory, and neurologic diseases. Arsenic metabolism involves the AS3MT (arsenic methyltransferase) gene, and arsenic metabolism efficiency (AME, measured as relative concentrations of arsenic metabolites in urine) varies among individuals. Inherited genetic variation in the 10q24.32 region, containing AS3MT, influences AME, but the mechanisms remain unclear. To better understand these mechanisms, we use tissue-specific expression data from GTEx (Genotype-tissue Expression project) to identify cis-eQTLs (expression quantitative trait loci) for AS3MT and other nearby genes. We combined these data with results from a genome-wide association study of AME using "colocalization analysis," to determine if 10q24.32 SNPs (single nucleotide polymorphisms) that affect AME also affect expression of AS3MT or nearby genes. These analyses identified cis-eQTLs for AS3MT in 38 tissue types. Colocalization results suggest that the casual variant represented by AME lead SNP rs4919690 impacts expression of AS3MT in 13 tissue types (> 80% probability). Our results suggest this causal SNP also regulates/coregulates expression of nearby genes: BORCS7 (43 tissues), NT5C2 (2 tissues), CYP17A1-AS1 (1 tissue), and RP11-724N1.1 (1 tissue). The rs4919690 allele associated with decreased AME is associated with decreased expression of AS3MT (and other coregulated genes). Our study provides a potential biological mechanism for the association between 10q24.32 variation and AME and suggests that the causal variant, represented by rs4919690, may impact AME (as measured in urine) through its effects on arsenic metabolism occurring in multiple tissue types.

Association of Arsenic Exposure with Whole Blood DNA Methylation: An Epigenome-Wide Study of Bangladeshi Adults.

BACKGROUND: Arsenic exposure affects [Formula: see text] people worldwide, including [Formula: see text] in Bangladesh. Arsenic exposure increases the risk of cancer and other chronic diseases, and one potential mechanism of arsenic toxicity is epigenetic dysregulation. OBJECTIVE: We assessed associations between arsenic exposure and genome-wide DNA methylation measured at baseline among 396 Bangladeshi adults participating in the Health Effects of Arsenic Longitudinal Study (HEALS) who were exposed by drinking naturally contaminated well water. METHODS: Methylation in whole blood DNA was measured at [Formula: see text] using the Illumina InfiniumMethylationEPIC (EPIC) array. To assess associations between arsenic exposure and CpG methylation, we used linear regression models adjusted for covariates and surrogate variables (SVs) (capturing unknown technical and biologic factors). We attempted replication and conducted a meta-analysis using an independent dataset of [Formula: see text] from 400 Bangladeshi individuals with arsenical skin lesions. RESULTS: We identified 34 CpGs associated with [Formula: see text] creatinine-adjusted urinary arsenic [[Formula: see text]]. Sixteen of these CpGs annotated to the [Formula: see text] array, and 10 associations were replicated ([Formula: see text]). The top two CpGs annotated upstream of the ABR gene (cg01912040, cg10003262 ). All urinary arsenic-associated CpGs were also associated with arsenic concentration measured in drinking water ([Formula: see text]). Meta-analysis ([Formula: see text] samples) identified 221 urinary arsenic-associated CpGs ([Formula: see text]). The arsenic-associated CpGs from the meta-analysis were enriched in non-CpG islands and shores ([Formula: see text]) and depleted in promoter regions ([Formula: see text]). Among the arsenic-associated CpGs ([Formula: see text]), we observed significant enrichment of genes annotating to the reactive oxygen species pathway, inflammatory response, and tumor necrosis factor [Formula: see text] ([Formula: see text]) signaling via nuclear factor kappa-B ([Formula: see text]) hallmarks ([Formula: see text]). CONCLUSIONS: The novel and replicable associations between arsenic exposure and DNA methylation at specific CpGs observed in this work suggest that epigenetic alterations should be further investigated as potential mediators in arsenic toxicity and as biomarkers of exposure and effect in exposed populations. https://doi.org/10.1289/EHP3849.

A missense variant in FTCD is associated with arsenic metabolism and toxicity phenotypes in Bangladesh.

Inorganic arsenic (iAs) is a carcinogen, and exposure to iAs via food and water is a global public health problem. iAs-contaminated drinking water alone affects >100 million people worldwide, including ~50 million in Bangladesh. Once absorbed into the blood stream, most iAs is converted to mono-methylated (MMA) and then di-methylated (DMA) forms, facilitating excretion in urine. Arsenic metabolism efficiency varies among individuals, in part due to genetic variation near AS3MT (arsenite methyltransferase; 10q24.32). To identify additional arsenic metabolism loci, we measured protein-coding variants across the human exome for 1,660 Bangladeshi individuals participating in the Health Effects of Arsenic Longitudinal Study (HEALS). Among the 19,992 coding variants analyzed exome-wide, the minor allele (A) of rs61735836 (p.Val101Met) in exon 3 of FTCD (formiminotransferase cyclodeaminase) was associated with increased urinary iAs% (P = 8x10-13), increased MMA% (P = 2x10-16) and decreased DMA% (P = 6x10-23). Among 2,401 individuals with arsenic-induced skin lesions (an indicator of arsenic toxicity and cancer risk) and 2,472 controls, carrying the low-efficiency A allele (frequency = 7%) was associated with increased skin lesion risk (odds ratio = 1.35; P = 1x10-5). rs61735836 is in weak linkage disequilibrium with all nearby variants. The high-efficiency/major allele (G/Valine) is human-specific and eliminates a start codon at the first 5´-proximal Kozak sequence in FTCD, suggesting selection against an alternative translation start site. FTCD is critical for catabolism of histidine, a process that generates one-carbon units that can enter the one-carbon/folate cycle, which provides methyl groups for arsenic metabolism. In our study population, FTCD and AS3MT SNPs together explain ~10% of the variation in DMA% and support a causal effect of arsenic metabolism efficiency on arsenic toxicity (i.e., skin lesions). In summary, this work identifies a coding variant in FTCD associated with arsenic metabolism efficiency, providing new evidence supporting the established link between one-carbon/folate metabolism and arsenic toxicity.

Circulating vitamin D concentrations and risk of breast and prostate cancer: a Mendelian randomization study.

BACKGROUND: Observational studies have suggested an association between circulating vitamin D concentrations [25(OH)D] and risk of breast and prostate cancer, which was not supported by a recent Mendelian randomization (MR) analysis comprising 15 748 breast and 22 898 prostate-cancer cases. Demonstrating causality has proven challenging and one common limitation of MR studies is insufficient power. METHODS: We aimed to determine whether circulating concentrations of vitamin D are causally associated with the risk of breast and prostate cancer, by using summary-level data from the largest ever genome-wide association studies conducted on vitamin D (N = 73 699), breast cancer (Ncase = 122 977) and prostate cancer (Ncase = 79 148). We constructed a stronger instrument using six common genetic variants (compared with the previous four variants) and applied several two-sample MR methods. RESULTS: We found no evidence to support a causal association between 25(OH)D and risk of breast cancer [OR per 25 nmol/L increase, 1.02 (95% confidence interval: 0.97-1.08), P = 0.47], oestrogen receptor (ER)+ [1.00 (0.94-1.07), P = 0.99] or ER- [1.02 (0.90-1.16), P = 0.75] subsets, prostate cancer [1.00 (0.93-1.07), P = 0.99] or the advanced subtype [1.02 (0.90-1.16), P = 0.72] using the inverse-variance-weighted method. Sensitivity analyses did not reveal any sign of directional pleiotropy. CONCLUSIONS: Despite its almost five-fold augmented sample size and substantially improved statistical power, our MR analysis does not support a causal effect of circulating 25(OH)D concentrations on breast- or prostate-cancer risk. However, we can still not exclude a modest or non-linear effect of vitamin D. Future studies may be designed to understand the effect of vitamin D in subpopulations with a profound deficiency.

Elevation of Stromal-Derived Mediators of Inflammation Promote Prostate Cancer Progression in African-American Men.

Progress in prostate cancer racial disparity research has been hampered by a lack of appropriate research tools and better understanding of the tumor biology. Recent gene expression studies suggest that the tumor microenvironment (TME) may contribute to racially disparate clinical outcomes in prostate cancer. Analysis of the prostate TME has shown increased reactive stroma associated with chronic inflammatory infiltrates in African-American (AA) compared with European-American (EA) patients with prostate cancer. To better understand stromal drivers of changes in TME, we isolated prostate fibroblasts (PrF) from AA (PrF-AA) and EA (PrF-EA) prostate cancer tissues and studied their functional characteristics. PrF-AA showed increased growth response to androgens FGF2 and platelet-derived growth factor. Compared with PrF-EA, conditioned media from PrF-AA significantly enhanced the proliferation and motility of prostate cancer cell lines. Expression of markers associated with myofibroblast activation (αSMA, vimentin, and tenascin-C) was elevated in PrF-AA In vivo tumorigenicity of an AA patient-derived prostatic epithelial cell line E006AA was significantly increased in the presence of PrF-AA compared with PrF-EA, and RNA-seq data and cytokine array analysis identified a panel of potential proinflammatory paracrine mediators (BDNF, CHI3L1, DPPIV, FGF7, IL18BP, IL6, and VEGF) to be enriched in PrF-AA E006AA cell lines showed increased responsiveness to BDNF ligand compared with EA-derived LNCaP and C4-2B cells. Addition of a TrkB-specific antagonist significantly reduced the protumorigenic effects induced by PrF-AA compared with PrF-EA These findings suggest that fibroblasts in the TME of AA patients may contribute to the health disparity observed in the incidence and progression of prostate cancer tumors.Significance: These findings suggest that stromal cells in the tumor microenvironment of African-American men promote progression of prostate cancer by increasing levels of a specific set of pro-inflammatory molecules compared with European-American men.Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/78/21/6134/F1.large.jpg Cancer Res; 78(21); 6134-45. ©2018 AACR.

Mendelian randomization studies of cancer risk: a literature review.

PURPOSE OF REVIEW: In this paper, we summarize prior studies that have used Mendelian Randomization (MR) methods to study the effects of exposures, lifestyle factors, physical traits, and/or biomarkers on cancer risk in humans. Many such risk factors have been associated with cancer risk in observational studies, and the MR approach can be used to provide evidence as to whether these associations represent causal relationships. MR methods require a risk factor of interest to have known genetic determinants that can be used as proxies for the risk factor (i.e., "instrumental variables" or IVs), and these can be used to obtain an effect estimate that, under certain assumptions, is not prone to bias caused by unobserved confounding or reverse causality. This review seeks to describe how MR studies have contributed to our understanding of cancer causation. RECENT FINDINGS: We searched the published literature and identified 76 MR studies of cancer risk published prior to October 31, 2017. Risk factors commonly studied included alcohol consumption, Vitamin D, anthropometric traits, telomere length, lipid traits, glycemic traits, and markers of inflammation. Risk factors showing compelling evidence of a causal association with risk for at least one cancer type include alcohol consumption (for head/neck and colorectal), adult body mass index (increases risk for multiple cancers, but decreases risk for breast), height (increases risk for breast, colorectal, and lung; decreases risk for esophageal), telomere length (increases risk for lung adenocarcinoma, melanoma, renal cell carcinoma, glioma, B-cell lymphoma subtypes, chronic lymphocytic leukemia, and neuroblastoma), and hormonal factors (affects risk for sex-steroid sensitive cancers). SUMMARY: This review highlights alcohol consumption, body mass index, height, telomere length, and the hormonal exposures as factors likely to contribute to cancer causation. This review also highlights the need to study specific cancer types, ideally subtypes, as the effects of risk factors can be heterogeneous across cancer types. As consortia-based genome-wide association studies increase in sample size and analytical methods for MR continue to become more sophisticated, MR will become an increasingly powerful tool for understanding cancer causation.

A study of telomere length, arsenic exposure, and arsenic toxicity in a Bangladeshi cohort.

BACKGROUND: Chronic arsenic exposure is associated with increased risk for arsenical skin lesions, cancer, and other adverse health outcomes. One potential mechanism of arsenic toxicity is telomere dysfunction. However, prior epidemiological studies of arsenic exposure, telomere length (TL), and skin lesion are small and cross-sectional. We investigated the associations between arsenic exposure and TL and between baseline TL and incident skin lesion risk among individuals participating in the Health Effects of Arsenic Longitudinal Study in Bangladesh (2000-2009). METHODS: Quantitative PCR was used to measure the average TL of peripheral blood DNA collected at baseline. The association between baseline arsenic exposure (well water and urine) and TL was estimated in a randomly-selected subcohort (n = 1469). A nested case-control study (466 cases and 464 age- and sex-matched controls) was used to estimate the association between baseline TL and incident skin lesion risk (diagnosed < 8 years after baseline). RESULTS: No association was observed between arsenic exposure (water or urine) and TL. Among incident skin lesion cases and matched controls, we observed higher skin lesion risk among individuals with shorter TL (Ptrend = 1.5 × 10-5) with odds ratios of 2.60, 1.59, and 1.10 for the first (shortest), second, and third TL quartiles compared to the fourth (longest). CONCLUSIONS: Arsenic exposure was not associated with TL among Bangladeshi adults, suggesting that leukocyte TL may not reflect a primary mode of action for arsenic's toxicity. However, short TL was associated with increased skin lesion risk, and may be a biomarker of arsenic susceptibility modifying arsenic's effect on skin lesion risk.

A meta-analysis approach with filtering for identifying gene-level gene-environment interactions.

There is a growing recognition that gene-environment interaction (G × E) plays a pivotal role in the development and progression of complex diseases. Despite a wealth of genetic data on various complex diseases/traits generated from association and sequencing studies, detecting G × E via genome-wide analysis remains challenging due to power issues. In genome-wide G × E studies, a common strategy to improve power is to first conduct a filtering test and retain only the genetic variants that pass the filtering step for subsequent G × E analyses. Two-stage, multistage, and unified tests have been proposed to jointly consider the filtering statistics in G × E tests. However, such G × E tests based on data from a single study may still be underpowered. Meanwhile, large-scale consortia have been formed to borrow strength across studies and populations. In this work, motivated by existing single-study G × E tests with filtering and the needs for meta-analysis G × E approaches based on consortia data, we propose a meta-analysis framework for detecting gene-based G × E effects, and introduce meta-analysis-based filtering statistics in the gene-level G × E tests. Simulations demonstrate the advantages of the proposed method-the ofGEM test. We apply the proposed tests to existing data from two breast cancer consortia to identify the genes harboring genetic variants with age-dependent penetrance (i.e., gene-age interaction effects). We develop an R software package ofGEM for the proposed meta-analysis tests.

Circulating vitamin D concentration and risk of seven cancers: Mendelian randomisation study.

Objective To determine if circulating concentrations of vitamin D are causally associated with risk of cancer.Design Mendelian randomisation study.Setting Large genetic epidemiology networks (the Genetic Associations and Mechanisms in Oncology (GAME-ON), the Genetic and Epidemiology of Colorectal Cancer Consortium (GECCO), and the Prostate Cancer Association Group to Investigate Cancer Associated Alterations in the Genome (PRACTICAL) consortiums, and the MR-Base platform).Participants 70 563 cases of cancer (22 898 prostate cancer, 15 748 breast cancer, 12 537 lung cancer, 11 488 colorectal cancer, 4369 ovarian cancer, 1896 pancreatic cancer, and 1627 neuroblastoma) and 84 418 controls.Exposures Four single nucleotide polymorphisms (rs2282679, rs10741657, rs12785878 and rs6013897) associated with vitamin D were used to define a multi-polymorphism score for circulating 25-hydroxyvitamin D (25(OH)D) concentrations.Main outcomes measures The primary outcomes were the risk of incident colorectal, breast, prostate, ovarian, lung, and pancreatic cancer and neuroblastoma, which was evaluated with an inverse variance weighted average of the associations with specific polymorphisms and a likelihood based approach. Secondary outcomes based on cancer subtypes by sex, anatomic location, stage, and histology were also examined.Results There was little evidence that the multi-polymorphism score of 25(OH)D was associated with risk of any of the seven cancers or their subtypes. Specifically, the odds ratios per 25 nmol/L increase in genetically determined 25(OH)D concentrations were 0.92 (95% confidence interval 0.76 to 1.10) for colorectal cancer, 1.05 (0.89 to 1.24) for breast cancer, 0.89 (0.77 to 1.02) for prostate cancer, and 1.03 (0.87 to 1.23) for lung cancer. The results were consistent with the two different analytical approaches, and the study was powered to detect relative effect sizes of moderate magnitude (for example, 1.20-1.50 per 25 nmol/L decrease in 25(OH)D for most primary cancer outcomes. The Mendelian randomisation assumptions did not seem to be violated.Conclusions There is little evidence for a linear causal association between circulating vitamin D concentration and risk of various types of cancer, though the existence of causal clinically relevant effects of low magnitude cannot be ruled out. These results, in combination with previous literature, provide evidence that population-wide screening for vitamin D deficiency and subsequent widespread vitamin D supplementation should not currently be recommended as a strategy for primary cancer prevention.

Trans-ethnic predicted expression genome-wide association analysis identifies a gene for estrogen receptor-negative breast cancer.

Genome-wide association studies (GWAS) have identified more than 90 susceptibility loci for breast cancer, but the underlying biology of those associations needs to be further elucidated. More genetic factors for breast cancer are yet to be identified but sample size constraints preclude the identification of individual genetic variants with weak effects using traditional GWAS methods. To address this challenge, we utilized a gene-level expression-based method, implemented in the MetaXcan software, to predict gene expression levels for 11,536 genes using expression quantitative trait loci and examine the genetically-predicted expression of specific genes for association with overall breast cancer risk and estrogen receptor (ER)-negative breast cancer risk. Using GWAS datasets from a Challenge launched by National Cancer Institute, we identified TP53INP2 (tumor protein p53-inducible nuclear protein 2) at 20q11.22 to be significantly associated with ER-negative breast cancer (Z = -5.013, p = 5.35×10-7, Bonferroni threshold = 4.33×10-6). The association was consistent across four GWAS datasets, representing European, African and Asian ancestry populations. There are 6 single nucleotide polymorphisms (SNPs) included in the prediction of TP53INP2 expression and five of them were associated with estrogen-receptor negative breast cancer, although none of the SNP-level associations reached genome-wide significance. We conducted a replication study using a dataset outside of the Challenge, and found the association between TP53INP2 and ER-negative breast cancer was significant (p = 5.07x10-3). Expression of HP (16q22.2) showed a suggestive association with ER-negative breast cancer in the discovery phase (Z = 4.30, p = 1.70x10-5) although the association was not significant after Bonferroni adjustment. Of the 249 genes that are 250 kb within known breast cancer susceptibility loci identified from previous GWAS, 20 genes (8.0%) were statistically significant associated with ER-negative breast cancer (p<0.05), compared to 582 (5.2%) of 11,287 genes that are not close to previous GWAS loci. This study demonstrated that expression-based gene mapping is a promising approach for identifying cancer susceptibility genes.