Citations

Abstract Background: Obesity and diabetes are major modifiable risk factors for pancreatic cancer. Interactions between genetic variants and diabetes/obesity have not previously been comprehensively investigated in pancreatic cancer at the genome-wide level. Methods: We conducted a gene–environment interaction (GxE) analysis including 8,255 cases and 11,900 controls from four pancreatic cancer genome-wide association study (GWAS) datasets (Pancreatic Cancer Cohort Consortium I–III and Pancreatic Cancer Case Control Consortium). Obesity (body mass index ≥30 kg/m2) and diabetes (duration ≥3 years) were the environmental variables of interest. Approximately 870,000 SNPs (minor allele frequency ≥0.005, genotyped in at least one dataset) were analyzed. Case–control (CC), case-only (CO), and joint-effect test methods were used for SNP-level GxE analysis. As a complementary approach, gene-based GxE analysis was also performed. Age, sex, study site, and principal components accounting for population substructure were included as covariates. Meta-analysis was applied to combine individual GWAS summary statistics. Results: No genome-wide significant interactions (departures from a log-additive odds model) with diabetes or obesity were detected at the SNP level by the CC or CO approaches. The joint-effect test detected numerous genome-wide significant GxE signals in the GWAS main effects top hit regions, but the significance diminished after adjusting for the GWAS top hits. In the gene-based analysis, a significant interaction of diabetes with variants in the FAM63A (family with sequence similarity 63 member A) gene (significance threshold P < 1.25 × 10−6) was observed in the meta-analysis (PGxE = 1.2 ×10−6, PJoint = 4.2 ×10−7). Conclusions: This analysis did not find significant GxE interactions at the SNP level but found one significant interaction with diabetes at the gene level. A larger sample size might unveil additional genetic factors via GxE scans. Impact: This study may contribute to discovering the mechanism of diabetes-associated pancreatic cancer.

AbstractBackgroundPostmenopausal hormone therapy (HT) is associated with a decreased colorectal cancer (CRC) risk. As CRC is a heterogeneous disease, we evaluated whether the association of HT and CRC differs across etiologically relevant, molecularly defined tumor subtypes and tumor location.MethodsWe pooled data on tumor subtypes (microsatellite instability status, CpG island methylator phenotype status, BRAF and KRAS mutations, pathway: adenoma-carcinoma, alternate, serrated), tumor location (proximal colon, distal colon, rectum), and HT use among 8220 postmenopausal women (3898 CRC cases and 4322 controls) from 8 observational studies. We used multinomial logistic regression to estimate odds ratios (OR) and 95% confidence intervals (CIs) for the association of ever vs never HT use with each tumor subtype compared with controls. Models were adjusted for study, age, body mass index, smoking status, and CRC family history. All statistical tests were 2-sided.ResultsAmong postmenopausal women, ever HT use was associated with a 38% reduction in overall CRC risk (OR =0.62, 95% CI = 0.56 to 0.69). This association was similar according to microsatellite instability, CpG island methylator phenotype and BRAF or KRAS status. However, the association was attenuated for tumors arising through the serrated pathway (OR = 0.81, 95% CI = 0.66 to 1.01) compared with the adenoma-carcinoma pathway (OR = 0.63, 95% CI = 0.55 to 0.73; Phet =.04) and alternate pathway (OR = 0.61, 95% CI = 0.51 to 0.72). Additionally, proximal colon tumors had a weaker association (OR = 0.71, 95% CI = 0.62 to 0.80) compared with rectal (OR = 0.54, 95% CI = 0.46 to 0.63) and distal colon (OR = 0.57, 95% CI = 0.49 to 0.66; Phet =.01) tumors.ConclusionsWe observed a strong inverse association between HT use and overall CRC risk, which may predominantly reflect a benefit of HT use for tumors arising through the adenoma-carcinoma and alternate pathways as well as distal colon and rectal tumors.

AbstractBackgroundBody mass index (BMI) and diabetes are established risk factors for colorectal cancer (CRC), likely through perturbations in metabolic traits (e.g. insulin resistance and glucose homeostasis). Identification of interactions between variation in genes and these metabolic risk factors may identify novel biologic insights into CRC etiology.MethodsTo improve statistical power and interpretation for gene‐environment interaction (G × E) testing, we tested genetic variants that regulate expression of a gene together for interaction with BMI (kg/m2) and diabetes on CRC risk among 26 017 cases and 20 692 controls. Each variant was weighted based on PrediXcan analysis of gene expression data from colon tissue generated in the Genotype‐Tissue Expression Project for all genes with heritability ≥1%. We used a mixed‐effects model to jointly measure the G × E interaction in a gene by partitioning the interactions into the predicted gene expression levels (fixed effects), and residual G × E effects (random effects). G × BMI analyses were stratified by sex as BMI‐CRC associations differ by sex. We used false discovery rates to account for multiple comparisons and reported all results with FDR <0.2.ResultsAmong 4839 genes tested, genetically predicted expressions of FOXA1 (P = 3.15 × 10−5), PSMC5 (P = 4.51 × 10−4) and CD33 (P = 2.71 × 10−4) modified the association of BMI on CRC risk for men; KIAA0753 (P = 2.29 × 10−5) and SCN1B (P = 2.76 × 10−4) modified the association of BMI on CRC risk for women; and PTPN2 modified the association between diabetes and CRC risk in both sexes (P = 2.31 × 10−5).ConclusionsAggregating G × E interactions and incorporating functional information, we discovered novel genes that may interact with BMI and diabetes on CRC risk.

Abstract Background: Results from epidemiologic studies examining polyunsaturated fatty acids (PUFA) and colorectal cancer risk are inconsistent. Mendelian randomization may strengthen causal inference from observational studies. Given their shared metabolic pathway, examining the combined effects of aspirin/NSAID use with PUFAs could help elucidate an association between PUFAs and colorectal cancer risk. Methods: Information was leveraged from genome-wide association studies (GWAS) regarding PUFA-associated SNPs to create weighted genetic scores (wGS) representing genetically predicted circulating blood PUFAs for 11,016 non-Hispanic white colorectal cancer cases and 13,732 controls in the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO). Associations per SD increase in the wGS were estimated using unconditional logistic regression. Interactions between PUFA wGSs and aspirin/NSAID use on colorectal cancer risk were also examined. Results: Modest colorectal cancer risk reductions were observed per SD increase in circulating linoleic acid [ORLA = 0.96; 95% confidence interval (CI) = 0.93–0.98; P = 5.2 × 10−4] and α-linolenic acid (ORALA = 0.95; 95% CI = 0.92–0.97; P = 5.4 × 10−5), whereas modest increased risks were observed for arachidonic (ORAA = 1.06; 95% CI = 1.03–1.08; P = 3.3 × 10−5), eicosapentaenoic (OREPA = 1.04; 95% CI = 1.01–1.07; P = 2.5 × 10−3), and docosapentaenoic acids (ORDPA = 1.03; 95% CI = 1.01–1.06; P = 1.2 × 10−2). Each of these effects was stronger among aspirin/NSAID nonusers in the stratified analyses. Conclusions: Our study suggests that higher circulating shorter-chain PUFAs (i.e., LA and ALA) were associated with reduced colorectal cancer risk, whereas longer-chain PUFAs (i.e., AA, EPA, and DPA) were associated with an increased colorectal cancer risk. Impact: The interaction of PUFAs with aspirin/NSAID use indicates a shared colorectal cancer inflammatory pathway. Future research should continue to improve PUFA genetic instruments to elucidate the independent effects of PUFAs on colorectal cancer.

Abstract Background Although 20 pancreatic cancer susceptibility loci have been identified through genome-wide association studies in individuals of European ancestry, much of its heritability remains unexplained and the genes responsible largely unknown. Methods To discover novel pancreatic cancer risk loci and possible causal genes, we performed a pancreatic cancer transcriptome-wide association study in Europeans using three approaches: FUSION, MetaXcan, and Summary-MulTiXcan. We integrated genome-wide association studies summary statistics from 9040 pancreatic cancer cases and 12 496 controls, with gene expression prediction models built using transcriptome data from histologically normal pancreatic tissue samples (NCI Laboratory of Translational Genomics [n = 95] and Genotype-Tissue Expression v7 [n = 174] datasets) and data from 48 different tissues (Genotype-Tissue Expression v7, n = 74–421 samples). Results We identified 25 genes whose genetically predicted expression was statistically significantly associated with pancreatic cancer risk (false discovery rate &lt; .05), including 14 candidate genes at 11 novel loci (1p36.12: CELA3B; 9q31.1: SMC2, SMC2-AS1; 10q23.31: RP11-80H5.9; 12q13.13: SMUG1; 14q32.33: BTBD6; 15q23: HEXA; 15q26.1: RCCD1; 17q12: PNMT, CDK12, PGAP3; 17q22: SUPT4H1; 18q11.22: RP11-888D10.3; and 19p13.11: PGPEP1) and 11 at six known risk loci (5p15.33: TERT, CLPTM1L, ZDHHC11B; 7p14.1: INHBA; 9q34.2: ABO; 13q12.2: PDX1; 13q22.1: KLF5; and 16q23.1: WDR59, CFDP1, BCAR1, TMEM170A). The association for 12 of these genes (CELA3B, SMC2, and PNMT at novel risk loci and TERT, CLPTM1L, INHBA, ABO, PDX1, KLF5, WDR59, CFDP1, and BCAR1 at known loci) remained statistically significant after Bonferroni correction. Conclusions By integrating gene expression and genotype data, we identified novel pancreatic cancer risk loci and candidate functional genes that warrant further investigation.

Abstract Background: Smoking has been associated with colorectal cancer (CRC) risk; but limited evidence has shown the association between smoking and molecular subtypes of CRC. Methods: We analyzed 9,422 CRC cases and 9,950 controls from 10 observational studies. Multinomial logistic regression analysis was performed to assess the association between sex-study-specific quartiles of pack years of smoking and risk of CRC molecular subtypes, using non-smokers as reference group, adjusting for age, sex, and study. Known oncogenic mutations in four somatic colorectal tumor markers were assessed individually and in combination, including BRAF mutations, KRAS mutations, CpG island methylator phenotype (CIMP), and microsatellite instability (MSI) status. Case-only analysis was also performed to estimate heterogeneity in risk of molecular subtypes of CRC. Results: Compared with controls, higher pack years of smoking were statistically significantly associated with increased CRC risk when stratified, individually, by all four markers, and the associations got stronger with higher quartiles pack years (p-trend&lt;0.001). Associations between smoking and CRC risk also differed significantly among molecular subtypes. Compared to nonsmokers, the risk of BRAFmut CRC was 83% higher for smokers within the highest quartile of pack-years (OR=1.83; 95% CI: 1.50, 2.25), and 29% higher for BRAFwt CRC (OR=1.29; 95% CI: 1.17, 1.43; Ratio of ORs (ROR)=1.45; 95% CI: 1.18, 1.17; p=3.45x10-4). Similarly, heavy pack-years of smoking was associated with almost two times higher risk of CIMP-high CRC (OR=1.93; 95% CI: 1.60, 2.31), but only 33% higher risk of CIMP-low/negative CRC (OR=1.33; 95% CI: 1.19, 1.48; ROR=1.49; 95% CI: 1.24, 1.79; p=1.72x10-5). The association between smoking and CRC was also stronger in MSI-high tumors (ORMSI-H=1.65; 95% CI: 1.36, 2.00; ORMSI-L/MSS=1.37; 95% CI: 1.23, 1.52; ROR=1.22; 95% CI: 1.00, 1.48; p=0.046). In contrast, the association between smoking and CRC risk was stronger for KRASwt (OR=1.43; 95% CI: 1.27, 1.60), than KRASmut tumors (OR=1.18; 95% CI: 1.02, 1.37; ROR=0.83; 95% CI: 0.71, 0.97; p =0.016). When combining tumor markers, smoking was found to be significantly associated with higher risk of colorectal tumors from the serrated pathway. Conclusion: In this largest study with a total of 19,372 subjects, we found that heavier pack years of smoking was associated with increased risk of all CRC molecular subtypes. Smokers with heavier pack-years of smoking had particularly higher risk of CRC subtypes with BRAF mutation and CIMP-high, suggesting smoking may be particularly involved in the development of these subtypes of colorectal tumor. Citation Format: Xiaoliang Wang, Efrat Amitay, Barbara L. Banbury, Hermann Brenner, Daniel D. Buchanan, Peter T. Campbell, Jenny Chang-Claude, Steven J. Gallinger, Graham G. Giles, Tabitha A. Harrison, John L. Hopper, Mark A. Jenkins, Yi Lin, Reiko Nishihara, Polly A. Newcomb, Shuji Ogino, Lori C. Sakoda, Robert E. Schoen, Martha L. Slattery, Steven N. Thibodeau, Bethany Van Guelpen, Michael O. Woods, Li Hsu, Michael Hoffmeister, Ulrike Peters. Smoking is associated with risks of molecular subtypes of colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 630.

Interindividual differences in DNA repair systems may play a role in modulating the individual risk of developing colorectal cancer. To better ascertain the role of DNA repair gene polymorphisms on colon and rectal cancer risk individually, we evaluated 15,419 single nucleotide polymorphisms (SNPs) within 185 DNA repair genes using GWAS data from the Colon Cancer Family Registry (CCFR) and the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO), which included 8,178 colon cancer, 2,936 rectum cancer cases and 14,659 controls. Rs1800734 (in MLH1 gene) was associated with colon cancer risk (p‐value = 3.5 × 10−6) and rs2189517 (in RAD51B) with rectal cancer risk (p‐value = 5.7 × 10−6). The results had statistical significance close to the Bonferroni corrected p‐value of 5.8 × 10−6. Ninety‐four SNPs were significantly associated with colorectal cancer risk after Binomial Sequential Goodness of Fit (BSGoF) procedure and confirmed the relevance of DNA mismatch repair (MMR) and homologous recombination pathways for colon and rectum cancer, respectively. Defects in MMR genes are known to be crucial for familial form of colorectal cancer but our findings suggest that specific genetic variations in MLH1 are important also in the individual predisposition to sporadic colon cancer. Other SNPs associated with the risk of colon cancer (e.g., rs16906252 in MGMT) were found to affect mRNA expression levels in colon transverse and therefore working as possible cis‐eQTL suggesting possible mechanisms of carcinogenesis.

3604 Background: Limited research has investigated the role of variation in the host genome as a determinant of colon carcinoma (CC) outcomes, including toxicity due to therapeutic agents. We examined the relationship between germline genetic factors and treatment-associated serious adverse events (SAEs) in a population of CC patients in which treatment was standardized and follow-up for outcomes was uniformly conducted. Methods: Using existing biospecimens from CC patients with resected stage III disease in a phase III randomized trial of FOLFOX adjuvant chemotherapy with and without cetuximab (NCCTG N0147), genome-wide genotyping arrays were conducted for 2200 patients for a total of ~20 million single nucleotide polymorphisms (SNPs). Using logistic regression models we assessed SNP-specific associations with SAEs, utilizing a discovery-based approach to search the genome in an unbiased manner. Detailed information on SAEs was collected using the Common Toxicity Criteria for Adverse Events (CTCAE, v3.0). Analyses evaluating associations with specific classes of common grade ≥3 SAEs were performed, including gastrointestinal toxicities, neutropenia, and paresthesias. A threshold of P < 5x10-8was used to denote genome-wide significance. Results: Among patients who received FOLFOX, several SNPs on chr 15 near the ANP32A gene and on chr 2 near the CD207 gene were statistically significantly associated with grade ≥3 neuropathy. The strongest SNP-specific associations in these regions were in the range of odds ratio (OR) = 1.3, P = 2.8×10−10 and OR = 1.5, P = 2.7×10−10, respectively. Conclusions: Findings from this genome-wide analysis demonstrate the potential importance of germline genetic variation in influencing CC patients’ experience of specific toxicities to FOLFOX regimens. These results highlight two genomic regions of potential interest for understanding the biological mechanism for such toxicities, although further evaluation and replication is needed. Support: U10CA180821, U10CA180882, U10CA180820, U10CA180863, U10CA180888, CCSRI 021039, R01CA176272, Eli Lilly & Co, Pfizer, Sanofi. Clinical trial information: NCT00079274 .

Abstract Genome-wide association studies of colorectal cancer (CRC) have identified over 50 susceptibility loci. These variants represent only a small fraction of total heritability for CRC. Gene-environment (GxE) interaction studies may help identify novel loci and biological interactions that give insight to the pathogenesis of CRC. Previous genome-wide GxE studies with dietary factors have identified interactions between loci and processed meat consumption and alcohol; however, limited statistical power remains a primary concern. Set-based SNP testing has the potential to increase statistical power to detect GxE interactions by aggregating functionally relevant SNPs. In this large pooled analysis using 14 case-control and nested case-control studies, we incorporated functional information from the transcriptome prediction tool, PrediXcan, into a novel set-based approach for testing GxE interactions. We used variant weights from the PrediXcan models of tissue-specific gene expression in the transverse colon as a priori variant information for a set-based GxE approach. We restricted our analysis to variants in the PrediXcan transverse colon gene models (n = 4,842). This discovery phase included 10,360 CRC and advanced adenoma cases, and 11,183 controls of European ancestry from the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO) and the Colon Cancer Family Registry. All 14 studies were analyzed together in a pooled data set using the Mixed Effects Score Tests for interactions. We tested for gene interactions with sex- and study- specific quartiles of dietary intake of red meat (servings/day), processed meat (servings/day), vegetables (servings/day), fruits (servings/day), and fiber (g/day). We detected two genes with suggestive interactions (false discovery rate (FDR) &lt; 0.2) with intake of red meat and risk of CRC: Superoxide Dismutase 2 (SOD2) and Ubiquitin Conjugating Enzyme E2 H (UBE2H). No interactions at FDR &lt; 0.2 were observed for processed meat, vegetables, fruits, or fiber. The SOD2 gene, which encodes an enzyme important in apoptotic signaling and clearing of reactive oxygen species, may regulate response to colonic exposure to heme iron or increased bile acid from high-fat content in red meat. UBE2H is part of the ubiquitin-proteasome system that has a role in Wnt signaling, which can be mediated by heme iron in red meat and is commonly found dysregulated in cancer. These findings highlight the efficacy of integrating functional information and set-based testing for novel discovery of genes interacting with known dietary risk factors of CRC. We plan to replicate these findings in additional studies. Citation Format: Paneen S. Petersen, Yu-Ru Su, Sonja I. Berndt, Stephanie A. Bien, Hermann Brenner, Graham Casey, Andrew T. Chan, Jenny Chang-Claude, Jane C. Figueiredo, Steven J. Gallinger, Robert W. Haile, Tabitha A. Harrison, Michael Hoffmeister, Mark A. Jenkins, Amit D. Joshi, Sébastien Küry, Loic Le Marchand, Yi Lin, Noralane M. Lindor, Polly A. Newcomb, John D. Potter, Robert Schoen, Martha L. Slattery, Stephen N. Thibodeau, Emily White, Li Hsu, Ulrike Peters, CCFR, GECCO. Interactions between genetic predictors of gene expression and dietary factors associated with risk of colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5268.