Potter, John D.

Abstract Background Physical activity (PA) is an established protective factor for colorectal cancer (CRC), but it is unclear if genetic variants modify this effect. To investigate this possibility, we conducted a genome-wide gene–PA interaction analysis. Methods Using logistic regression and two-step and joint tests, we analyzed interactions between common genetic variants across the genome and PA in relation to CRC risk. Self-reported PA levels were categorized as active (≥ 8.75 MET-h/wk) vs. inactive (< 8.75 MET-h/wk) and as study- and sex-specific quartiles of activity. Results PA had an overall protective effect on CRC (OR [active vs. inactive] = 0.85; 95%CI = 0.81–0.90). The two-step GxE method identified an interaction between rs4779584, an intergenic variant near the GREM1 and SCG5 genes, and PA for CRC risk (p-interaction = 2.6×10 − 8 ). Stratification by genotype at this locus showed a significant reduction in CRC risk by 20% in active vs. inactive participants with the CC genotype (OR = 0.80; 95%CI = 0.75–0.85), but no significant PA–CRC association among CT or TT carriers. When PA was modeled as quartiles, the 1-d.f. GxE test identified that rs56906466, an intergenic variant near the KCNG1 gene, modified the association between PA and CRC (p-interaction = 3.5×10 − 8 ). Stratification at this locus showed that increase in PA (highest vs. lowest quartile) was associated with a lower CRC risk solely among TT carriers (OR = 0.77; 95%CI = 0.72–0.82). Conclusions In summary, we identified two genetic variants that modified the association between PA and CRC risk. One of them, related to GREM1 and SCG5 , suggests that the bone morphogenetic protein (BMP)-related, inflammatory, and/or insulin signaling pathways may be associated with the protective influence of PA on colorectal carcinogenesis.

Regular, long-term aspirin use may act synergistically with genetic variants, particularly those in mechanistically relevant pathways, to confer a protective effect on colorectal cancer (CRC) risk. We leveraged pooled data from 52 clinical trial, cohort, and case-control studies that included 30,806 CRC cases and 41,861 controls of European ancestry to conduct a genome-wide interaction scan between regular aspirin/nonsteroidal anti-inflammatory drug (NSAID) use and imputed genetic variants. After adjusting for multiple comparisons, we identified statistically significant interactions between regular aspirin/NSAID use and variants in 6q24.1 (top hit rs72833769 ), which has evidence of influencing expression of TBC1D7 (a subunit of the TSC1-TSC2 complex, a key regulator of MTOR activity), and variants in 5p13.1 (top hit rs350047 ), which is associated with expression of PTGER4 (codes a cell surface receptor directly involved in the mode of action of aspirin). Genetic variants with functional impact may modulate the chemopreventive effect of regular aspirin use, and our study identifies putative previously unidentified targets for additional mechanistic interrogation.

Abstract Colorectal cancer risk can be impacted by genetic, environmental, and lifestyle factors, including diet and obesity. Gene-environment interactions (G × E) can provide biological insights into the effects of obesity on colorectal cancer risk. Here, we assessed potential genome-wide G × E interactions between body mass index (BMI) and common SNPs for colorectal cancer risk using data from 36,415 colorectal cancer cases and 48,451 controls from three international colorectal cancer consortia (CCFR, CORECT, and GECCO). The G × E tests included the conventional logistic regression using multiplicative terms (one degree of freedom, 1DF test), the two-step EDGE method, and the joint 3DF test, each of which is powerful for detecting G × E interactions under specific conditions. BMI was associated with higher colorectal cancer risk. The two-step approach revealed a statistically significant G×BMI interaction located within the Formin 1/Gremlin 1 (FMN1/GREM1) gene region (rs58349661). This SNP was also identified by the 3DF test, with a suggestive statistical significance in the 1DF test. Among participants with the CC genotype of rs58349661, overweight and obesity categories were associated with higher colorectal cancer risk, whereas null associations were observed across BMI categories in those with the TT genotype. Using data from three large international consortia, this study discovered a locus in the FMN1/GREM1 gene region that interacts with BMI on the association with colorectal cancer risk. Further studies should examine the potential mechanisms through which this locus modifies the etiologic link between obesity and colorectal cancer. Significance: This gene-environment interaction analysis revealed a genetic locus in FMN1/GREM1 that interacts with body mass index in colorectal cancer risk, suggesting potential implications for precision prevention strategies.

INTRODUCTION: Early-onset colorectal cancer diagnosed before the age of 50 years has been increasing. Likely reflecting the pathogenic role of the intestinal microbiome, which gradually changes across the entire colorectal length, the prevalence of certain tumor molecular characteristics gradually changes along colorectal subsites. Understanding how colorectal tumor molecular features differ by age and tumor location is important in personalized patient management. METHODS: Using 14,004 cases with colorectal cancer including 3,089 early-onset cases, we examined microsatellite instability (MSI), CpG island methylator phenotype (CIMP), and KRAS and BRAF mutations in carcinomas of the cecum, ascending colon, transverse colon, descending colon, sigmoid colon, and rectum and compared early-onset cases with later-onset cases. RESULTS: The proportions of MSI-high, CIMP-high, and BRAF -mutated early-onset tumors were lowest in the rectum (8.8%, 3.4%, and 3.5%, respectively) and highest in the ascending colon (46% MSI-high; 15% CIMP-high) or transverse colon (8.6% BRAF -mutated) (all P trend <0.001 across the rectum to ascending colon). Compared with later-onset tumors, early-onset tumors showed a higher prevalence of MSI-high status and a lower prevalence of CIMP-high status and BRAF mutations in most subsites. KRAS mutation prevalence was higher in the cecum compared with that in the other subsites in both early-onset and later-onset tumors ( P < 0.001). Notably, later-onset MSI-high tumors showed a continuous decrease in KRAS mutation prevalence from the rectum (36%) to ascending colon (9%; P trend <0.001), followed by an increase in the cecum (14%), while early-onset MSI-high cancers showed no such trend. DISCUSSION: Our findings support biogeographical and pathogenic heterogeneity of colorectal carcinomas in different colorectal subsites and age groups.

Abstract In 1997, the American Institute for Cancer Research (AICR) published 14 recommendations related to diet for individuals to reduce cancer incidence on a global basis; smoking was also discouraged. We operationalized these into nine recommendations that are particularly relevant to western populations in a cohort of 29,564 women ages 55 to 69 years at baseline in 1986 who had no history of cancer or heart disease. The cohort was followed through 1998 for cancer incidence (n = 4,379), cancer mortality (n = 1,434), cardiovascular disease (CVD) mortality (n = 1,124), and total mortality (n = 3,398). The median number (range) of recommendations followed was 4 (0-8), and 33% of the cohort had ever smoked. Women who followed no or one recommendation compared with six to nine recommendations were at an increased risk of cancer incidence [relative risk (RR) 1.35, 95% confidence interval (CI) 1.15-1.58] and cancer mortality (RR 1.43, 95% CI 1.11-1.85), but there was no association with CVD mortality (RR 1.06, 95% CI 0.78-1.43). We calculated the population attributable risk (PAR) to estimate the proportion of cancer incidence, cancer mortality, and CVD mortality that theoretically would have been avoidable if the entire cohort had never smoked, had followed six to nine recommendations, or had done both. The PARs for smoking were 11% (95% CI 10-13) for cancer incidence, 21% (95% CI 17-24) for cancer mortality, and 20% (95% CI 16-23) for CVD mortality. The PARs for not following six to nine recommendations were 22% (95% CI 12-30) for cancer incidence, 11% (95% CI −5 to 24) for cancer mortality, and 4% (95% CI −20 to 19) for CVD mortality. When smoking and the operationalized AICR recommendations were combined together, the PARs were 31% (95% CI 19-37) for cancer incidence, 30% (95% CI 15-40) for cancer mortality, and 22% (95% CI 4-36) for CVD mortality. These data suggest that the adherence to the AICR recommendations, independently and in conjunction with not smoking, is likely to have a substantial public health impact on reducing cancer incidence and, to a lesser degree, cancer mortality at the population level.

Abstract Background The use of menopausal hormone therapy (MHT) may interact with genetic variants to influence colorectal cancer (CRC) risk. Methods We conducted a genome-wide, gene-environment interaction between single nucleotide polymorphisms and the use of any MHT, estrogen only, and combined estrogen-progestogen therapy with CRC risk, among 28 486 postmenopausal women (11 519 CRC patients and 16 967 participants without CRC) from 38 studies, using logistic regression, 2-step method, and 2– or 3–degree-of-freedom joint test. A set-based score test was applied for rare genetic variants. Results The use of any MHT, estrogen only and estrogen-progestogen were associated with a reduced CRC risk (odds ratio [OR] = 0.71, 95% confidence interval [CI] = 0.64 to 0.78; OR = 0.65, 95% CI = 0.53 to 0.79; and OR = 0.73, 95% CI = 0.59 to 0.90, respectively). The 2-step method identified a statistically significant interaction between a GRIN2B variant rs117868593 and MHT use, whereby MHT-associated CRC risk was statistically significantly reduced in women with the GG genotype (OR = 0.68, 95% CI = 0.64 to 0.72) but not within strata of GC or CC genotypes. A statistically significant interaction between a DCBLD1 intronic variant at 6q22.1 (rs10782186) and MHT use was identified by the 2–degree-of-freedom joint test. The MHT-associated CRC risk was reduced with increasing number of rs10782186-C alleles, showing odds ratios of 0.78 (95% CI = 0.70 to 0.87) for TT, 0.68 (95% CI = 0.63 to 0.73) for TC, and 0.66 (95% CI = 0.60 to 0.74) for CC genotypes. In addition, 5 genes in rare variant analysis showed suggestive interactions with MHT (2-sided P &lt; 1.2 × 10−4). Conclusion Genetic variants that modify the association between MHT and CRC risk were identified, offering new insights into pathways of CRC carcinogenesis and potential mechanisms involved.

Abstract Background: Currently known associations between common genetic variants and colorectal cancer explain less than half of its heritability of 25%. As alcohol consumption has a J-shape association with colorectal cancer risk, nondrinking and heavy drinking are both risk factors for colorectal cancer. Methods: Individual-level data was pooled from the Colon Cancer Family Registry, Colorectal Transdisciplinary Study, and Genetics and Epidemiology of Colorectal Cancer Consortium to compare nondrinkers (≤1 g/day) and heavy drinkers (&gt;28 g/day) with light-to-moderate drinkers (1–28 g/day) in GxE analyses. To improve power, we implemented joint 2df and 3df tests and a novel two-step method that modifies the weighted hypothesis testing framework. We prioritized putative causal variants by predicting allelic effects using support vector machine models. Results: For nondrinking as compared with light-to-moderate drinking, the hybrid two-step approach identified 13 significant SNPs with pairwise r2 &gt; 0.9 in the 10q24.2/COX15 region. When stratified by alcohol intake, the A allele of lead SNP rs2300985 has a dose–response increase in risk of colorectal cancer as compared with the G allele in light-to-moderate drinkers [OR for GA genotype = 1.11; 95% confidence interval (CI), 1.06–1.17; OR for AA genotype = 1.22; 95% CI, 1.14–1.31], but not in nondrinkers or heavy drinkers. Among the correlated candidate SNPs in the 10q24.2/COX15 region, rs1318920 was predicted to disrupt an HNF4 transcription factor binding motif. Conclusions: Our study suggests that the association with colorectal cancer in 10q24.2/COX15 observed in genome-wide association study is strongest in nondrinkers. We also identified rs1318920 as the putative causal regulatory variant for the region. Impact: The study identifies multifaceted evidence of a possible functional effect for rs1318920.

AbstractDiabetes is an established risk factor for colorectal cancer. However, colorectal cancer is a heterogeneous disease and it is not well understood whether diabetes is more strongly associated with some tumor molecular subtypes than others. A better understanding of the association between diabetes and colorectal cancer according to molecular subtypes could provide important insights into the biology of this association. We used data on lifestyle and clinical characteristics from the Colorectal Cancer Family Registry (CCFR) and the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO), including 9756 colorectal cancer cases (with tumor marker data) and 9985 controls, to evaluate associations between reported diabetes and risk of colorectal cancer according to molecular subtypes. Tumor markers included BRAF and KRAS mutations, microsatellite instability and CpG island methylator phenotype. In the multinomial logistic regression model, comparing colorectal cancer cases to cancer‐free controls, diabetes was positively associated with colorectal cancer regardless of subtype. The highest OR estimate was found for BRAF‐mutated colorectal cancer, n = 1086 (ORfully adj: 1.67, 95% confidence intervals [CI]: 1.36‐2.05), with an attenuated association observed between diabetes and colorectal cancer without BRAF‐mutations, n = 7959 (ORfully adj: 1.33, 95% CI: 1.19‐1.48). In the case only analysis, BRAF‐mutation was differentially associated with diabetes (Pdifference = .03). For the other markers, associations with diabetes were similar across tumor subtypes. In conclusion, our study confirms the established association between diabetes and colorectal cancer risk, and suggests that it particularly increases the risk of BRAF‐mutated tumors.

Abstract Background Observational studies have shown higher folate consumption to be associated with lower risk of colorectal cancer (CRC). Understanding whether and how genetic risk factors interact with folate could further elucidate the underlying mechanism. Aggregating functionally relevant genetic variants in set-based variant testing has higher power to detect gene-environment (GxE) interactions and may provide information on the underlying biological pathway. Objective We investigated interactions between folate consumption and predicted gene expression on colorectal cancer risk across the genome. Methods We used variant weights from the PrediXcan models of colon tissue-specific gene expression as a priori variant information for a set-based GxE approach. We harmonized total folate intake (mcg/day) based on dietary intake and supplemental use across cohort and case-control studies and calculated sex and study specific quantiles. Analyses were performed using a mixed effects score tests for interactions between folate and genetically predicted expression of 4,839 genes with available genetically predicted expression. We meta-analyzed results across 23 studies for a total of 13,498 cases with colorectal tumors and 13,918 controls of European ancestry. Results We found suggestive evidence of interaction with folate intake for genes including glutathione S-Transferase Alpha 1 (GSTA1; p=4.3E-4), Tonsuko Like, DNA Repair Protein (TONSL; p=4.3E-4), and Aspartylglucosaminidase (AGA: p=4.5E-4). Glutathione is an antioxidant, preventing cellular damage and is a downstream metabolite of homocysteine and metabolized by GSTA1. TONSL is part of a complex that functions in the recovery of double strand breaks and AGA plays a role in lysosomal breakdown of glycoprotein. Conclusion We identified three genes involved in preventing or repairing DNA damage that may interact with folate consumption to alter CRC risk.

Objective An understanding of the etiologic heterogeneity of colorectal cancer (CRC) is critical for improving precision prevention, including individualized screening recommendations and the discovery of novel drug targets and repurposable drug candidates for chemoprevention. Known differences in molecular characteristics and environmental risk factors among tumors arising in different locations of the colorectum suggest partly distinct mechanisms of carcinogenesis. The extent to which the contribution of inherited genetic risk factors for CRC differs by anatomical subsite of the primary tumor has not been examined. Design To identify new anatomical subsite-specific risk loci, we performed genome-wide association study (GWAS) meta-analyses including data of 48 214 CRC cases and 64 159 controls of European ancestry. We characterised effect heterogeneity at CRC risk loci using multinomial modelling. Results We identified 13 loci that reached genome-wide significance (p<5×10 −8 ) and that were not reported by previous GWASs for overall CRC risk. Multiple lines of evidence support candidate genes at several of these loci. We detected substantial heterogeneity between anatomical subsites. Just over half (61) of 109 known and new risk variants showed no evidence for heterogeneity. In contrast, 22 variants showed association with distal CRC (including rectal cancer), but no evidence for association or an attenuated association with proximal CRC. For two loci, there was strong evidence for effects confined to proximal colon cancer. Conclusion Genetic architectures of proximal and distal CRC are partly distinct. Studies of risk factors and mechanisms of carcinogenesis, and precision prevention strategies should take into consideration the anatomical subsite of the tumour.