Burnett‐Hartman, Andrea N.

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 The roles of sex hormones such as estradiol, testosterone, and sex hormone-binding globulin (SHBG) in the etiology of lung and colorectal cancers in women, among the most common cancers after breast cancer, are unclear. This Mendelian randomization (MR) study evaluated such potential causal associations in women of European ancestry. We used summary statistics data from genome-wide association studies (GWASs) on sex hormones and from the Trøndelag Health (HUNT) Study and large consortia on cancers. There was suggestive evidence of genetically predicted 1-standard deviation increase in total testosterone levels being associated with a lower risk of lung non-adenocarcinoma (hazard ratio (HR) 0.60, 95% CI 0.37–0.98) in the HUNT Study. However, this was not confirmed by using data from a larger consortium. In general, we did not find convincing evidence to support a causal role of sex hormones on risk of lung and colorectal cancers in women of European ancestry.

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.

451 Background: Classifications for molecular subtypes of colorectal cancer based on microsatellite instability (MSI), the CpG island methylator phenotype (CIMP), and somatic mutations in BRAFV600E and KRAS have been proposed to reflect distinct pathways of colorectal tumorigenesis. We assessed the relationship between these subtype classifications and colorectal cancer survival in a population-based study. Methods: Tumor-markers were evaluated in incident colorectal cancer cases diagnosed between 1997-2007 in western Washington State. Cases were classified into pathway-based subtypes according to the following tumor-marker combinations: (1) traditional pathway [microsatellite stable / low MSI (MSS/MSI-L), non-CIMP, BRAF-wildtype, KRAS-wildtype, n = 631]; (2) MSI-high serrated (MSI-high, CIMP-positive, BRAF-mutated, KRAS-wildtype, N=100); (3) MSS/MSI-L serrated (MSS/MSI-L, CIMP-positive, BRAF-mutated, KRAS-wildtype, n = 55); (4) alternate pathway (MSS/MSI-L, non-CIMP, BRAF-wildtype, KRAS-mutated, n = 353); and (5) MSI-high familial (MSI-high, non-CIMP, BRAF-wildtype, KRAS-wildtype, n = 50). Multiple-imputation was used to classify tumor-marker status for cases with missing data on one to three markers. Differences in survival across subtypes were assessed through multivariable-adjusted Cox regression. Results: Relative to cases of the predominant traditional pathway subtype, cases with MSS/MSI-L serrated and alternate pathway tumor subtypes experienced statistically significantly worse disease-specific survival [hazard ratio (HR) = 2.25, 95% confidence interval (CI): 1.50-3.36 and HR = 1.39, 95% CI: 1.12-1.71, respectively]; cases with MSI-high familial tumors had the most favorable disease-specific prognosis (HR = 0.28, 95% CI: 0.12-0.64). With respect to overall survival, associations were similar but slightly attenuated. Conclusions: In this large, population-based study, colorectal cancer subtype classifications based on integrated pathways were associated with marked differences in survival, highlighting the significance of molecular heterogeneity in colorectal cancer.