Salicylic acid and risk of colorectal cancer: a two sample Mendelian randomization study

Background Salicylic acid (SA) is a metabolite that can be obtained from the diet via fruit and vegetable ingestion, of which increased consumption has observationally been shown to decrease risk of colorectal cancer (CRC). Whilst primary prevention trials of SA and CRC risk are lacking, there is strong evidence from clinical trials and prospective cohort studies that aspirin (acetylsalicylic acid) is an effective primary and secondary chemopreventative agent. Since aspirin is rapidly deacetylated to form SA, it follows that SA may have a central role for aspirin chemoprevention. Through a Mendelian randomization (MR) approach, we aimed to address whether levels of SA affected CRC risk, and whether aspirin intake as a proxy for increased SA levels was required to identify an effect. Methods and Findings A two sample MR analysis was carried out using genome-wide association study summary statistics of SA from INTERVAL and EPIC-Norfolk (N= 14,149) and CRC from Colon Cancer Family Registry (CCFR), Colorectal Cancer Transdisciplinary Study (CORECT), Genetics and Epidemiology of Colorectal Cancer (GECCO) consortia and UK Biobank (55,168 cases and 65,160 controls). The Darmkrebs: Chancen der Verhütung durch Screening (DACHS) study (4,410 cases and 3,441 controls) was used for replication and stratification of aspirin-users and non-users. Single nucleotide polymorphisms (SNPs) for SA were selected via three methods: (1) Functional SNPs that influence aspirin and SA metabolising enzymes' activity; (2) Pathway SNPs, those that are present in the coding regions of genes involved in aspirin and SA metabolism; and (3) genome-wide significant SNPs associated with levels of circulating SA. No association was found between the functional SNPs and SA levels, therefore they were not taken forward in an MR analysis. We identified 2 pathway SNPs (explaining 0.03% of the variance in SA levels and with an F statistic of 1.74) and 1 genome-wide independent SNP (explaining 0.05% of the variance and with an F statistic of 7.44) to proxy for SA levels. Using the pathway SNPs, an inverse variance weighted approach found no association between an SD increase in SA and CRC risk (GECCO OR:1.03, 95% CI: 0.84-1.27 and DACHS OR:1.10, 95% CI:0.58-2.07) and no association was found upon stratification between aspirin users and non-users in the DACHS study (OR:0.93, 95% CI:0.23-3.73 and OR:1.24, 95% CI:0.57-2.69, respectively). Wald ratio results using the genome-wide SNP also showed no association between an SD increase in SA and CRC risk (GECCO OR: 1.08, 95% CI:0.86-1.34 and DACHS OR: 1.01, 95% CI:0.44-2.31) and no effect was observed upon stratification by aspirin use (users OR:0.66, 95% CI: 0.11-4.12 and non-users OR: 1.12, 95% CI: 0.42-2.97). Conclusions We found no evidence to suggest that an SD increase in genetically predicted SA protects against CRC risk in the general population and upon stratification by aspirin use. However, based on the calculated variance explained by the SNPs and the F statistic, we acknowledge the possibility of weak instrument bias and the need to find better instruments for SA levels.

32Do the risks of Lynch syndrome-related cancers depend on the parent-of-origin of the mutation?

Background Individuals who carry pathogenic mutations in DNA mismatch repair (MMR) genes have high risks of cancer, and small studies have suggested that these risks depend on the sex of the parent from whom the mutation was inherited. We have conducted the first large study of such a parent-of-origin effect (POE). Methods Our study was based on all MMR gene mutation carriers and their relatives in the Colon Cancer Family Registry, comprising 18,226 people. The POE was estimated as a hazard ratio (HR) using a segregation analysis approach that adjusted for ascertainment. HR = 1 corresponds to no POE and HR > 1 corresponds to higher risks for maternal mutations. Results For all MMR genes combined, the estimated POE HRs were 1.02 (95% confidence interval (CI) 0.75-1.39, p = 0.9) for male colorectal cancer, 1.12 (95% CI 0.81-1.54, p = 0.5) for female colorectal cancer and 0.84 (95% CI 0.52-1.36, p = 0.5) for endometrial cancer. Separate results for each MMR gene were similar. Conclusions Despite being well-powered, our study did not find any evidence that cancer risks for MMR gene mutation carriers depend on the parent-of-origin of the mutation. Based on current evidence, we don’t recommend that POEs be incorporated into the clinical guidelines or advice for such carriers. Key messages MMR gene mutations inherited from the maternal and paternal side confer similar risks of developing colorectal and endometrial cancer.

Adiposity, metabolites, and colorectal cancer risk: Mendelian randomization study

Background Higher adiposity increases the risk of colorectal cancer (CRC), but whether this relationship varies by anatomical sub-site or by sex is unclear. Further, the metabolic alterations mediating the effects of adiposity on CRC are not fully understood. Methods We examined sex- and site-specific associations of adiposity with CRC risk and whether adiposity-associated metabolites explain the associations of adiposity with CRC. Genetic variants from genome-wide association studies of body mass index (BMI) and waist-to-hip ratio (WHR, unadjusted for BMI; N = 806,810), and 123 metabolites from targeted nuclear magnetic resonance metabolomics (N = 24,925), were used as instruments. Sex-combined and sex-specific Mendelian randomization (MR) was conducted for BMI and WHR with CRC risk (58,221 cases and 67,694 controls in the Genetics and Epidemiology of Colorectal Cancer Consortium, Colorectal Cancer Transdisciplinary Study, and Colon Cancer Family Registry). Sex-combined MR was conducted for BMI and WHR with metabolites, for metabolites with CRC, and for BMI and WHR with CRC adjusted for metabolite classes in multivariable models. Results In sex-specific MR analyses, higher BMI (per 4.2 kg/m2) was associated with 1.23 (95% confidence interval (CI) = 1.08, 1.38) times higher CRC odds among men (inverse-variance-weighted (IVW) model); among women, higher BMI (per 5.2 kg/m2) was associated with 1.09 (95% CI = 0.97, 1.22) times higher CRC odds. WHR (per 0.07 higher) was more strongly associated with CRC risk among women (IVW OR = 1.25, 95% CI = 1.08, 1.43) than men (IVW OR = 1.05, 95% CI = 0.81, 1.36). BMI or WHR was associated with 104/123 metabolites at false discovery rate-corrected P ≤ 0.05; several metabolites were associated with CRC, but not in directions that were consistent with the mediation of positive adiposity-CRC relations. In multivariable MR analyses, associations of BMI and WHR with CRC were not attenuated following adjustment for representative metabolite classes, e.g., the univariable IVW OR for BMI with CRC was 1.12 (95% CI = 1.00, 1.26), and this became 1.11 (95% CI = 0.99, 1.26) when adjusting for cholesterol in low-density lipoprotein particles. Conclusions Our results suggest that higher BMI more greatly raises CRC risk among men, whereas higher WHR more greatly raises CRC risk among women. Adiposity was associated with numerous metabolic alterations, but none of these explained associations between adiposity and CRC. More detailed metabolomic measures are likely needed to clarify the mechanistic pathways.

Risks of Colorectal Cancer and Cancer-Related Mortality in Familial Colorectal Cancer Type X and Lynch Syndrome Families

Background The risk of cancers is well characterized in Lynch syndrome (LS) families but has been less studied in familial colorectal cancer type X (FCCTX) families. Methods In this article, we compare the risk estimates of first and second colorectal cancers (CRCs) in 168 FCTTX and 780 LS families recruited through the Colon Cancer Family Registry as well as the risk of cancer-related deaths and disease-free survival (DFS) after a first CRC. Our methodology is based on a survival analysis approach, developed specifically to model the occurrence of successive cancers (ie, first and second CRCs) in the presence of competing risk events (ie, death from any causes). Results We found an excess risk of first and second CRC in individuals with LS compared to FCCTX family members. However, for an average age at first CRC of 60 years in FCCTX families and 50 years in LS families, the DFS rates were comparable in men but lower in women from FCCTX vs LS families, eg , 75.1% (95% confidence interval [CI] = 69.0% to 80.9%) vs 78.9% (95% CI = 76.3% to 81.3%) for the 10-year DFS. The 10-year risk of cancer-related death was higher in FCCTX families vs LS families, eg, 15.4% in men (95% CI = 10.9% to 19.8%) and 19.3% in women (95% CI = 13.6% to 24.7%) vs 8.9% (95% CI = 7.5% to 11.4%) and 8.7% (95% CI = 7.1% to 10.8%), respectively. Conclusions Individuals with CRCs arising in the context of FCCTX do not experience the same improved DFS and overall survival of those with LS, and that difference may be relevant in management decisions.