Characterization of additive gene-environment interactions for colorectal cancer risk.

BACKGROUND: Colorectal cancer (CRC) is a common, fatal cancer. Identifying subgroups who may benefit more from intervention is of critical public health importance. Previous studies have assessed multiplicative interaction between genetic risk scores and environmental factors, but few have assessed additive interaction, the relevant public health measure. METHODS: Using resources from colorectal cancer consortia including 45,247 CRC cases and 52,671 controls, we assessed multiplicative and additive interaction (relative excess risk due to interaction, RERI) using logistic regression between 13 harmonized environmental factors and genetic risk score including 141 variants associated with CRC risk. RESULTS: There was no evidence of multiplicative interaction between environmental factors and genetic risk score. There was additive interaction where, for individuals with high genetic susceptibility, either heavy drinking [RERI = 0.24, 95% confidence interval, CI, (0.13, 0.36)], ever smoking [0.11 (0.05, 0.16)], high BMI [female 0.09 (0.05, 0.13), male 0.10 (0.05, 0.14)], or high red meat intake [highest versus lowest quartile 0.18 (0.09, 0.27)] was associated with excess CRC risk greater than that for individuals with average genetic susceptibility. Conversely, we estimate those with high genetic susceptibility may benefit more from reducing CRC risk with aspirin/NSAID use [-0.16 (-0.20, -0.11)] or higher intake of fruit, fiber, or calcium [highest quartile versus lowest quartile -0.12 (-0.18, -0.050); -0.16 (-0.23, -0.09); -0.11 (-0.18, -0.05), respectively] than those with average genetic susceptibility. CONCLUSIONS: Additive interaction is important to assess for identifying subgroups who may benefit from intervention. The subgroups identified in this study may help inform precision CRC prevention.

Intake and biomarkers of folate and folic acid as determinants of chemotherapy-induced toxicities in patients with colorectal cancer: a cohort study.

BACKGROUND: Capecitabine is an oral chemotherapeutic drug showing antitumor activity through inhibition of thymidylate synthase, an enzyme involved in folate metabolism. There are concerns about the high intake of certain vitamins, and specifically folate, during chemotherapy with capecitabine. Whether folate or folic acid, the synthetic variant of the vitamin, impact treatment toxicity remains unclear. OBJECTIVE: We studied associations between intake and biomarkers of folate as well as folic acid and toxicities in patients with colorectal cancer (CRC) receiving capecitabine. METHODS: Within the prospective COLON (Colorectal cancer: Longitudinal, Observational study on Nutritional and lifestyle factors that influence recurrence, survival, and quality of life) cohort, 290 patients with stage II to III CRC receiving capecitabine were identified. Dietary and supplemental intake of folate and folic acid were assessed at diagnosis and during chemotherapy using questionnaires (available for 280 patients). Plasma folate and folic acid levels were determined by liquid chromatography tandem mass spectrometry (LC-MS/MS) and were available for 212 patients. Toxicities were defined as toxicity-related modifications of treatment, including dose reductions, regimen switches, and early discontinuation. Associations of intake and biomarkers of folate and folic acid with toxicities were determined using Cox proportional hazards regression adjusted for age and sex. RESULTS: In total, 153 (53%) patients experienced toxicities leading to modification of capecitabine treatment. Folate intake and plasma folate levels were not associated with risk of toxicities. However, use of folic acid-containing supplements during treatment (hazard ratio (HR) 1.81 and 95% confidence interval (CI) 1.15-2.85) and presence of folic acid in plasma at diagnosis (HR 2.09, 95% CI: 1.24, 3.52) and during treatment (HR 2.31, 95% CI: 1.29, 4.13) were associated with an increased risk of toxicities. CONCLUSIONS: This study suggests a potential association between folic acid and capecitabine-induced toxicities, providing a rationale to study diet-drug interactions and raise further awareness of the use of dietary supplements during oncological treatment. CLINICAL TRIAL DETAILS: This trial was registered at clinicaltrials.gov as NCT03191110.

Postdiagnostic intake of a more proinflammatory diet is associated with a higher risk of recurrence and all-cause mortality in colorectal cancer survivors.

BACKGROUND: The inflammatory potential of the diet has been associated with colorectal cancer (CRC) risk, but its association with CRC prognosis is unclear. OBJECTIVE: To investigate the inflammatory potential of the diet in relation to recurrence and all-cause mortality among persons diagnosed with stage I to III CRC. METHODS: Data of the COLON study, a prospective cohort among CRC survivors were used. Dietary intake, 6 mo after diagnosis, was assessed by using a food frequency questionnaire and was available for 1631 individuals. The empirical dietary inflammatory pattern (EDIP) score was used as a proxy for the inflammatory potential of the diet. The EDIP score was created by using reduced rank regression and stepwise linear regression to identify food groups that explained most of the variations in plasma inflammatory markers (IL6, IL8, C-reactive protein, and tumor necrosis factor-α) measured in a subgroup of survivors (n = 421). Multivariable Cox proportional hazard models with restricted cubic splines were used to investigate the relation between the EDIP score and CRC recurrence and all-cause mortality. Models were adjusted for age, sex, BMI, PAL, smoking status, stage of disease, and tumor location. RESULTS: The median follow-up time was 2.6 y (IQR: 2.1) for recurrence and 5.6 y (IQR: 3.0) for all-cause mortality, during which 154 and 239 events occurred, respectively. A nonlinear positive association between the EDIP score and recurrence and all-cause mortality was observed. For example, a more proinflammatory diet (EDIP score +0.75) compared with the median (EDIP score 0) was associated with a higher risk of CRC recurrence (HR: 1.15; 95% CI: 1.03, 1.29) and all-cause mortality (HR: 1.23; 95% CI: 1.12, 1.35). CONCLUSIONS: A more proinflammatory diet was associated with a higher risk of recurrence and all-cause mortality in CRC survivors. Further intervention studies should investigate whether a switch to a more anti-inflammatory diet improves CRC prognosis.

Combining Asian-European Genome-Wide Association Studies of Colorectal Cancer Improves Risk Prediction Across Race and Ethnicity.

Polygenic risk scores (PRS) have great potential to guide precision colorectal cancer (CRC) prevention by identifying those at higher risk to undertake targeted screening. However, current PRS using European ancestry data have sub-optimal performance in non-European ancestry populations, limiting their utility among these populations. Towards addressing this deficiency, we expanded PRS development for CRC by incorporating Asian ancestry data (21,731 cases; 47,444 controls) into European ancestry training datasets (78,473 cases; 107,143 controls). The AUC estimates (95% CI) of PRS were 0.63(0.62-0.64), 0.59(0.57-0.61), 0.62(0.60-0.63), and 0.65(0.63-0.66) in independent datasets including 1,681-3,651 cases and 8,696-115,105 controls of Asian, Black/African American, Latinx/Hispanic, and non-Hispanic White, respectively. They were significantly better than the European-centric PRS in all four major US racial and ethnic groups (p-values<0.05). Further inclusion of non-European ancestry populations, especially Black/African American and Latinx/Hispanic, is needed to improve the risk prediction and enhance equity in applying PRS in clinical practice.

Inflammatory potential of the diet and colorectal tumor risk in persons with Lynch syndrome.

Background: Persons with Lynch syndrome (LS) have high lifetime risk of developing colorectal tumors (CRTs) because of a germline mutation in one of their mismatch repair (MMR) genes. An important process in the development of CRTs is inflammation, which has been shown to be modulated by diet.Objective: We aimed to investigate the association between the inflammatory potential of the diet and the risk of CRTs in persons with LS.Design: We used the dietary intake of 457 persons with LS from a prospective cohort study to calculate the adapted dietary inflammatory index (ADII). The ADII was split into tertiles in which the highest tertile reflects the most proinflammatory potential of the diet. Cox proportional hazard models, with robust sandwich variance estimates to adjust for dependency within families, were used to calculate HRs and 95% CIs of CRTs by ADII tertile. HRs were adjusted for age, smoking status, and education level, and number of colonoscopies as a time-dependent variable. A potential effect measure modification was explored by stratifying the results by mutated MMR gene, sex, and a history of CRTs. We performed sensitivity analyses by repeating the analyses in non-nonsteroidal anti-inflammatory drug (NSAID) users (n = 315).Results: During a median follow-up time of 59 mo, 200 participants (43.8%) developed CRTs. No significant association was shown between highest compared with lowest ADII tertiles (HR for highest compared with lowest tertiles: 1.37; 95% CI: 0.80, 2.34). Stratification by mutated MMR gene, sex, and CRT history did not show significantly differential associations (P-interactions ≥ 0.64). In non-NSAID users, an HR of 1.60 (95% CI: 0.88, 2.93) for highest compared with lowest tertiles was shown. No significant effect modification was shown in this group either (P-interactions ≥ 0.24).Conclusion: A proinflammatory potential of the diet does not seem to be significantly associated with CRT risk in persons with LS.