Person:

Hanyuda, Akiko

Background. High-level physical activity is associated with lower colorectal cancer (CRC) mortality, likely through insulin sensitization. Insulin receptor substrate 1 (IRS1) is a mediator of insulin and insulin-like growth factor (IGF) signaling pathways, and its down-regulation is associated with insulin resistance. Therefore, we hypothesized that tumor IRS1 expression status might modify cellular sensitivity to insulin and IGF, and the prognostic association of physical activity.Methods. We assessed IRS1 expression level in 371 stage I-III rectal and colon cancers in the Nurses' Health Study and the Health Professionals Follow-up Study by immunohistochemistry. In survival analysis, Cox proportional hazards model was used to assess an interaction between post-diagnosis physical activity (ordinal scale of sex-specific quartiles Q1 to Q4) and IRS1 expression (ordinal scale of negative, low, and high), controlling for potential confounders, including microsatellite instability, CpG island methylator phenotype, long interspersed nucleotide element-1 (LINE-1) methylation level, and KRAS, BRAF, and PIK3CA mutation status.Results. There was a statistically significant interaction between post-diagnosis physical activity and tumor IRS1 expression in CRC-specific mortality analysis (P-interaction = 0.005). Multivariable hazard ratio (95 % confidence interval) for higher post-diagnosis physical activity (Q3-Q4 vs. Q1-Q2) was 0.15 (0.02-1.38) in the IRS1-negative group, 0.45 (0.19-1.03) in the IRS1-low group, and 1.32 (0.50-3.53) in the IRS1-high group.Conclusions. The association of post-diagnosis physical activity with colorectal carcinoma patient survival may differ by tumor IRS1 expression level. If validated, tumor IRS1 expression status may serve as a predictive marker to identify subgroups of patients who might gain greater survival benefit from an increased level of exercise.

Higher body mass index (BMI), higher body adiposity, and obesity have been associated with increased risk of colorectal cancer. Evidence suggests that excess energy balance may influence systemic immune and inflammatory status. Thus, we hypothesized that the positive association between BMI and colorectal cancer risk might differ according to colorectal carcinoma subtypes according to levels of histopathological lymphocytic reaction to tumor. We collected biennial questionnaire data on weight and baseline height information in two prospective cohort studies, the Nurses’ Health Study (1980–2010) and the Health Professionals Follow-up Study (1986–2010). Utilizing duplication-method Cox proportional hazards regression models, we prospectively assessed the association between BMI and risk of colorectal cancer subtypes according to the degree of Crohn’s-like lymphoid reaction, peritumoral lymphocytic reaction, intratumoral periglandular reaction, tumor-infiltrating lymphocytes, the overall lymphocytic reaction score, or T-cell [CD3+, CD8+, CD45RO (PTPRC)+, or FOXP3+] density in tumor tissue. Statistical significance level was adjusted for multiple hypotheses testing by Bonferroni correction. During follow up of 1,708,029 men and women (over 3,346,752 person-years), we documented 1,436 incident rectal and colon cancer cases with available formalin-fixed paraffin-embedded tumor tissue materials and pathological immunity data. BMI was significantly associated with higher risk of overall colorectal cancer (Ptrend<0.001); however, the association of BMI with colorectal carcinoma risk did not significantly differ by the level of lymphocytic reaction or T-cell infiltration in tumor tissue status (Pheterogeneity>0.10). BMI may be associated with risk of colorectal cancer regardless of levels of lymphocytic response to tumor.