Aya Kuchiba

Glycemic index (GI) and glycemic load (GL) are markers for postprandial glucose level. Since insulin, a hormone secreted to control hyperglycemia, is likely to promote the progression of tumor cells, the association between GI/GL and risk of colorectal cancer (CRC) has been researched for decades but still remains controversial. This study investigated the association between GI/GL and CRC risk, considering subtypes based on insulin receptor beta (IRβ) expression. In a large-scale, population-based prospective cohort study involving 18,537 Japanese participants, a total of 415 CRC cases were evaluated for IRβ expression using immunohistochemistry. GI and GL were calculated using a validated food frequency questionnaire. The Cox proportional hazards model was used to assess the hazard ratios (HRs) and 95% confidence intervals (CIs) of the risk of CRC and its specific subtypes. Additionally, we conducted sensitivity analyses to confirm the robustness of the results. No significant associations were observed between dietary GI, GL and overall CRC risk. Further, no significant associations were detected in IRβ-stratified analyses. The heterogeneities in the associations by IRβ status were also not statistically significant. (GI: p for heterogeneity 0.83 for men and 0.96 for women; GL: p for heterogeneity 0.84 for men and 0.60 for women) Sensitivity analyses yielded robust results. This study did not observe a significant association between GI/GL and overall CRC or IRβ-defined subtypes. These results, particularly those from the assessment of IRβ status, do not support a possible association between GI/GL and CRC development.

Background: Accumulating evidence suggests that one-carbon nutrient intake reduces the risk of colorectal cancer (CRC), although folate fortification has been associated with a temporary increase in CRC incidence. We hypothesized that one-carbon nutrients might harbor preventive and protumor effects on CRC according to tumor conditions and investigated whether the effect of one-carbon nutrients on CRC risk differs by TP53 status. Methods: In this prospective study of 21 708 Japanese participants, we applied a multivariable Cox proportional hazards model and examined the associations of dietary intakes of folate, vitamin B6, vitamin B12, and methionine with TP53-overexpressing (n = 192), TP53-nonoverexpressing (n = 301), TP53-mutated (n = 180), and TP53 wild-type (n = 134) CRC risk defined by TP53 immunohistochemistry and target sequence. Results: Vitamin B12 and methionine intakes were not associated with any CRC subtypes defined by TP53 status. Meanwhile, folate intake was marginally associated with decreased TP53-mutated CRC risk (hazard ratio [HR] with 95% confidence interval [CI] for the highest folate intake quartile compared with the lowest (HR = 0.82, 95% CI = 0.46 to 1.45) and increased TP53 wild-type CRC risk (HR = 1.50, 95% CI = 0.78 to 2.90). A heterogeneous effect of folate on CRC subtypes was detected (P = .03 for heterogeneity between TP53 mutation statuses). In women, the association between vitamin B6 and CRC also differed by TP53 mutation status (P = .007 for heterogeneity). The hazard ratio of vitamin B6 was 0.71 (95% CI = 0.30 to 1.67) for TP53-mutated CRC and 3.89 (95% CI = 1.79 to 8.49) for TP53 wild-type CRC. However, no heterogeneous effects were observed between TP53 expression statuses. Conclusion: This study supports the hypothesis that the effect of one-carbon nutrient intake on CRC differs according to tumor conditions.

Serial measurements of circulating tumor DNA (ctDNA) with next-generation sequencing (NGS) technology enable the real-time, noninvasive evaluation of longitudinal changes of molecular profiles in tumor tissues. These profiles can assist in monitoring disease progression and tumor response to targeted therapies, thereby facilitating informed therapeutic decision making through precise molecular characterization. While base calling errors are inherent in detecting ctDNA mutations, there is limited consideration of the effect of base calling errors on detecting variant allele frequency (VAF) changes. This study introduces the likelihood functions that incorporate the base calling error probabilities and proposes the permutation test for detecting VAF changes between two time points for a patient. Simulation studies, with scenarios based on real NGS analysis data from the TOP-GEAR project, showed that the proposed test maintained the nominal significance level at two-sided 0.05 regardless of the base calling error probabilities and VAFs. In our scenarios with 500 depth at each time point, the power of 80 % was achievable for a twofold or more increase when the VAF was 0.05 at baseline and a half or more decrease when the VAF was 0.1. Our empirical results show the utility and potential of the permutation test to detect VAF changes.

A disease of interest can often be classified into subtypes based on its various molecular or pathological characteristics. Recent epidemiological studies have increasingly provided evidence that some molecular subtypes in a disease may have distinct etiologies, by assessing whether the associations of a potential risk factor vary by disease subtypes (i.e., etiologic heterogeneity). Case-control and case-case studies are popular study designs in molecular epidemiology, and both can be validly applied in studies of etiologic heterogeneity. This study compared the efficiency of the etiologic heterogeneity parameter estimation between these two study designs by theoretical and numerical examinations. In settings where the two study designs have the same number of cases, the results showed that, compared with the case-case study, case-control studies always provided more efficient estimates or estimates with at least equivalent efficiency for heterogeneity parameters. In addition, we illustrated both approaches in a study for aiming to evaluate the association between plasma free estradiol and breast cancer risk according to the status of tumor estrogen and progesterone receptors, the results of which were originally provided through case-control study data.

Background: The mechanistic associations between obesity and risk of colorectal cancer (CRC) remain unclear. Here, using body mass index (BMI) as an obesity indicator, we decomposed the total effects of obesity on the risk of CRC into: (1) direct effects, which are possibly mediated by unmeasured or currently unknown factors; (2) indirect effects mediated by circulating leptin and adiponectin; and (3) indirect effects that are not mediated by circulating leptin and adiponectin but by hyperinsulinemia and chronic inflammation (assessed via circulating connecting peptide and C-reactive protein, respectively).Methods: We adopted a causal mediation framework, using data from a large prospective cohort study of 44,271 Japanese men.Results: BMI was not associated with the risk of CRC due to direct and indirect effects that were not mediated by circulating leptin and adiponectin. By contrast, individuals with BMIs of 25.0–27.4 kg/m2 (risk ratio, 1.29; 95% confidence interval, 0.98–1.69) and ≥27.5 kg/m2 (risk ratio, 1.28; 95% confidence interval, 0.98–1.68) had a higher risk of CRC due to indirect effects of circulating leptin and adiponectin.Conclusions: Our mediation analyses suggest that the association between BMI and CRC risk may be largely mediated by a pathway involving circulating leptin and adiponectin.