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Background: Type 2 diabetes increases risk of developing colorectal cancer, but the association of preexisting diabetes with colorectal cancer survival remains unclear. Methods: We analyzed survival by diabetes status at cancer diagnosis among 4,038 patients with colorectal cancer from two prospective U.S. cohorts. Cox proportional hazards regression was used to calculate HRs and 95% confidence intervals (CI) for overall and cause-specific mortality, with adjustment for tumor characteristics and lifestyle factors. Results: In the first 5 years after colorectal cancer diagnosis, diabetes was associated with a modest increase in overall mortality in women (HR, 1.22; 95% CI, 1.00-1.49), but not in men (HR, 0.83; 95% CI, 0.62-1.12; P heterogeneity by sex = 0.04). Beyond 5 years, diabetes was associated with substantially increased overall mortality with no evidence of sex heterogeneity; in women and men combined, the HRs were 1.45 (95% CI, 1.09-1.93) during >5-10 years and 2.58 (95% CI, 1.91-3.50) during >10 years. Compared with those without diabetes, patients with colorectal cancer and diabetes had increased mortality from other malignancies (HR, 1.78; 95% CI, 1.18-2.67) and cardiovascular disease (HR, 1.93; 95% CI, 1.29-2.91). Only women with diabetes for more than 10 years had increased mortality from colorectal cancer (HR, 1.33; 95% CI, 1.01-1.76). Conclusions: Among patients with colorectal cancer, preexisting diabetes was associated with increased risk of long-term mortality, particularly from other malignancies and cardiovascular disease. [ABSTRACT FROM AUTHOR]

Background: Low serum 25-hydroxyvitamin D [25(OH)D] concentrations in patients with colorectal cancer have been consistently associated with higher mortality in observational studies. It is unclear whether low 25(OH)D levels directly influence colorectal cancer mortality. To minimize bias, we use genetic variants associated with vitamin D levels to evaluate the association with overall and colorectal cancer-specific survival. Methods: Six genetic variants have been robustly identified to be associated with 25(OH)D levels in genome-wide association studies. On the basis of data from the International Survival Analysis in Colorectal Cancer Consortium, the individual genetic variants and a weighted genetic risk score were tested for association with overall and colorectal cancer-specific survival using Cox proportional hazards models in 7,657 patients with stage I to IV colorectal cancer, of whom 2,438 died from any cause and 1,648 died from colorectal cancer. Results: The 25(OH)D decreasing allele of SNP rs2282679 (GC gene, encodes group-specific component/vitamin D-binding protein) was associated with poorer colorectal cancer-specific survival, although not significant after multiple-testing correction. None of the other five SNPs showed an association. The genetic risk score showed nonsignificant associations with increased overall [HR = 1.54; confidence interval (CI), 0.86-2.78] and colorectal cancer-specific mortality (HR = 1.76; 95% CI, 0.86-3.58). A significant increased risk of overall mortality was observed in women (HR = 3.26; 95% CI, 1.45-7.33; Pheterogeneity = 0.01) and normal-weight individuals (HR = 4.14; 95% CI, 1.50-11.43, Pheterogeneity = 0.02). Conclusions: Our results provided little evidence for an association of genetic predisposition of lower vitamin D levels with increased overall or colorectal cancer-specific survival, although power might have been an issue. Impact: Further studies are warranted to investigate the association in specific subgroups. [ABSTRACT FROM AUTHOR]

Background: Higher intake of long-chain ω-3 polyunsaturated fatty acids and nuts, rich plant sources of unsaturated fats, after colon cancer diagnosis are associated with improved survival. It is not known whether the amount or the distribution of other types of fat is associated with survival after colon cancer. Methods: We prospectively examined postdiagnostic total, animal, and vegetable fats, as well as the saturated, monounsaturated, polyunsaturated, and trans fat in relation to disease-free survival among 1,011 patients with stage III colon cancer. Patients were enrolled between 1999 and 2001 at the onset of adjuvant chemotherapy and followed for recurrence or death through 2009. Results: During median follow-up of 7 years, we observed 305 deaths and 81 recurrences (total events: 386). Neither total nor any specific type of dietary fat examined was statistically significantly associated with risk of cancer recurrence or death from any cause (disease-free survival) after stage III colon cancer. Conclusions: The amount and type (animal, vegetable, saturated, monounsaturated, polyunsaturated, and trans) of dietary fat consumed after colon cancer does not appear to be substantially associated with risk of recurrence or survival. Impact: Neither total nor major types (animal, vegetable, saturated, monounsaturated, polyunsaturated, and trans) of dietary fat consumed after colon cancer was associated with cancer recurrence or survival. [ABSTRACT FROM AUTHOR]

Background: High body mass index (BMI) is consistently linked to increased risk of colorectal cancer for men, whereas the association is less clear for women. As risk estimates from observational studies may be biased and/or confounded, we conducted a Mendelian randomization study to estimate the causal association between BMI and colorectal cancer. Methods: We used data from 10,226 colorectal cancer cases and 10,286 controls of European ancestry. The Mendelian randomization analysis used a weighted genetic risk score, derived from 77 genome-wide association study-identified variants associated with higher BMI, as an instrumental variable (IV). We compared the IV odds ratio (IV-OR) with the OR obtained using a conventional covariate-adjusted analysis. Results: Individuals carrying greater numbers of BMI-increasing alleles had higher colorectal cancer risk [per weighted allele OR, 1.31; 95% confidence interval (CI), 1.10-1.57]. Our IV estimation results support the hypothesis that genetically influenced BMI is directly associated with risk for colorectal cancer (IV-OR per 5 kg/m², 1.50; 95% CI, 1.13-2.01). In the sex-specific IV analyses higher BMI was associated with higher risk of colorectal cancer among women (IV-OR per 5 kg/m², 1.82; 95% CI, 1.26-2.61). For men, genetically influenced BMI was not associated with colorectal cancer (IV-OR per 5 kg/m², 1.18; 95% CI, 0.73-1.92). Conclusions: High BMI was associated with increased colorectal cancer risk for women. Whether abdominal obesity, rather than overall obesity, is a more important risk factor for men requires further investigation. Impact: Overall, conventional epidemiologic and Mendelian randomization studies suggest a strong association between obesity and the risk of colorectal cancer. [ABSTRACT FROM AUTHOR]

Information about the 38th Annual Meeting of American Society of Preventive Oncology (ASPO) held March 9-11, 2014, in Arlington, Virginia, in association with the Molecular Epidemiology and the Environment Special Interest Group (SIG) is presented. Topics include challenges in international molecular cancer prevention research, role of biomarkers in cancer research, environmental exposures and cancer, and molecular pathologic epidemiology (MPE).

The article a cohort study that examined the association of prediagnostic circulating C-reactive protein (CRP), interleukin-6 (IL-6) and TNF-α receptor II (TNF-&#945R2) and subsequent pancreatic cancer risk. Also examined are the effect of chronic inflammation in cancer development, as well as such chronic inflammatory conditions like chronic pancreatitis, obesity and type-II diabetes.

The article presents a prospective cohort study on the implications of cathepsin B (CTSB) expression and survival in colon cancer for molecular detection of neoplasia. For the study, researchers examined 558 men and women diagnosed with colon cancer with tumors. They found that 82 percent of the patients had tumors with CTSB expression and 18 percent has tumors without CTSB expression. They concluded that CTSB is linked to increased risk of colon cancer-specific and overall mortality.

The article discusses a study that explored the association between prostaglandin E receptors 2 (PTGER2) overexpression in colorectal cancer and microsatellite instability (MSI). The importance of PTGER2 in human colorectal cancer is examined and the overall prevalence of PTGER2 expression in a large number of tumors is determined. The study confirmed the association between PTGER2 overexpression and MSI-high in colorectal cancer.

The article presents a study on the association of vitamin D receptor (VDR) to phosphatidylinositol 3-kinase-AKT (PIK3CA) and K-Ras oncogene-associated gene (KRAS) mutations in colorectal cancer. VDR is associated in reducing the risks in various cancers. The study was undertaken through analyzing PIK3CA and KRAS mutations by Pyrosequencing, microsatellite instability (MSI) and DNA methylation. Results show that VDR expression displays an independent association with KRAS and PIK3CA mutations.

The article offers a study which examines the effect of tumoral p21 loss, patient age, and body mass index (BMI) on patient survival in patients with stages I to IV colon cancer. It mentions that tumoral p21 loss was related to longer survival, independent of patient characteristics and other related molecular variables. It is stated that the adverse effect of obesity on clinical results was observed only among patients with p21-expressing tumors.

The article discusses a cohort study which investigates the p27 gene localization in colon cancer, body mass index (BMI) and cancer patient survival. It discovers that the effect of p27 gene alteration on overall mortality varied by BMI and obesity is linked with inferior overall survival among p27-nuclear+ cases. It concludes that p27 alterations in colon cancer are associated with superior prognosis.

The article presents a study which examines the relation between dietary intake of one-carbon nutrients such as folate and B vitamins, and the incidence of microsatellite instability (MSI) and KRAS mutation in colon cancers. The results of the study based on the MSI or KRAS status are presented and discussed. The study concludes that the influence of dietary one-carbon nutrient intake on colon cancer risk does not seem to differ according to MSI or KRAS mutational status.

Dysregulation of the WNT/β-catenin (CTNNB1) signaling pathway is implicated in colorectal carcinoma and metabolic diseases. Considering these roles and cancer prevention, we hypothesized that tumor CTNNB1 status might influence cellular sensitivity to obesity and physical activity. In clinical follow-up of 109,046 women in the Nurses' Health Study and 47,684 men in the Health Professionals Follow-up Study, there were 861 incident rectal and colon cancers with tissue immunohistochemistry data on nuclear CTNNB1 expression. Using this molecular pathological epidemiology database, we conducted Cox proportional hazards regression analysis using data duplication method to assess differential associations of body mass index (BMI) or exercise activity with colorectal cancer risk according to tumor CTNNB1 status. Greater BMI was associated with a significantly higher risk of CTNNB1-negative cancer [multivariate HR = 1.34; 95% confidence interval (CI), 1.18-1.53 for 5.0 kg/m² increment; Ptrend = 0.0001] but not with CTNNB1-positive cancer risk (multivariate HR = 1.07; 95% CI, 0.92-1.25 for 5.0 kg/m² increment; Ptrend = 0.36; Pheterogeneity = 0.027, between CTNNB1-negative and CTNNB1-positive cancer risks). Physical activity level was associated with a lower risk of CTNNB1-negative cancer (multivariate HR = 0.93; 95% CI, 0.87-1.00 for 10 MET-h/wk increment; Ptrend = 0.044) but not with CTNNB1-positive cancer risk (multivariate HR = 0.98; 95% CI, 0.91-1.05 for 10 MET-h/wk increment; Ptrend = 0.60). Our findings argue that obesity and physical inactivity are associated with a higher risk of CTNNB1-negative colorectal cancer but not with CTNNB1-positive cancer risk. Furthermore, they suggest that energy balance and metabolism status exerts its effect in a specific carcinogenesis pathway that is less likely dependent on WNT/CTNNB1 activation. [ABSTRACT FROM AUTHOR]

Experimental studies have shown that estrogen- or progesterone-activated signaling leads to growth inhibition effects on colon cancer cells through the upregulation of several cell-cycle regulators. However, epidemiologic studies evaluating hormone therapy use and colorectal cancer risk by the status of cell-cycle regulators are lacking. In this study, we used data from the prospective Nurses' Health Study to evaluate whether the association between hormone therapy use and colorectal cancer risk differs by the molecular pathologic status of microsatellite instability (MSI) and expression of cell-cycle--related tumor biomarkers, including CDKN1A (p21, CIP1), CDKN1B (p27, KIP1), and TP53 (p53) by immunohistochemistry. Duplication Cox regression analysis was used to determine an association between hormone therapy use, cancer risk, and specific tumor biomarkers in 581 incident colon and rectal cancer cases that occurred during 26 years of follow-up among 105,520 postmenopausal women. We found a difference between hormone therapy use and colorectal cancer risk according to CDKN1A expression (Pheterogeneity 1/4 0.01). Current hormone therapy use was associated with a reduced risk for CDKN1A-nonexpressed [multivariate relative risk (RR), 0.61; 95% confidence interval (CI), 0.46-0.82] but not for CDKN1A-expressed (RR, 1.32; 95% CI, 0.76-2.31) tumors. The lower risk for CDKN1A- nonexpressed but not for CDKN1A-expressed cancers was also present among current users of estrogen-alone therapy. We found no significant difference in the relations between hormone therapy use and cancer risk according to MSI, CDKN1B, or TP53 status. Together, our molecular pathological epidemiology findings suggest a preventive effect of hormone therapy against colorectal carcinogenesis that depends, in part, on loss of cyclin-dependent kinase inhibitor CDKN1A. [ABSTRACT FROM AUTHOR]

Colorectal cancers (CRC) express the WNT effector protein β-catenin in a heterogeneous subcellular pattern rather than uniformly in the nucleus. In this study, we investigated this important aspect of molecular heterogeneity in CRCs by analyzing its basis and relationship with tumor-initiating capability. CRC cells with the highest WNT levels showed only a marginal increase in tumor initiation capacity. Notably, high WNT activity correlated with a coincident activation of robust mitogen-activated protein kinase (MAPK) signaling, which when upregulated by KRAS expression or downregulated by epidermal growth factor receptor inhibition elicited parallel effects on WNT activity. These findings suggested that on its own high WNT activity may not be a reliable signifier of tumor-initiating potential or stem-like potential. Furthermore, they suggest that MAPK signaling is a critical modifier of intratumoral heterogeneity that contributes significantly to determining the impact of WNT activity on stemness phenotypes in colon cancer cells. [ABSTRACT FROM AUTHOR]

Summary: Biological characteristics of tumors are heterogeneous, forming spectra in terms of several factors such as age at onset, anatomic spatial localization, tumor subtyping, and the degree of tumor aggressiveness (encompassing a neoplastic property spectrum). Instead of blindly using dichotomized approaches, the application of the multicategorical and continuous analysis approaches to detailed cancer spectrum data can contribute to a better understanding of the etiology of cancer, ultimately leading to effective prevention and precision oncology. We provide examples of cancer spectra and emphasize the importance of integrating the cancer spectrum theory into large-scale population cancer research., (©2024 American Association for Cancer Research.)

Background: The genotoxin colibactin causes a tumor single-base substitution (SBS) mutational signature, SBS88. It is unknown whether epidemiologic factors' association with colorectal cancer risk and survival differs by SBS88., Methods: Within the Genetic Epidemiology of Colorectal Cancer Consortium and Colon Cancer Family Registry, we measured SBS88 in 4,308 microsatellite stable/microsatellite instability low tumors. Associations of epidemiologic factors with colorectal cancer risk by SBS88 were assessed using multinomial regression (N = 4,308 cases, 14,192 controls; cohort-only cases N = 1,911), and with colorectal cancer-specific survival using Cox proportional hazards regression (N = 3,465 cases)., Results: 392 (9%) tumors were SBS88 positive. Among all cases, the highest quartile of fruit intake was associated with lower risk of SBS88-positive colorectal cancer than SBS88-negative colorectal cancer [odds ratio (OR) = 0.53, 95% confidence interval (CI) 0.37-0.76; OR = 0.75, 95% CI 0.66-0.85, respectively, Pheterogeneity = 0.047]. Among cohort studies, associations of body mass index (BMI), alcohol, and fruit intake with colorectal cancer risk differed by SBS88. BMI ≥30 kg/m2 was associated with worse colorectal cancer-specific survival among those SBS88-positive [hazard ratio (HR) = 3.40, 95% CI 1.47-7.84], but not among those SBS88-negative (HR = 0.97, 95% CI 0.78-1.21, Pheterogeneity = 0.066)., Conclusions: Most epidemiologic factors did not differ by SBS88 for colorectal cancer risk or survival. Higher BMI may be associated with worse colorectal cancer-specific survival among those SBS88-positive; however, validation is needed in samples with whole-genome or whole-exome sequencing available., Impact: This study highlights the importance of identification of tumor phenotypes related to colorectal cancer and understanding potential heterogeneity for risk and survival., (©2024 American Association for Cancer Research.)

Colorectal cancer risk can be impacted by genetic, environmental, and lifestyle factors, including diet and obesity. Gene-environment interactions (G × E) can provide biological insights into the effects of obesity on colorectal cancer risk. Here, we assessed potential genome-wide G × E interactions between body mass index (BMI) and common SNPs for colorectal cancer risk using data from 36,415 colorectal cancer cases and 48,451 controls from three international colorectal cancer consortia (CCFR, CORECT, and GECCO). The G × E tests included the conventional logistic regression using multiplicative terms (one degree of freedom, 1DF test), the two-step EDGE method, and the joint 3DF test, each of which is powerful for detecting G × E interactions under specific conditions. BMI was associated with higher colorectal cancer risk. The two-step approach revealed a statistically significant G×BMI interaction located within the Formin 1/Gremlin 1 (FMN1/GREM1) gene region (rs58349661). This SNP was also identified by the 3DF test, with a suggestive statistical significance in the 1DF test. Among participants with the CC genotype of rs58349661, overweight and obesity categories were associated with higher colorectal cancer risk, whereas null associations were observed across BMI categories in those with the TT genotype. Using data from three large international consortia, this study discovered a locus in the FMN1/GREM1 gene region that interacts with BMI on the association with colorectal cancer risk. Further studies should examine the potential mechanisms through which this locus modifies the etiologic link between obesity and colorectal cancer., Significance: This gene-environment interaction analysis revealed a genetic locus in FMN1/GREM1 that interacts with body mass index in colorectal cancer risk, suggesting potential implications for precision prevention strategies., (©2023 The Authors; Published by the American Association for Cancer Research.)

Serrated polyps (SP) are precursors for colorectal cancer and contribute disproportionately to postcolonoscopy cancers. Leveraging three U.S. cohorts (43,974 women and 5,322 men), we developed prediction models for high-risk SPs (sized ≥10 mm or ≥3) among individuals undergoing their first colonoscopy screening. We then validated the model in the Partners Colonoscopy Cohort (51,203 women and 39,077 men). We evaluated discrimination and calibration using the C-statistic and Hosmer-Lemeshow test, respectively. The age and family history model generated a C-statistic [95% confidence interval (CI)] of 0.57 (0.56-0.58) in women and 0.58 (0.55-0.61) in men. Further inclusion of smoking, alcohol, and body mass index (the simple model) increased the C-statistic (95% CI) to 0.68 (0.67-0.69) in women and 0.68 (0.66-0.71) in men (all P < 0.001). Adding more predictors did not provide much incremental predictivity. In the validation cohort, moderate discrimination was observed in both women (0.60, 0.58-0.61) and men (0.60, 0.59-0.62). Notably, the simple model also yielded similar C-statistics for a composite endpoint of SPs and high-risk conventional adenomas (women, 0.62, 0.62-0.63; men, 0.63, 0.61-0.64). The model was adequately calibrated in both sets of cohorts. In summary, we developed and externally validated a simple prediction model based on five major risk factors for high-risk SPs that may be useful for healthy lifestyle recommendations and tailored colorectal cancer screening., Prevention Relevance: On the basis of four prospective studies in the United States, we developed and externally validated a simple risk prediction model for high-risk SPs in the setting of colonoscopy screening. Our model showed moderate discriminatory accuracy and has potential utility for individualized risk assessment, healthy lifestyle recommendations, and tailored colorectal cancer prevention., (©2023 American Association for Cancer Research.)

Background: Tobacco smoking is an established risk factor for colorectal cancer. However, genetically defined population subgroups may have increased susceptibility to smoking-related effects on colorectal cancer., Methods: A genome-wide interaction scan was performed including 33,756 colorectal cancer cases and 44,346 controls from three genetic consortia., Results: Evidence of an interaction was observed between smoking status (ever vs. never smokers) and a locus on 3p12.1 (rs9880919, P = 4.58 × 10-8), with higher associated risk in subjects carrying the GG genotype [OR, 1.25; 95% confidence interval (CI), 1.20-1.30] compared with the other genotypes (OR <1.17 for GA and AA). Among ever smokers, we observed interactions between smoking intensity (increase in 10 cigarettes smoked per day) and two loci on 6p21.33 (rs4151657, P = 1.72 × 10-8) and 8q24.23 (rs7005722, P = 2.88 × 10-8). Subjects carrying the rs4151657 TT genotype showed higher risk (OR, 1.12; 95% CI, 1.09-1.16) compared with the other genotypes (OR <1.06 for TC and CC). Similarly, higher risk was observed among subjects carrying the rs7005722 AA genotype (OR, 1.17; 95% CI, 1.07-1.28) compared with the other genotypes (OR <1.13 for AC and CC). Functional annotation revealed that SNPs in 3p12.1 and 6p21.33 loci were located in regulatory regions, and were associated with expression levels of nearby genes. Genetic models predicting gene expression revealed that smoking parameters were associated with lower colorectal cancer risk with higher expression levels of CADM2 (3p12.1) and ATF6B (6p21.33)., Conclusions: Our study identified novel genetic loci that may modulate the risk for colorectal cancer of smoking status and intensity, linked to tumor suppression and immune response., Impact: These findings can guide potential prevention treatments., (©2022 American Association for Cancer Research.)

Current recommendations for colorectal cancer screening have not accounted for type 2 diabetes (T2D) status. It remains unknown whether the colorectal cancer-preventive benefit of endoscopic screening and the recommended age for screening initiation differ by T2D. Among 166,307 women (Nurses' Health Study I and II, 1988-2017) and 42,875 men (Health Professionals Follow-up Study, 1988-2016), endoscopic screening and T2D diagnosis were biennially updated. We calculated endoscopic screening-associated hazard ratios (HR) and absolute risk reductions (ARR) for colorectal cancer incidence and mortality according to T2D, and age-specific colorectal cancer incidence according to T2D. During a median of 26 years of follow-up, we documented 3,457 colorectal cancer cases and 1,129 colorectal cancer deaths. Endoscopic screening was associated with a similar HR of colorectal cancer incidence in the T2D and non-T2D groups (P-multiplicative interaction = 0.57). In contrast, the endoscopic screening-associated ARR for colorectal cancer incidence was higher in the T2D group (2.36%; 95% CI, 1.55%-3.13%) than in the non-T2D group (1.73%; 95% CI, 1.29%-2.16%; P-additive interaction = 0.01). Individuals without T2D attained a 10-year cumulative risk of 0.35% at the benchmark age of 45 years, whereas those with T2D reached this threshold risk level at the age of 36 years. Similar results were observed for colorectal cancer mortality. In conclusion, the absolute benefit of endoscopic screening for colorectal cancer prevention may be substantially higher for individuals with T2D compared with those without T2D. Although T2D is comparatively rare prior to the fifth decade of life, the rising incidence of young-onset T2D and heightened colorectal cancer risk associated with T2D support the consideration of earlier endoscopic screening in individuals with T2D., Prevention Relevance: The endoscopic screening-associated ARRs for colorectal cancer incidence and mortality were higher for individuals with T2D than those without T2D. Endoscopic screening confers a greater benefit for colorectal cancer prevention among T2D individuals, who may also benefit from an earlier screening than the current recommendation., (©2022 American Association for Cancer Research.)