Molecular markers associated with elevated colorectal cancer risk: a mini review

Increasing evidence suggests that red and processed meat consumption may elevate the risk of colorectal cancer (CRC), yet the magnitude and consistency of this association remain debated. This meta-analysis aims to quantify the relationship between red and processed meat intake and the risk of CRC, colon cancer, and rectal cancer using the most comprehensive set of prospective studies to date. We conducted a comprehensive search in PubMed, Web of Science, Cochrane Library, Embase, and Google Scholar databases from 1990 to November 2024, to identify relevant prospective studies examining red, processed, and total meat consumption in relation to colorectal, colon, and rectal cancer risk. Hazard ratios (HR) and 95% confidence intervals (CI) were extracted for each study and pooled using a random-effects model to account for variability among studies. Statistical evaluation was executed using the online platform MetaAnalysisOnline.com. A total of 60 prospective studies were included. Red meat consumption was associated with a significantly increased risk of colon cancer (HR = 1.22, 95% CI 1.15–1.30), colorectal cancer (HR = 1.15, 95% CI 1.10–1.21), and rectal cancer (HR = 1.22, 95% CI 1.07–1.39). Processed meat consumption showed similar associations with increased risk for colon cancer (HR = 1.13, 95% CI 1.07–1.20), colorectal cancer (HR = 1.21, 95% CI 1.14–1.28), and rectal cancer (HR = 1.17, 95% CI 1.05–1.30). Total meat consumption also correlated with an elevated risk of colon cancer (HR = 1.22, 95% CI 1.11–1.35), colorectal cancer (HR = 1.17, 95% CI 1.12–1.22), and rectal cancer (HR = 1.28, 95% CI 1.10–1.48). This meta-analysis provides robust evidence that high consumption of red and processed meats is significantly associated with an increased risk of colorectal, colon, and rectal cancers. These findings reinforce current dietary recommendations advocating for the limitation of red and processed meat intake as part of cancer prevention strategies.

352 Elevated Risk of Advanced Adenomas and Colorectal Cancer in Relatives of Patients With Advanced Adenomas: A Population-Based Study in Utah

Waist circumference (WC) and its allometric counterpart, "a body shape index" (ABSI), are risk factors for colorectal cancer; however, it is uncertain whether associations with these body measurements are limited to specific molecular subtypes of the disease. Data from 2,772 colorectal cancer cases and 3,521 controls were pooled from four cohort studies within the Genetics and Epidemiology of Colorectal Cancer Consortium. Four molecular markers (BRAF mutation, KRAS mutation, CpG island methylator phenotype, and microsatellite instability) were analyzed individually and in combination (Jass types). Multivariable logistic and multinomial logistic models were used to assess the associations of WC and ABSI with overall colorectal cancer risk and, in case-only analyses, to evaluate heterogeneity by molecular subtype, respectively. Higher WC (ORper 5 cm = 1.06, 95% confidence interval, 1.04-1.09) and ABSI (ORper 1-SD = 1.07, 95% confidence interval, 1.00-1.14) were associated with elevated colorectal cancer risk. There was no evidence of heterogeneity between the molecular subtypes. No difference was observed regarding the influence of WC and ABSI on the four major molecular markers in proximal colon, distal colon, and rectal cancers, as well as in early- and late-onset colorectal cancers. Associations did not differ in the Jass-type analysis. Higher WC and ABSI were associated with elevated colorectal cancer risk; however, they do not differentially influence all four major molecular mutations involved in colorectal carcinogenesis but underscore the importance of maintaining a healthy body weight in colorectal cancer prevention. The proposed results have potential utility in colorectal cancer prevention.

<div>AbstractBackground:<p>Waist circumference (WC) and its allometric counterpart, “a body shape index” (ABSI), are risk factors for colorectal cancer; however, it is uncertain whether associations with these body measurements are limited to specific molecular subtypes of the disease.</p>Methods:<p>Data from 2,772 colorectal cancer cases and 3,521 controls were pooled from four cohort studies within the Genetics and Epidemiology of Colorectal Cancer Consortium. Four molecular markers (<i>BRAF</i> mutation, <i>KRAS</i> mutation, CpG island methylator phenotype, and microsatellite instability) were analyzed individually and in combination (Jass types). Multivariable logistic and multinomial logistic models were used to assess the associations of WC and ABSI with overall colorectal cancer risk and, in case-only analyses, to evaluate heterogeneity by molecular subtype, respectively.</p>Results:<p>Higher WC (OR<sub>per 5 cm</sub> = 1.06, 95% confidence interval, 1.04–1.09) and ABSI (OR<sub>per 1-SD</sub> = 1.07, 95% confidence interval, 1.00–1.14) were associated with elevated colorectal cancer risk. There was no evidence of heterogeneity between the molecular subtypes. No difference was observed regarding the influence of WC and ABSI on the four major molecular markers in proximal colon, distal colon, and rectal cancers, as well as in early- and late-onset colorectal cancers. Associations did not differ in the Jass-type analysis.</p>Conclusions:<p>Higher WC and ABSI were associated with elevated colorectal cancer risk; however, they do not differentially influence all four major molecular mutations involved in colorectal carcinogenesis but underscore the importance of maintaining a healthy body weight in colorectal cancer prevention.</p>Impact:<p>The proposed results have potential utility in colorectal cancer prevention.</p></div>

The androgen dependence of prostate cancer has led to therapeutic strategies designed to lower androgen levels to treat this cancer. Circulating male hormones including the principal androgen, testosterone, are synthesized primarily in the testes and also in the adrenal glands and peripheral tissues. In most prostate cancer patients, treatment with gonadotrophin-releasing hormone agonists or orchidectomy effectively inhibits testicular androgen synthesis and lowers plasma testosterone levels close to the detection limit of most conventional assays, leading to a reduction in plasma levels of prostate-specific antigen and tumor regression. However, the treatment also comes with several adverse effects and, over time, a subset of tumor cells survives in the androgen-depleted environment and becomes resistant to the therapies. Although colorectal cancer is generally not considered to be a hormone-related malignancy, accumulating evidence has suggested that sex hormones are relevant to its development. Over the past three decades, epidemiological studies in women have consistently shown that an increase in female hormones such as estrogens and progestin as a result of pregnancy or use of exogenous steroid hormones is associated with a lower risk for developing colorectal cancer (1–3). In support of these results, the Women’s Health Initiative estrogen plus progestin clinical trial reported an approximately 40% lower risk for colorectal cancer in the treatment group as compared with the placebo group (4,5). By contrast, the other Women’s Health Initiative trial did not demonstrate a lower risk of colorectal cancer among hysterectomized women treated with estrogen alone (6,7). Two recent observational studies also found no reduced risk for colorectal cancer incidence among postmenopausal women with higher circulating levels of estradiol and estrone (8,9). These observations seem to suggest that progesterone, but not estrogen, may be the key candidate for reduction of colorectal cancer risk in women. Because the endogenous synthesis of sex hormones and their activation of transcription in target tissues are determined by biosynthetic enzymes, metabolizing enzymes, and steroid receptors, genetic and epigenetic modifications of the genes for these proteins may also affect the risk of cancer associated with sex hormones. Little is known about the association between sex hormone levels and colorectal cancer risk in men. Two observational studies have supported the hypothesis that lower androgenicity may increase men’s risk of developing colorectal cancer (10,11). An increase (≥23) in the number of CAG repeats in the gene for the androgen receptor, which is related to lower transcriptional activation by the androgen receptor and thus lower androgenic action in tissues, was associated with elevated risk of colon cancer (10). An inverse association with borderline statistical significance was observed between plasma dehydroepiandrosterone sulfate and colon cancer risk (11). These preliminary data await confirmation in large prospective cohort studies. In this issue of the Journal, Gillessen et al. (12) present an interesting evaluation of the association between androgen deprivation therapies and subsequent risk of developing colorectal cancer in 107 859 prostate cancer patients aged 67 years or older in the Surveillance, Epidemiology, and End Results–Medicare database beginning in 1993. As of 2004, they identified 2035 patients who subsequently developed colorectal cancer. Patients who received treatment with gonadotrophin-releasing hormone agonists or orchiectomy had a 30%–40% increased risk of developing colorectal cancer relative to those who did not have the therapies. The observed associations were not modified by tumor location and grade. The authors also reported a dose–response trend of increased colorectal cancer risk with longer duration of the anti-androgen therapies. The increased risk appeared to arise relatively quickly, perhaps as early as within one year, suggesting that hormones may influence relatively late processes of carcinogenesis. The risk appeared to increase across years of duration of treatment, but the cut point for the upper category was only “greater than 2 years,” so it is not known whether risk would increase further with longer treatment. A meta-analysis of five prospective studies in postmenopausal women (3) found no additional reduction in the risk of colorectal cancer with longer duration of hormone therapy use (ie, ≥5 years) as compared with shorter exposures (<5 years). Medical history and several lifestyle and dietary factors have a potential role in colorectal cancer development and may confound the associations observed by Gillessen et al. For instance, patients who receive gonadotrophin-releasing hormone agonist injections may have more medical health-care contacts and are thus more likely to receive screening examinations by colonoscopy or sigmoidoscopy as well as other physical checkups. The authors have prudently addressed these issues with adjustment for screening examinations received after diagnosis of prostate cancer, obesity diagnosis, and incident diabetes in their models. In this study population, patients with androgen-deprivation therapies were more likely to have advanced prostate cancer. Conceivably, these patients might be more physically inactive and might engage in fewer outdoor activities and thus may potentially have lower vitamin D, all of which have been associated with an increased risk of colorectal cancer (13). The authors have additionally adjusted for prostate tumor grade and stage as a proxy for lifestyle or dietary factors that potentially differ in patients who did or did not receive anti-hormone therapy. The mechanisms underlying the inverse association between androgen levels and colorectal cancer risk in men are unclear. Findings from laboratory studies in male rodents have suggested that androgens inhibit colorectal tumor growth, likely through the activation of androgen receptor signaling pathway. Male rats with azoxymethane-induced cancers of the colon have increased colonic tumorigenesis following castration (13) but have reduced formation of aberrant crypt foci and tumors when treated with the potent androgen dihydrotestosterone (14,15). Treatment of nude mice with dihydrotestosterone also resulted in growth inhibition of xenografts of colorectal adenocarcinoma where expression of androgen receptor was present (16). It has further been shown in human colon cancer cell lines that activation of the ligand-bound androgen receptor results in the suppression of β-catenin transcription, leading to decreased expression of β-catenin target oncogenes, including cyclin D1 (17). Obesity has been consistently associated with increased colorectal cancer risk in men. Hyperinsulinemia and insulin resistance may be causally linked to obesity and colorectal cancer development (18). Obese men also tend to have lower androgen levels (19). Treatment with testosterone reduces insulin resistance in men (20), suggesting a role of androgens in promoting insulin sensitivity. Thus, insulin resistance as a consequence of anti-androgen therapies is another plausible mechanism for the elevated colorectal cancer risk. Interestingly, although obesity has been also associated with an increased risk of colorectal cancer in women, the magnitude of the association is substantially stronger in men (21). A plausible explanation for this sex difference is that obesity is associated with lower testosterone levels only in men. However, because the finding in the study by Gillessen et al. is limited to the relatively immediate effects of very low testosterone levels, further research is needed to evaluate whether moderate differences in androgen profiles over longer time scales, as associated with obesity, are associated with colorectal cancer risk in the general male population. Although some subgroups of prostate cancer patients will benefit overall from androgen deprivation therapies, the medical side effects and effects on quality of life are important considerations (22). The findings of Gillessen et al. suggest that an elevated risk of colorectal cancer may be an additional consideration to weigh in the risk vs benefit profile. Their findings also reinforce the need for routine screening for colorectal cancer and the adoption of lifestyle practices such as physical activity that may help to counter some of the drawbacks of anti-androgen therapies.

Background:The present study aimed to examine the association between cigarette smoking, alcohol consumption and colorectal cancer risk among Korean adults.Methods:Data from the Korean Multi-center Cancer Cohort between 1993 and 2005 were analyzed. The study population comprised 18,707 subjects aged older than 20 years old. The subjects were followed until December 31, 2011 (median follow-up of 11.2 years). The Cox proportional hazard model was used to estimate the hazard ratio (HR) and 95% confidence intervals of cigarette smoking and alcohol consumption for colorectal cancer risk.Results:In men, longer duration and higher average amount of alcohol consumption were associated with elevated risk of colorectal cancer (HR 1.93 [1.17–3.18] for ≥ 30 years of consumption compared to non-drinkers; HR 2.24 [1.31–3.84] for ≥ 30 g/d). Former smokers showed a non-significantly elevated risk of colorectal cancer in men. There was no apparent association between alcohol consumption or cigarette smoking and colorectal cancer risk among women.Conclusions:Alcohol consumption was associated with increased colorectal cancer risk among Korean men, and both a longer duration and a higher amount of consumption were associated with elevated risk.

Hyperinsulinemia and insulin resistance have been hypothesized to be involved in colorectal carcinogenesis ([1][1], [2][2]). Observational data evaluating the association using circulating insulin levels have been inconclusive, likely because insulin levels differ dramatically during early and late

Hyperinsulinemia may explain excess colorectal cancer among individuals who are overweight or inactive. Recent studies have observed elevated colorectal cancer risk among individuals with elevated insulin levels 2 hours after oral glucose challenge or with elevated plasma C-peptide levels. The effect of consuming a high glycemic diet on colorectal risk, however, remains uncertain. Two prospective cohort studies, the Nurses' Health Study and the Health Professionals Follow-up Study, contributed up to 20 years of follow-up. After exclusions, 1,809 incident colorectal cancers were available for analyses. Dietary glycemic load (GL) was calculated as a function of glycemic index (postprandial blood glucose response as compared with a reference food), carbohydrate content, and frequency of intake of individual foods reported on food frequency questionnaires. Multivariable Cox proportional hazards models were used to adjust for potential confounders. Intakes of dietary carbohydrate, GL, overall glycemic index, sucrose, and fructose were not associated with colorectal cancer risk in women. A small increase in risk was observed in men with high dietary GL (multivariate relative risk, 1.32; 95% confidence interval, 0.98-1.79; highest versus lowest quintile), sucrose or fructose (multivariate relative risk, 1.37; 95% confidence interval, 1.05-1.78; highest versus lowest quintile of fructose, P = 0.008). Associations were slightly stronger among men with elevated body mass index (≥25 kg/m2). Results among women were similar after stratifying by body mass index or physical activity. High intakes of GL, fructose, and sucrose were related to an elevated colorectal cancer risk among men. For women, however, these factors did not seem to increase the risk of colorectal cancer.

Adult survivors of childhood cancer are at elevated risk of morbidity and mortality compared to the general population, but their adherence to lifelong periodic surveillance is suboptimal. We aimed to examine adherence to surveillance guidelines for high-yield tests and identify risk factors for nonadherence in adult survivors of childhood cancer. In this retrospective, population-based cohort study, we used health care administrative data from Ontario, Canada, to identify adult survivors of childhood cancer diagnosed between 1986 and 2014 who were at elevated risk of therapy-related colorectal cancer, breast cancer, or cardiomyopathy. Using a Poisson regression framework, we assessed longitudinal adherence and predictors of adherence to the Children's Oncology Group surveillance guideline. Among 3241 survivors, 327 (10%), 234 (7%), and 3205 (99%) were at elevated risk for colorectal cancer, breast cancer, and cardiomyopathy, respectively. Within these cohorts, only 13%, 6%, and 53% were adherent to recommended surveillance as of February 2020. During a median follow-up of 7.8 years, the proportion of time spent adherent was 14% among survivors at elevated risk for colorectal cancer, 10% for breast cancer, and 43% for cardiomyopathy. Significant predictors of adherence varied across the risk groups, but higher comorbidity was associated with adherence to recommended surveillance. Survivors of childhood cancer in Ontario are rarely up to date for recommended surveillance tests. Tailored interventions beyond specialized clinics are needed to improve surveillance adherence.

Recently a common variant of the TGFBR1 gene, TGFBR1*6A, has been proposed to act as a low-penetrance tumor susceptibility allele for colorectal cancer, but data from published studies with individually low statistical power are conflicting. To further evaluate the relationship between TGFBR1*6A and colorectal cancer risk, we have conducted a large case-control study and a meta-analysis of previously published studies. A total of 1,042 colorectal cancer cases and 856 population controls were genotyped for the TGFBR1*6A polymorphism. Previously published case-control studies of the relationship between TGFBR1*6A and colorectal cancer were identified, and a meta-analysis was conducted. We found no evidence that homozygosity, heterozygosity or carrier status for the TGFBR1*6A allele confers an increased risk of colorectal cancer; respective odds ratios (OR) were 1.05 [95% confidence interval (95% CI), 0.83-1.32], 0.82 (95% CI, 0.34-1.99), and 0.92 (95% CI, 0.74-1.15), respectively. A meta-analysis of our case-control study and seven other studies that provided data on 2,627 colorectal cancer cases and 3,387 controls also yielded no evidence that possession of the TGFBR1*6A allele is associated with an elevated risk of colorectal cancer; pooled estimate of the OR were 1.20 (95% CI, 0.64-2.24) for homozygosity, 1.11 (95% CI, 0.96-1.29) for heterozygosity, and 1.13 (95% CI, 0.98-1.30) for carriers of TGFBR1*6A. Current data provide limited support for the hypothesis that sequence variation in TGFBR1 defined by the TGFBR1*6A allele confers an elevated risk of colorectal cancer.

Dietary mercury intake and colorectal cancer risk: A case-control study.

Result of this study shows that elevated colorectal cancer risk in Mississippi River floodplain of the United States is likely linked to historically high pesticide application. Mississippi River basin produces about 80% of major US crops and has about two-thirds of US pesticides used for agriculture. Historically, heavy pesticide application and agricultural irrigation were reported to result in high pesticide residues in surface water, fish and wells of Mississippi embayment. Risk ratio of colorectal cancer incidence in 86 counties of Mississippi River floodplain was about 29% higher than that of other counties in the 48 contiguous states. Risk ratio of colon cancer mortality in 63 counties of Mississippi embayment was 33% higher than that of other counties in the 48 states between 1999 and 2016. Risk ratios of colorectal cancer incidence and colon cancer mortality in Mississippi River floodplain are higher after smoking and diabetes factors were filtered off. Previous studies have linked exposure to pesticide with type-II diabetes and the latter was linked to increasing colon cancer risk by about 27%. Result here suggests that pesticide may be an independent risk factor directly associated with elevated colon cancer risk in Mississippi River floodplain.

Familial occurrence is common in colorectal cancer (CRC), but whether this increased familial risk differs by colonic subsite of the index patients CRC is not well understood. To quantify the risk of CRC in first-degree (FDR), second-degree (SDR) and first cousin (FC) relatives of individuals with CRC, stratified by subsite in the colorectum and age at diagnosis. Colorectal cancers diagnosed between 1980 and 2010 were identified from the Utah Cancer Registry and linked to pedigrees from the Utah Population Database. Age and gender-matched CRC-free controls were selected to form the comparison group for determining CRC risk in relatives using Cox regression analysis. Of the 18,208 index patients diagnosed with CRC, 6584 (36.2%) were located in the proximal colon, 5986 (32.9%) in the distal colon and 5638 (31%) in the rectum. The elevated risk of CRC in relatives was similar in analysis stratified for CRC colorectal subsites in the index cases. FDR had similarly elevated risk of all site CRC, whether the index patient had cancer in the proximal colon [hazards ratio (HR): 1.85; 95% CI: 1.70-2.02], distal colon (HR: 1.90; 95% CI: 1.73-2.08) or rectum (HR: 1.83; 95% CI: 1.66-2.02) compared to relatives of controls. This risk was consistently greater for FDR when cases developed CRC below the age of 60 years. Relatives of CRC patients have a similarly elevated risk of CRC regardless of colonic tumour subsite in the index patient, and it is greatest for relatives of younger age index cases.

American Gastroenterological Association Technical Review on the Diagnosis and Management of Lynch Syndrome

We aimed to assess the relationship between dietary soyfood and isoflavone intake and colorectal cancer risk in a case-control study. A total of 901 colorectal cancer cases and 2669 controls were recruited at the National Cancer Center, Korea. A semi-quantitative food frequency questionnaire was used to assess the usual dietary habits, and the isoflavone intake level was estimated from five soyfood items. A high intake of total soy products, legumes, and sprouts was associated with a reduced risk for colorectal cancer in men and women, although the middle quartiles of intake of total soy products were associated with an elevated risk. In contrast, a high intake of fermented soy paste was associated with an elevated risk for colorectal cancer in men. The groups with the highest intake quartiles of isoflavones showed a decreased risk for colorectal cancer compared to their counterparts with the lowest intake quartiles in men (odds ratio (OR): 0.67, 95% confidence interval (CI): 0.51–0.89) and women (OR: 0.65, 95% CI: 0.43–0.99). The reduced risk for the highest intake groups persisted for distal colon cancer in men and rectal cancer in women. The association between soyfood intake and colorectal cancer risk was more prominent among post-menopausal women than pre-menopausal women. In conclusion, a high intake of total soy products or dietary isoflavones was associated with a reduced risk for overall colorectal cancer, and the association may be more relevant to distal colon or rectal cancers.