Risk Of Rectal Cancer Research Articles

Central obesity may account for most of the colorectal cancer risk linked to obesity: evidence from the UK Biobank prospective cohort.

General obesity commonly represented by body mass index (BMI) is an established risk factor for colorectal cancer (CRC). However, it is unclear to what extent this association is accounted for by central obesity. We aimed to evaluate the associations between BMI, waist-to-hip ratio (WHR), and waist circumference (WC) with CRC risk and to investigate if and to what extent these associations are independent from each other. Data from more than 500,000 male and female participants aged 40-69, recruited in the UK Biobank study between 2006 and 2010, were analyzed. Multivariable Cox proportional hazards models were fitted and hazard ratios (HR) and their 95% confidence intervals (CI) were calculated. During a median follow-up of 12.5 years, of 460,784 participants, 5,977 developed CRC. Multivariable adjusted HRs (95% CIs) per standard deviation increase of BMI, WHR, and WC were 1.10 (1.07-1.13), 1.18 (1.14-1.22), and 1.14 (1.11-1.18), respectively. After mutual adjustment, the association with CRC was substantially attenuated for BMI (1.04 (1.01-1.07)), and remained substantially stronger for WHR (1.15 (1.11-1.20)). Furthermore, WHR showed strong, statistically significant associations with CRC risk within all BMI categories, whereas associations of BMI with CRC risk were weak and not statistically significant within WHR categories. BMI was also not associated with CRC risk in women and with rectal cancer after mutual adjustment. Conversely, WHR was strongly associated with CRC risk in both sexes and with both colon and rectal cancer risk before and after adjustment for BMI. BMI and WC could not be mutually adjusted for due to their high correlation. Central obesity is a much stronger predictor of CRC and may account for most of the CRC risk linked to obesity. Our findings also emphasize the need for incorporating measures such as WHR alongside BMI in clinical practice to improve obesity prevention and management.

Exploring causal correlations between inflammatory cytokines and colorectal cancer: A 2-sample Mendelian randomization study.

Colorectal cancer (CRC) is a significant global public health concern. Several observational studies have examined the association between inflammatory cytokines and the risk of colorectal cancer, but the findings have been inconsistent. In this study, we employed a 2-sample Mendelian randomization (MR) analysis, primarily using the inverse variance weighted approach, to investigate the causal relationship between inflammatory cytokines and CRC. The forward MR analysis revealed a positive association between higher levels of interleukin (IL)-16 (OR: 1.37, P = .002), vascular endothelial growth factor (OR: 1.44, P = .001), and MIG (OR: 1.23, P = .040) with an increased risk of rectal cancer. Conversely, higher levels of macrophage colony-stimulating factor (OR: 0.80, P = .010) may potentially decrease the risk of colon cancer. In the reverse MR analysis, it was found that rectal cancer is linked to higher levels of IL-1b (OR: 0.93, P = .022), IL-1ra (OR: 0.90, P = .001), IL-5 (OR: 0.93, P = .022), IL-9 (OR: 0.93, P = .017), and TNF-a (OR: 0.91, P = .003). Additionally, colon cancer is associated with elevated levels of FGF-Basic (OR: 1.10, P = .028). Consistent results were also found in MR-Egger, weighted median, and weighted mode analysis. Our study presents novel evidence supporting the causal relationship between inflammatory cytokines and CRC.

MRI-based radiomics for stratifying recurrence risk of early-onset rectal cancer: a multicenter study

Early-onset rectal cancer (EORC) is characterized by a unique disease process with different clinicopathological features compared with late-onset rectal cancer (LORC). Research on the risk of recurrence in EORC patients, however, is limited. We aim to develop a predictive model to accurately predict EORC recurrence risk. Rectal cancer patients who underwent radical surgery and T2-weighted imaging and diffusion-weighted imaging magnetic resonance imaging (MRI) were retrospectively enrolled from three medical institutions from November 2012 to November 2018. Differences in clinicopathological characteristics between EORC and LORC were compared. Five prediction models for disease-free survival were constructed based on clinicopathological variables and five radiomic features from pretreatment MRI of the EORC. A fixed cut-off value calculated in the training set was used to stratify EORC patients into high-risk and low-risk groups of post-operative recurrence. Model performance was evaluated by concordance index (C-index) and receiver operating characteristic curve. A total of 264 EORC patients (median age, 43 years, 163 males) and 778 LORC patients (median age, 62 years, 520 males) were enrolled. Pretreatment positive carcinoembryonic antigen [hazard ratio (HR)= 2.84, P= 0.006], pathological positive lymph node status (pN positive) [HR= 2.86, P= 0.011] and MRI-based radiomics score [HR= 2.72, P < 0.001] are independent risk factors for disease-free survival in EORC patients. The EORC-ClinPathRadiom model, constructed by integrating the clinicopathological characteristics and MRI-based radiomics features of EORC, showed C-index of 0.82, 0.82, and 0.81 in the training, internal, and external test sets, respectively. This model effectively stratified EORC patients into high risk and low risk of recurrence (HRs for the training, internal, and external test sets were 8.96, 6.81, and 7.46, respectively). The EORC-ClinPathRadiom model can effectively predict and stratify the risk of post-operative recurrence in EORC patients.

Statins and the risk of colorectal cancer; a systematic review and meta-analysis of cohort and case-control studies

Introduction: Colorectal malignancy is the third furthermost frequent malignancy in the world, and approximately 80% of the cases are related to nongenetic causes, including high cholesterol levels. Accordingly, the present systematic review and meta-analysis aimed to investigate the relationship between statin treatment and the risk of colorectal cancer. Materials and Methods: The current study was a systematic review and meta-analysis designed based on PRISMA. International databases, including PubMed, Scopus, Web of Science, Cochrane, and Google Scholar search engine, were used to search for studies published until July 7, 2023. Data analysis was directed by STATA software version 14, and P values below than 0.05 (P&lt;0.05) indicated the significance of statistical tests. Results: The results obtained from a combination of 30 studies with 2436650 samples indicated that statin use increased the risk of colorectal malignancy by 11% (OR: 0.89; 95% CI: 0.84, 0.95) and reduced the risk of rectal cancer by 16% (R: 0.84; 95% CI: 0.74, 0.94). Instead, statin administration reduced the hazard of colorectal cancer in individuals aged 50 to 59 by 22% (R: 0.78; 95% CI: 0.63, 0.95), 60 to 69 by 14% (OR: 0.86; 95% CI: 0.75, 0.98), and 70 to 79 by 8% (OR: 0.92; 95% CI: 0.87, 0.98). Utilization of statin in male (OR: 0.71; 95% CI: 0.58, 0.87) and female (OR: 0.84; 95% CI: 0.77, 0.92) patients reduced the risk of colorectal cancer by 29% and 16%, respectively. Furthermore, statin use in men (OR: 0.41; 95% CI: 0.26, 0.67) and women (OR: 0.64; 95% CI: 0.42, 0.97) reduced the risk of colon cancer by 59% and 36%, respectively. Conclusion: Statin administration reduced the risk of colorectal cancer, and the possibility of reduction in risk of colorectal cancer at lower ages was higher than in older adults and also higher in males compared with females. Registration: This study has been compiled based on the PRISMA checklist, and its protocol was registered on the PROSPERO (CRD42023450984) and Research Registry (UIN: reviewregistry1779) website.

Allostatic Load, Genetic Susceptibility, Incidence Risk, and All-cause Mortality of Colorectal Cancer.

Allostatic load (AL) reflects the cumulative burden of chronic stress throughout life, potentially influencing the onset and prognosis of cancer. However, the associations between AL, colorectal cancer (CRC) risk and all-cause mortality in patients with CRC remain unclear. We analyzed the association between AL and CRC risk in 304,959 adults and all-cause mortality in 1,794 patients with CRC from the UK Biobank, using Cox proportional hazards regression models. Compared to the AL level in the first quartile, individuals in the second to fourth quartiles had a respective 20%, 29%, and 43% increased risk of CRC; 15%, 24%, and 42% increased risk for colon cancer; and 30%, 38%, and 45% increased risk for rectal cancer. We identified a positive dose-gradient association of AL score with CRC risk, including colon and rectal cancer. Additionally, the association between AL and increased risk of CRC was observed across different strata of genetic susceptibility for CRC. Eliminating AL exposures could prevent nearly 39.24% (95% CI: 36.16-42.32) of CRC incident cases. Meanwhile, a significant association between the AL and all-cause mortality in patients with CRC was found, with a HR of 1.71 (95% CI: 1.16-2.50) for the fourth quartile compared to the AL score in the first quartile, demonstrating a positive dose-response relationship. High AL was associated with increased CRC risk and all-cause mortality in CRC patients. Future research should prioritize the development of cognitive or behavioral intervention strategies to mitigate the adverse effects of AL on CRC incidence and prognosis.

Incidence of rectal cancer after colectomy for inflammatory bowel disease: nationwide study.

Inflammatory bowel disease increases the risk of colorectal neoplasia. A particular problem arises in patients who have undergone subtotal colectomy leaving a rectal remnant. The risk of future rectal cancer must be accurately estimated and weighed against the risks of further surgery or surveillance. The aim of this study was to estimate the 10-year cumulative incidence of rectal cancer in such patients. A nationwide study using England's hospital administrative data was performed. A cohort of patients undergoing subtotal colectomy between April 2002 and March 2014 was identified. A competing risks survival analysis was performed to calculate the cumulative incidence of rectal cancer. The effect of the COVID-19 pandemic on endoscopic surveillance was investigated using time-trend analysis. A total of 8120 patients were included and 61 patients (0.8%) were diagnosed with cancer. The cumulative incidence of rectal cancer was 0.26% (95% c.i. 0.17% to 0.39%), 0.49% (95% c.i. 0.36% to 0.68%), and 0.77% (95% c.i. 0.57% to 1.02%) at 5, 10, and 15 years respectively. A previous diagnosis of colonic dysplasia (HR 3.34, 95% c.i. 1.01 to 10.97; P = 0.047), primary sclerosing cholangitis (HR 5.42, 95% c.i. 1.34 to 21.85; P = 0.018), and elective colectomy (HR 1.83, 95% c.i. 1.11 to 3.02; P = 0.018) was associated with an increased incidence of rectal cancer. Regarding endoscopic surveillance, there was a 43% decline in endoscopic procedures performed in 2020 (333 procedures) compared with 2019 (585 procedures). The incidence of rectal cancer after subtotal colectomy is low. Asymptomatic patients without evidence of rectal dysplasia should be carefully counselled on the possible benefits and risks of prophylactic proctectomy.

Dietary advanced glycation end-products (dAGEs) are not associated with the risk of cancer incidence. A systematic review and meta-analysis of prospective cohort studies.

A growing body of evidence indicates the association of dietary advanced glycation end-products (dAGEs) with the risk of cancer. This systematic review and meta-analysis aimed to assess the overall association between dAGEs and cancer incidence. An extensive search was carried out through online databases including PubMed, Scopus, and Web of Science up to June 2024. All reported HRs and their 95% CIs for risk of cancer were used to estimate log HRs and their standard errors (SEs). The overall risk estimate was obtained using a random effects model. Inter-study heterogeneity was determined using Cochrane's Q test and I-squared. Five prospective cohort studies with a total of 1,220,096 participants and 23,229 incident cancer cases (2193 pancreatic cancers, 11,443 breast cancers, 6162 colorectal cancers, and 3431 total cancers) were included in this meta-analysis. Compared with the lowest category of dAGEs, the pooled hazard ratio (HR) for overall cancers was 1.04 (95% CI: 0.94, 1.15; I 2 = 67.9%) for the highest category of dAGEs. Pooled estimates for different types of cancer showed no significant relationship between dAGEs and risk of breast cancer (HR: 1.119; 95% CI: 0.868, 1.444; I 2 = 77.6%; N = 2 studies), pancreatic cancer (HR: 1.242; 95% CI: 0.971, 1.588; I 2 = 0.0%; N = 2 studies), colon cancer (HR: 10.985; 95% CI: 0.887, 1.094; I 2 = 0.0%; N = 2 studies) and rectal cancer (HR: 0.940; 95% CI: 0.616, 1.433; I 2 = 57.7%; N = 2 studies). Dietary AGEs had no significant link with cancer risk. More well-designed prospective studies are required.

Genetic susceptibility association between viral infection and colorectal cancer risk: a two-sample Mendelian randomization analysis

BackgroundThe genetic susceptibility association between viral infection and the risk of colorectal cancer (CRC) has not been established.MethodsWe conducted two-sample Mendelian randomization (MR) analysis using genome-wide association study (GWAS) data. In addition to traditional MR methods, we employed several other approaches, including cML, ConMix, MR-RAPS, and dIVW, to comprehensively assess causal effects. Sensitivity analyses were also performed to ensure the robustness of the results.ResultsAfter sensitivity analysis, presence of SNPs linked to increased susceptibility to cold sores infection was found to decrease the risk of CRC (OR: 0.73, 95% CI: 0.57–0.93, P = 0.01). In subgroup analysis, presence of SNPs linked to increased susceptibility to viral hepatitis (OR: 0.89, 95% CI: 0.81–0.98, P = 0.02) and infectious mononucleosis (OR: 0.91, 95% CI: 0.84–0.98, P = 0.02) were associated with a decreased risk of colon cancer, while measles virus (OR: 1.41, 95% CI: 1.07–1.85, P = 0.01) was associated with an increased risk of colon cancer. Presence of SNPs linked to increased susceptibility to herpes zoster (OR: 1.26, 95% CI: 1.05–1.52, P = 0.01) was associated with an increased risk of rectal cancer, while infectious mononucleosis (OR: 0.809, 95% CI: 0.80–0.98, P = 0.02) was associated with a decreased risk.ConclusionThe study provides the first evidence of the genetic susceptibility associations between different viral infections and CRC, enhancing our understanding of the etiology of CRC.

Triglyceride-Glucose Index, Modifiable Lifestyle, and Risk of Colorectal Cancer: A Prospective Analysis of the Korean Genome and Epidemiology Study.

Insulin-mediated pathways plausibly explain the pathogenesis of colorectal cancer (CRC). The triglyceride-glucose index (TyG) is a surrogate of insulin resistance (IR), but its association with CRC in the Korean population has not been evaluated. From the 2004-2013 Korean Genome and Epidemiology Study, 98,800 participants aged 40-69 years were followed through 2020. Data on CRC incidence were obtained from the Korean National Cancer Center registry. Cox regression models and restricted cubic splines were fitted to examine the association between the TyG; In [(triglycerides) × (fasting glucose)/2] and CRC incidence. Joint effects of modifiable lifestyle factors and TyG on CRC risk were also investigated. Median follow-up time was 10.6 years, and 699 CRC cases were observed. A unit-increment in TyG was associated with increased risk of CRC combined (hazard ratio, HR: 1.28, and 95% confidence interval, CI: 1.12-1.46), colon (1.29, 1.10-1.54), and rectal cancer (1.24, 1.01-1.52). Associations were dose-dependent, with linear associations observed for CRC and colon, but non-linear associations were observed for rectal cancer. A high TyG index (above 8.4) combined with overweight/obesity was linked to an increased risk of CRC (1.31, 1.07-1.61) and colon cancer (1.33, 1.03-1.72). When combined with low fruit and vegetable intake, the risks were higher for CRC (1.40, 1.12-1.74) and colon cancer (1.57, 1.18-2.09). Combined with high red meat consumption, the risks were elevated for CRC (1.32, 1.05-1.65) and colon cancer (1.52, 1.15-2.02). A high TyG index was associated with a higher risk of colorectal cancer, and the risk was highest among participants with a high BMI, low fruit and vegetable intake, and high intake of red meat, suggesting a role of both insulin resistance and modifiable lifestyle in colorectal cancer development.

Risk of colorectal cancer and adenoma after an appendectomy: results from three large prospective cohort studies and meta-analysis.

The relationship between appendectomy and subsequent colorectal cancer risk remains unclear, and no study has examined its association with colorectal adenoma. We used data from three prospective cohorts: Health Professionals Follow-up Study, Nurses' Health Study (NHS), and NHSII. Appendectomy history was self-reported at baseline. Colorectal cancer risk was analyzed with Cox proportional hazard models among 224,109 participants followed up to 32years. Colorectal adenoma risk was evaluated among 157,490 participants with at least one lower gastrointestinal endoscopy during follow-up with logistic regression models accounting for repeated observations. We also performed a meta-analysis of cohort studies that examined association between appendectomy and colorectal cancer risk. We documented 3,384 colorectal cancers, 13,006 conventional adenomas, and 11,519 serrated polyps during the follow-up period. Compared to participants without appendectomy, those whoreported appendectomy history were not at higher risk of colorectal (HR [95% CI], 0.92 [0.84-1.00]), colon (0.92 [0.83-1.01]), or rectal (0.85 [0.70-1.03]) cancer. Similarly, appendectomy history was not associated with higher risk of conventional adenoma (OR [95% CI], 1.00 [0.97-1.02]), serrated polyp (0.97 [0.94-1.00]), or high-risk adenoma (0.96 [0.92-1.01]). The meta-analysis showed appendectomy was associated with a higher risk of colorectal cancer within a short time after the procedure (1.68 [1.01-2.81]), while the long-term risk was slightly inverse (0.94 [0.90-0.97]). We found no evidence of an association between appendectomy history and long-term risk of colorectal cancer or its precursors. The observed higher risk of colorectal cancer right after appendectomy in the first few years is likely due to reverse causation.

Association between serum uric acid and colorectal cancer risk in European population: a two-sample Mendelian randomization study.

This study aimed to explore the potential causal associations between serum uric acid (SUA) and the risk of colorectal cancer, colon cancer and rectal cancer. Twenty-six SUA-related single nucleotide polymorphisms which were identified by a large meta-analysis of genome-wide association studies (GWASs) were used as instrumental variables in the two-sample Mendelian randomization (MR) study. Meta-analyses were used to synthesize the results of multiple GWASs which were extracted from the MRC Integrative Epidemiology Unit GWAS database for each type of cancer. The inverse variance weighted (IVW) method was used as the primary MR method to analyze the association between SUA and colorectal cancer risk. Several sensitivity analyses were performed to test the robustness of results. The IVW method showed that there were no causal relationships between SUA and the risk of colorectal cancer [odds ratio (OR): 1.0015; 95% confidence interval (CI): 0.9975-1.0056] and colon cancer (OR: 1.0015; 95% CI: 0.9974-1.0055). The SUA levels were negative correlated with rectal cancer risk (OR: 0.9984; 95% CI: 0.9971-0.9998). The similar results were observed in both males (OR: 0.9987; 95% CI: 0.9975-0.9998) and females (OR: 0.9985; 95% CI: 0.9971-0.9999). The sensitivity analyses suggested no evidence of heterogeneity or horizontal pleiotropy. The leave-one-out analyses showed that one SNP (rs1471633) significantly drove the causal effect of SUA on rectal cancer risk. The MR-Egger regression and weighted median both showed that there were no causal relationships between SUA and the risk of colorectal cancer and its subtypes. Overall, there was no linear causal association between SUA and the risk of colorectal cancer. However, further research is needed to investigate the role of higher SUA levels such as hyperuricemia or gout in the occurrence of colorectal cancer.

The association of the dietary inflammatory potential with risk of overall and site-specific cancers: A community-based longitudinal study in the UK Biobank

ObjectivesThe association of the dietary inflammatory potential with cancer risk remains uncertain. We examined the relationship of the dietary inflammatory potential with risk of overall and site-specific cancers and explored its sex and age differences. DesignA community-based longitudinal study. SettingParticipants from the UK Biobank completed baseline surveys during 2006–2010 and were followed for up to 15 years to detect incident cancer. Participants170,899 cancer-free participants with dietary data available (mean age: 55.73 ± 7.95, 54.10% female). MeasurementsAt baseline, dietary intake was assessed with a 24-h dietary record for up to 5 times. The inflammatory diet index (IDI) was calculated to assess the dietary inflammatory potential as a weighted sum of 31 food groups (including 14 anti-inflammatory and 17 pro-inflammatory) based on plasma high-sensitivity C-reactive protein (hsCRP) levels, and tertiled as low (indicating low-inflammatory diet), moderate, and high IDI (as reference). Overall and site-specific cancers were ascertained via linkage to routine hospital admission, cancer registry, and death certificate data. Data were analyzed using Cox regression and Laplace regression. ResultsDuring the follow-up (median 10.32 years, interquartile range: 9.95–11.14 years), 18,884 (11.05%) participants developed cancer. In multi-adjusted Cox regression, low IDI scores were associated with decreased risk of rectal cancer (hazard ratio [95% confidence interval, CI] 0.76 [0.61, 0.94]), thyroid cancer [0.45 (0.27, 0.74)], lung cancer [0.73 (0.61, 0.88)]. However, the association between IDI score and the risk of overall cancer was not significant. Laplace regression analysis showed that 10th percentile differences (95% CIs) of cancer onset time for participants with low IDI scores was prolonged by 1.29 (0.32, 2.27), 1.44 (0.58, 2.30), and 2.62 (0.98, 4.27) years for rectal cancer, thyroid cancer, and lung cancer, respectively, compared to those with high IDI scores. Stratified analysis revealed that low IDI scores were associated with a lower risk of rectal cancer (p interaction between IDI score and sex = 0.035) and lung cancer in males, but not in females, and with a reduced risk of thyroid cancer in females, but not in males. Moreover, low IDI scores were associated with a reduced risk of rectal cancer and lung cancer in the participants aged ≥60 years, but not in those <60 years, and with a reduced risk of thyroid cancer in those aged ≥60 years and <60 years. ConclusionsA low-inflammatory diet is associated with decreased risk and prolonged onset time of rectal cancer and lung cancer, especially among males and individuals aged ≥60 years, and thyroid cancer among females.

Diverging likelihood of colon and rectal cancer in Yogyakarta, Indonesia: A cross sectional study.

Colon and rectal cancer are associated with different risk factors and prognostic. However, this discrepancy has not been widely explored in the local population. This study aimed to investigate the site-specific likelihood of colorectal cancer (CRC) incidence in the Yogyakarta province, Indonesia. This cross-sectional study analyses 1,295 CRC cases diagnosed in 2008-2019 registered in the Yogyakarta population-based cancer registry (PBCR) database. Cases were grouped into colon and rectal cancer. Log-binomial regression was used to determine the relative risk of either colon or rectal cancer across different gender, age group, and rurality of residence. The age-specific rates were calculated by age group and temporal trend for each group were analyzed using joinpoint regression. Females displayed higher odds of colon cancer (relative risk/RR = 1.20, 95%CI = 1.02-1.41) and lower odds of rectal cancer (RR = 0.92, 95%CI = 0.85-0.99). Elevated odds of colon cancer were observed in younger age group, especially 30-39 (RR = 1.87, 95%CI = 1.10-3.19), while decreased odds of rectal cancer was apparent in age group 30-39 and 40-49 (RR = 0.75, 95%CI = 0.60-0.93 and RR = 0.82, 95%CI = 0.69-0.98, respectively). Living in urban or rural areas did not significantly influence the odds of either having colon (RR = 0.98, 95%CI = 0.82-1.17) or rectal cancer (RR = 1.01, 95%CI = 0.93-1.10). During 2008-2019, trends of colon cancer in age <50 increased by 8.15% annually while rectal cancer displayed a 9.71% increase annually prior to 2017, followed by a 17.23% decrease until 2019. Yogyakarta population shows higher odds of young-onset colon cancer, especially between age 30-39 years old. Overall observation of trend shows increasing incidence in young-onset colon cancer, and non-significant decrease in rectal cancer.

Abstract 3431: Genetically determined circulating lactase/phlorizin hydrolase concentrations and risk of colorectal cancer: A two-sample mendelian randomization study

Abstract Background: Colorectal cancer (CRC) ranks as the third most common cancer worldwide. Despite its established connection with genetic, dietary, and lifestyle factors, gaps remain in the understanding of its etiology. Lactase-phlorizin hydrolase (LPH) plays a critical role in milk digestion and influences crucial nutrient absorption and gut microbiota composition. A direct relationship of CRC risk with LPH level remains unexplored. Our study aims to elucidate the potential causal link between genetically determined LPH levels and CRC risk. Methods: We applied a two-sample Mendelian Randomization (MR) strategy to investigate the causal link between elevated LPH levels and CRC risks. Genetic instruments for LPH (one cis-variant and three trans-variants) were derived from the Fenland Study, and CRC-associated summary statistics for these instruments were extracted from the FinnGen Study, PLCO Atlas Project, and Pan-UK Biobank. Primary MR analyses focused on a cis-variant (rs4988235) for LPH levels, with results integrated via meta-analysis. MR analyses using all variants were also undertaken. This analytical approach was further extended to assess CRC subtypes, specifically colon and rectal cancer. Results: Meta-analysis across the three datasets illustrated an inverse association between genetically predicted LPH level and CRC risk (OR: 0.92 [95% CI, 0.89-0.95]). Subtype analyses revealed associations of genetically predicted elevated LPH levels with reduced risks for both colon cancer (OR: 0.92 [95% CI, 0.89-0.96]) and rectal cancer (OR: 0.92 [95% CI, 0.87, 0.98]). Consistency was observed across varied analytical methods and different datasets. Conclusions: Our study suggests an inverse relationship between genetically determined LPH level and CRC risk. Further exploration is warranted to unveil the underlying mechanisms and validate LPH’s potential role in CRC prevention. Citation Format: Sihao Han, Jiemin Yao, Hajime Yamazaki, Samantha Streicher, Jianyu Rao, Roch Nianogo, Zuo-Feng Zhang, Brian Huang. Genetically determined circulating lactase/phlorizin hydrolase concentrations and risk of colorectal cancer: A two-sample mendelian randomization study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3431.

Sex-specific associations of empirically derived dietary patterns with colorectal cancer risk in a Korean population: a case‒control study

Dietary patterns may be a crucial modifiable factor in colorectal cancer (CRC) risk. This study aimed to examine the associations of dietary patterns derived from two methods with CRC risk in Korea. In a study of 1420 CRC patients and 2840 control participants, we obtained dietary patterns by principal component analysis (PCA) and reduced rank regression (RRR) using 33 predefined food groups. The associations between dietary patterns and CRC risk were assessed using unconditional logistic regression models to calculate odds ratios (ORs) and 95% confidence intervals (CIs). We identified two similar dietary patterns, derived from PCA 1 (prudent) and RRR (healthy), characterized by higher consumption of green/yellow vegetables, light-colored vegetables, fruits, eggs, and milk in both men and women. In women, higher prudent and healthy pattern scores were significantly associated with a lower risk of CRC (prudent, ORQ4 vs. Q1 = 0.59, 95% CI 0.40–0.86, P for trend = 0.005; healthy, ORQ4 vs. Q1 = 0.62, 95% CI 0.43–0.89, P for trend = 0.007). In men, a significant inverse association between dietary pattern and risk of rectal cancer was found only for the healthy dietary pattern (ORQ4 vs. Q1 = 0.66, 95% CI 0.45–0.97, P for trend = 0.036). Compared with the dietary pattern derived by PCA, the RRR dietary pattern had a slightly stronger association with a lower risk of distal colon cancer (ORQ4 vs. Q1 = 0.58, 95% CI 0.35–0.97, P for trend = 0.025) and rectal cancer (ORQ4 vs. Q1 = 0.29, 95% CI 0.15–0.57, P for trend < 0.001) in women. Our findings suggest cancer prevention strategies focusing on a diet rich in vegetables, fruits, eggs, and milk. Moreover, the use of both PCA and RRR methods may be advantageous to explore the associations between dietary patterns and risk of CRC.

Genetically Determined Circulating Lactase/Phlorizin Hydrolase Concentrations and Risk of Colorectal Cancer: A Two-Sample Mendelian Randomization Study.

Previous research has found that milk is associated with a decreased risk of colorectal cancer (CRC). However, it is unclear whether the milk digestion by the enzyme lactase-phlorizin hydrolase (LPH) plays a role in CRC susceptibility. Our study aims to investigate the direct causal relationship of CRC risk with LPH levels by applying a two-sample Mendelian Randomization (MR) strategy. Genetic instruments for LPH were derived from the Fenland Study, and CRC-associated summary statistics for these instruments were extracted from the FinnGen Study, PLCO Atlas Project, and Pan-UK Biobank. Primary MR analyses focused on a cis-variant (rs4988235) for LPH levels, with results integrated via meta-analysis. MR analyses using all variants were also undertaken. This analytical approach was further extended to assess CRC subtypes (colon and rectal). Meta-analysis across the three datasets illustrated an inverse association between genetically predicted LPH levels and CRC risk (OR: 0.92 [95% CI, 0.89-0.95]). Subtype analyses revealed associations of elevated LPH levels with reduced risks for both colon (OR: 0.92 [95% CI, 0.89-0.96]) and rectal cancer (OR: 0.92 [95% CI, 0.87, 0.98]). Consistency was observed across varied analytical methods and datasets. Further exploration is warranted to unveil the underlying mechanisms and validate LPH's potential role in CRC prevention.

Inflammation and Gut Barrier Function-Related Genes and Colorectal Cancer Risk in Western European Populations.

Gut barrier dysfunction and related inflammation are known to be associated with the development and progression of colorectal cancer (CRC). We investigated associations of 292 single-nucleotide polymorphisms (SNPs) from 27 genes related to endotoxins/lipopolysaccharide (LPS) sensing and tolerance, mucin synthesis, inflammation, and Crohn's disease with colon and rectal cancer risks. Incident CRC cases (N=1,374; colon=871, rectum=503) were matched 1:1 to controls nested within the European Prospective Investigation into Cancer and Nutrition cohort. Previously measured serum concentrations of gut barrier function and inflammation biomarkers (flagellin/LPS-specific immunoglobulins and C-reactive protein [CRP]) were available for a sub-set of participants (Ncases=1,001; Ncontrols=667). Forty-two unique SNPs from 19 different genes were associated with serum biomarkers at Punadjusted≤0.05 among controls. Among SNPs associated with a gut permeability score, 24 SNPs were in genes related to LPS sensing and mucin synthesis. Nine out of 12 SNPs associated with CRP were in genes related to inflammation or Crohn's disease. TLR4 was associated with colon cancer at the SNP level (nine SNPs, all Punadjusted≤0.04) and at the gene level (Punadjusted≤0.01). TLR4 rs10759934 was associated with rectal cancer but not colon cancer. Similarly, IL10 was associated with rectal cancer risk at a SNP and gene level (both Punadjusted ≤ 0.01), but not colon cancer. Genes and SNPs were selected a priori therefore we present unadjusted P-values. However, no association was statistically significant after multiple testing correction. This large and comprehensive study has identified gut barrier function and inflammation-related genes possibly contributing to CRC risk in European populations and is consistent with potential etiological links between host genetic background, gut barrier permeability, microbial endotoxemia and CRC development.

Alteration of metabolic syndrome and the risk of colorectal cancer in individuals younger than 50 years.

81 Background: Colorectal cancer (CRC) is a significant global health concern, with a rising incidence of early-onset cases in individuals under 50. This trend may be influenced by various factors, including metabolic syndrome (MetS), obesity, dietary habits, and lifestyle choices. However, the impact of changing MetS status on the risk of early-onset CRC remains understudied. Methods: A total of 3,340,635 Korean national insurance beneficiaries that received two consecutive biennial mandatory health exams (2009–2011) were followed-up until 2019. Participants were categorized into MetS-free, recovered, developed, or persistent groups. The study assessed CRC risk patterns associated with these MetS dynamics, considering factors like age, sex, smoking, alcohol consumption, exercise, and income status. Results: Among 20-39-year-olds, those with persistent MetS had a 16% higher risk of CRC (adjusted hazard ratio [aHR] 1.16; 95% CI, 1.00–1.33) compared to MetS-free individuals. Furthermore, persistent MetS was associated with a 29% higher risk of rectal cancer in this age group, while recovery from MetS also increased rectal cancer risk by 28%. Among 40-49-year-olds, the MetS-persistent group had a 22% higher risk of CRC (aHR 1.22; 95% CI, 1.14-1.30), with a 34% higher risk of distal colon cancer, while those who developed MetS showed a 26% higher risk of CRC compared to the MetS-free group. Conclusions: This study highlights that the persistence of MetS in young adults is associated with an increased risk of early-onset CRC. The findings suggest that managing MetS in young individuals through lifestyle modifications, such as weight reduction and regular exercise, could be beneficial in reducing the risk of early-onset CRC.

Risk of second cancers in long term survivors of neuroendocrine tumors of the large intestine.

600 Background: There is an increasing incidence of neuroendocrine tumors (NET) of the colon and rectum likely related to increased screening colonoscopy and availability of better diagnostics. Most of these tumors identified during screening are low grade early-stage tumors with high cure rates. Data on long term risk of recurrence of NET and other second cancers is lacking. We studied the incidence rates of all second malignancies in survivors of NET of the colon and rectum. Methods: We analyzed data from the Surveillance, Epidemiology and End Results (SEER), Research Data 17 Registries, Nov 2022 Sub (2000-2022) to determine the risk of second malignancies in patients with an initial cancer diagnosis of NET of the colon and rectum. With these criteria we had overall 17,907 patients and 157,720 patient years of follow up. The relative risk of subsequent malignancies is reported as a standardized incidence ratio (observed incidence [O]/expected incidence [E]). Incidence ratios are analyzed over time from initial diagnosis to assess long term risk. Results: Survivors of NET of the large intestine are at highest risk of malignancy of the rectum (O/E: 6.4, CI: 7.26 - 5.21, N= 239) and this increased risk of rectal cancer persists even 10 years after the initial diagnosis (0/E: 3.8, CI: 5.37- 2.6, N= 32). There is no increased risk of cancer of the colon excluding rectum (O/E: 0.98, CI: 1.18-0.81, N= 114). Even after 10 years from diagnosis there is increased risk of recurrence of the NET of the Colon (O/E: 1.28, CI: 1.55-1.06, N=110) and NET of the Rectum (O/E: 1.12, CI: 1.23- 1.02, N= 433). There is also increased incidence of small intestine cancer (O/E: 2.92, CI: 4.17- 1.97, N=30), Prostate cancer (O/E: 1.28, CI: 1.41- 1.15, N=400), Kidney and renal pelvis cancer (O/E: 1.53, CI: 1.86 -1.25, N= 104), Thyroid cancer (O/E: 1.63, CI: 2.12-1.23, N= 55) and Nodal Non-Hodgkins Lymphoma (O/E: 1.34, CI: 1.71-1.03, N=64). Conclusions: Survivors of NET of the large intestine are at risk of developing subsequent malignancies. The information presented may help physicians in effectively monitoring survivors for second cancers at various timeframes from their initial diagnosis.

Methylenetetrahydrofolate reductase polymorphic variants C677T and A1298C in rectal cancer in Slavic population: significance for cancer risk and response to chemoradiotherapy.

Background: Methylenetetrahydrofolate reductase (MTHFR) single nucleotide polymorphisms (SNPs) have been suggested as risk, prognostic, and predictive factors for colorectal cancer in various populations, but have not been validated so far. The aim of this study was to examine the association of MTHFR C677T (rs1801133) and A1298C (rs1801131) single nucleotide polymorphisms with the risk of rectal cancer as well as the response to neoadjuvant chemoradiotherapy (nCRT) based on 5-Fluorouracil (5-FU)/leucovorin (LV) in the locally advanced setting. Patients and methods: This case-control study included 119 healthy controls and 97 patients with locally advanced rectal cancer (LARC). For MTHFR genotyping, restriction fragment length polymorphism analysis (PCR-RFLP) was employed. Results: In silico analysis highlighted that SNPs C677T and A1298T correlate with MTHFR gene expression, and that gene expression profile correlates with cancer risk and stage. Using dominant and recessive models, it was found that the MTHFR 677CC vs. 677CT+677TT have increased risk of cancer development (odds ratio (OR): 2.27; 95% confidence interval (CI): 1.30-3.95, p = 0.002) as well as 677CC+677CT compared to 677TT (OR: 4.18, 95% CI: 1.16-14.99, p = 0.014). MTHFR 1298AA also shown increased risk for cancer development compared to 1298AC+1298CC (OR:2.0, 95% CI: 1.20-3.59, p = 0.035) Statistical analysis of combined genotypes highlighted the protective role of CT/AC combined genotype (OR: 3.15 95% CI: 1.576-6.279, p = 0.002) while the CC/AA genotype showed an increased risk for rectal cancer development (OR: 2.499, 95% CI: 1.246-5.081, p = 0.016) The carriers of the 677C/1298A haplotype had the highest risk for developing rectal cancer (OR: 1.74; 95% CI: 1.198-2.530, p = 0.002) while the 677T/1298C haplotype seems to provide a protective effect. (OR: 0.44; 95%CI 0.248-0.795, p = 0.003). No significant association with response to chemoradiotherapy was found. Conclusion: Our data point to MTHFR 667C allele and 1298A alleles as low-penetrance risk factors for rectal cancer in our population. To the best of our knowledge, this is the first study of this type performed on the Slavic population in the Western Balkan, as various population-based factors might also be significant our findings can be used for future meta-analyses and the construction of genetic cancer risk prediction panels.