Higher Risk Of Colorectal Cancer Research Articles

A novel colorectal cancer screening framework with feature interpretability to identify high-risk populations for colonoscopy.

Risk assessment is of paramount importance for the detection and treatment of colorectal cancer. We developed and validated a feature interpretability screening framework to identify high-risk populations and recommend colonoscopy for them. We utilized a training cohort consisting of 1252605 participants who underwent colonoscopies in Shanghai from 2013 to 2015 to develop the screening framework. We incorporated Shapley additive explanation values into feature selection to provide interpretability for the framework. Two sampling methods were separately employed to mitigate potential model bias caused by class imbalance. Furthermore, we employed various machine learning algorithms to construct risk assessment models and compared their performance. We tested the screening models on an external validation cohort of 359462 samples and conducted comprehensive evaluation and statistical analysis of the validation results. The external validation results demonstrated that the models in the proposed framework achieved sensitivity over 0.734, specificity over 0.790, and area under the receiver operating characteristic curve ranging from 0.808 to 0.859. In the predictions of the best-performing model, the prevalence rates of colorectal cancer were 0.059% and 1.056% in the low- and high-risk groups, respectively. If colonoscopies were performed only on the high-risk group predicted by the model, only 14.36% of total colonoscopies would be needed to detect 74.86% of colorectal cancer cases. We developed and validated a novel framework to identify populations at high risk for colorectal cancer. Those classified as high risk should undergo colonoscopy for further diagnosis.

Abstract PO5-08-01: Investigating the Link between APC I1307K Mutation and Breast Cancer in Arab Population

Abstract Background: Identifying asymptomatic individuals with an increased risk of hereditary breast cancer may significantly enhance early detection and prevention strategies and may inform treatment decision of patients who carry such variants. The APC I1307K missense mutation is known to be unrelated to conditions such as familial adenomatous polyposis (FAP), attenuated FAP, or gastric adenocarcinoma. However, individuals of Ashkenazi Jewish ancestry who carry this variant, have increase risk of colon cancer compared to the general population. The association of this variant with other cancer types, such as breast cancer, and in individuals of other ancestries, like Arabs, remains unknown. In this study, we investigate the potential association between APC gene (I1307K variant) and breast cancer risk. Method: Over a course of 18 months, all newly diagnosed patients with solid tumors were offered to participate in a universal germline genetic screening study, utilizing a standard 21-gene or an investigational 84-gene panel testing. A retrospective analysis was conducted on the 153 patients within the study group who carry the APCI1307K missense variant irrespective of cancer type. Patients were classified as meeting the criteria or not meeting the criteria of the National Comprehensive Cancer Network (NCCN) v.1.2020. Data were extracted from electronic medical records and our institutional cancer registry. Descriptive statistics test was employed. Results: Among the screened cancer patients (n=3400), 153 (4.5%) were tested positive for the APC I1307K missense mutation are included in this analysis. Median age at cancer diagnosis was 52 (range,19-80) years, and 99 (64.7%) were female. Breast cancer was the most common primary tumor (n=67, 43.8%) followed by colorectal (n=38, 24.8%), lung (n=7, 4.6%) and pancreatic cancer (n=6,3.9%). Among the 67 breast cancer patients included, 16 (23.9%) were not eligible for genetic testing as per the NCCN guidelines, and were tested as part of the universal genetic testing study. Among the patients with breast cancer, 53 (79.1%) had screening colonoscopy and 9 (17.0%) were found to have polyps (range, 1-3); 8 (88.9%) were low-grade dysplasia, while the other 44 (83.0%) had completely normal colonoscopy. On the other hand, among the 38 patients with colorectal cancer, 21 (55.3%) had tumors presenting as polyps, or exhibited concomitant polyps (range, 1-3), or displayed abnormalities in the background that were polypoid in nature. Notably, 24 (63.2%) of patients with colorectal cancer, have a family history of breast cancer. Conclusions: APC I1307K variant is unexpectedly common among our cohort of Arab patients. Individuals who carry this variant may face an elevated risk of developing breast cancer; potentially contributing to hereditary and familial cases, and such patients are at higher risk for colorectal cancer, too. Citation Format: Baha' Sharaf, Hira Bani Hani, Anas Zayed, Maha Barbar, Ahmad Hushki, Rashid Abdel-Razeq, Mohammad Titi, Reem Al-Halalsheh, Suleiman Mahafdah, Hikmat Abdel-Razeq. Investigating the Link between APC I1307K Mutation and Breast Cancer in Arab Population [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO5-08-01.

Development and Validation of a Colorectal Cancer Prediction Model: A Nationwide Cohort-Based Study.

Early diagnosis of colorectal cancer (CRC) is critical to increasing survival rates. Computerized risk prediction models hold great promise for identifying individuals at high risk for CRC. In order to utilize such models effectively in a population-wide screening setting, development and validation should be based on cohorts that are similar to the target population. Establish a risk prediction model for CRC diagnosis based on electronic health records (EHR) from subjects eligible for CRC screening. A retrospective cohort study utilizing the EHR data of Clalit Health Services (CHS). The study includes CHS members aged 50-74 who were eligible for CRC screening from January 2013 to January 2019. The model was trained to predict receiving a CRC diagnosis within 2years of the index date. Approximately 20,000 EHR demographic and clinical features were considered. The study includes 2935 subjects with CRC diagnosis, and 1,133,457 subjects without CRC diagnosis. Incidence values of CRC among subjects in the top 1% risk scores were higher than baseline (2.3% vs 0.3%; lift 8.38; P value < 0.001). Cumulative event probabilities increased with higher model scores. Model-based risk stratification among subjects with a positive FOBT, identified subjects with more than twice the risk for CRC compared to FOBT alone. We developed an individualized risk prediction model for CRC that can be utilized as a complementary decision support tool for healthcare providers to precisely identify subjects at high risk for CRC and refer them for confirmatory testing.

Nfe2l2/NRF2 deletion attenuates tumorigenesis and increases bacterial diversity in a mouse model of Lynch syndrome.

Lynch syndrome (LS) is the most prevalent heritable form of colorectal cancer (CRC). Its early onset and high lifetime risk for CRC emphasize the necessity for effective chemoprevention. NFE2L2 (NRF2) is often considered a potential druggable target, and many chemopreventive compounds do induce NRF2. However, while NRF2 counteracts oxidative stress, it is also overexpressed in CRC and may promote tumorigenesis. Herein, we evaluated the role of NRF2 in prevention of LS-associated neoplasia. We found an increased levels of NRF2 in intestinal epithelia of mice with intestinal epithelial-specific Msh2 deletion (MSH2ΔIEC) as compared to C57BL/6 (wild type) mice, as well as an increase in downstream NRF2 targets Nqo1 and Gclc. Likewise, NRF2 levels were increased in human MSH2-deficient LS tumors compared to healthy controls. In silico analysis of a publicly accessible RNA-sequencing LS dataset also found an increase in downstream NRF2 targets. Upon crossing MSH2ΔIEC with Nrf2null mice (MSH2ΔIECNrf2null), we unexpectedly found reduced tumorigenesis in MSH2ΔIECNrf2null compared to MSH2ΔIEC after 40 weeks. This occurred despite an increase in oxidative damage in MSH2ΔIECNrf2null mice. Loss of NRF2 impaired proliferation as seen by Ki67 intestinal staining and in organoid cultures. This was accompanied by diminished WNT/β-catenin signaling. Apoptosis was unaffected. Microbial alpha-diversity increased over time with loss of NRF2 based upon 16S rRNA gene amplicon sequencing of murine fecal samples. Altogether, we show that NRF2 protein levels are increased in MSH2-deficiency and associated neoplasia, but loss of NRF2 attenuates tumorigenesis. Activation of NRF2 may not be a feasible strategy for chemoprevention in LS.

Diet changes due to urbanization in South Africa are linked to microbiome and metabolome signatures of Westernization and colorectal cancer

Transition from traditional high-fiber to Western diets in urbanizing communities of Sub-Saharan Africa is associated with increased risk of non-communicable diseases (NCD), exemplified by colorectal cancer (CRC) risk. To investigate how urbanization gives rise to microbial patterns that may be amenable by dietary intervention, we analyzed diet intake, fecal 16 S bacteriome, virome, and metabolome in a cross-sectional study in healthy rural and urban Xhosa people (South Africa). Urban Xhosa individuals had higher intakes of energy (urban: 3,578 ± 455; rural: 2,185 ± 179 kcal/d), fat and animal protein. This was associated with lower fecal bacteriome diversity and a shift from genera favoring degradation of complex carbohydrates (e.g., Prevotella) to taxa previously shown to be associated with bile acid metabolism and CRC. Urban Xhosa individuals had higher fecal levels of deoxycholic acid, shown to be associated with higher CRC risk, but similar short-chain fatty acid concentrations compared with rural individuals. Fecal virome composition was associated with distinct gut bacterial communities across urbanization, characterized by different dominant host bacteria (urban: Bacteriodota; rural: unassigned taxa) and variable correlation with fecal metabolites and dietary nutrients. Food and skin microbiota samples showed compositional differences along the urbanization gradient. Rural-urban dietary transition in South Africa is linked to major changes in the gut microbiome and metabolome. Further studies are needed to prove cause and identify whether restoration of specific components of the traditional diet will arrest the accelerating rise in NCDs in Sub-Saharan Africa.

Fruit but not vegetable consumption is beneficial for low prevalence of colorectal polyps in a high-risk population: findings from a Chinese Lanxi Pre-colorectal Cancer Cohort study.

The available evidence regarding the role of fruit and vegetable consumption in the development of colorectal polyps remains inconclusive, and there is a lack of data on different histopathologic features of polyps. We aimed to evaluate the associations of fruit and vegetable consumption with the prevalence of colorectal polyps and its subtypes in a high-risk population in China. We included 6783 Chinese participants aged 40-80 years who were at high risk of colorectal cancer (CRC) in the Lanxi Pre-colorectal Cancer Cohort (LP3C). Dietary information was obtained through a validated food-frequency questionnaire (FFQ), and colonoscopy screening was used to detect colorectal polyps. Dose-response associations of fruit and vegetable intake with the prevalence of polyps were calculated using multivariate-adjusted regression models, which was reported as odds ratios (ORs) with 95% confidence intervals (CIs). 2064 cases of colorectal polyps were ascertained in the LP3C during 2018-2019. Upon multivariable adjustments, including the diet quality, fruit consumption was inversely associated with the prevalence of polyps (P trend = 0.02). Participants in the highest tertile of fruit intake had a 25% lower risk (OR: 0.75; 95% CI 0.62‒0.92) compared to non-consumers, while vegetable consumption had no significant association with polyp prevalence (P trend = 0.86). In terms of colorectal histopathology and multiplicity, higher fruit intake was correlated with 24, 23, and 33% lower prevalence of small polyps (OR: 0.76; 95% CI 0.62‒0.94; P trend = 0.05), single polyp (OR: 0.77; 95% CI 0.62‒0.96; P trend = 0.04), and distal colon polyps (OR: 0.67; 95% CI 0.51‒0.87; P trend = 0.003), respectively. Fresh fruit is suggested as a protective factor to prevent colorectal polyps in individuals at high risk of CRC, and should be underscored in dietary recommendations, particularly for high-risk populations.

Predicting Risk of Colorectal Cancer After Adenoma Removal in a Large Community-Based Setting.

Colonoscopy surveillance guidelines categorize individuals as high or low risk for future colorectal cancer (CRC) based primarily on their prior polyp characteristics, but this approach is imprecise, and consideration of other risk factors may improve postpolypectomy risk stratification. Among patients who underwent a baseline colonoscopy with removal of a conventional adenoma in 2004-2016, we compared the performance for postpolypectomy CRC risk prediction (through 2020) of a comprehensive model featuring patient age, diabetes diagnosis, and baseline colonoscopy indication and prior polyp findings (i.e., adenoma with advanced histology, polyp size ≥10 mm, and sessile serrated adenoma or traditional serrated adenoma) with a polyp model featuring only polyp findings. Models were developed using Cox regression. Performance was assessed using area under the receiver operating characteristic curve (AUC) and calibration by the Hosmer-Lemeshow goodness-of-fit test. Among 95,001 patients randomly divided 70:30 into model development (n = 66,500) and internal validation cohorts (n = 28,501), 495 CRC were subsequently diagnosed; 354 in the development cohort and 141 in the validation cohort. Models demonstrated adequate calibration, and the comprehensive model demonstrated superior predictive performance to the polyp model in the development cohort (AUC 0.71, 95% confidence interval [CI] 0.68-0.74 vs AUC 0.61, 95% CI 0.58-0.64, respectively) and validation cohort (AUC 0.70, 95% CI 0.65-0.75 vs AUC 0.62, 95% CI 0.57-0.67, respectively). A comprehensive CRC risk prediction model featuring patient age, diabetes diagnosis, and baseline colonoscopy indication and polyp findings was more accurate at predicting postpolypectomy CRC diagnosis than a model based on polyp findings alone.

Abstract LB149: Metabolic syndrome and obesity-related cancer risk and survival: An umbrella review

Abstract Background: Recent evidence suggests that metabolic syndrome (MetS) may be a potential risk factor for obesity-related cancer (ORC) owing to shared risk factors like physical inactivity, hyperglycemia, insulin resistance, gut microbiome dysfunction, and inflammation. We conducted an umbrella review of systematic reviews with meta-analysis to synthesize the evidence on the association between MetS and ORC incidence and survival. Methods: The study protocol was registered with PROSPERO (CRD42021230899). Searches in five databases (Medline, Embase, CINAHL, Cochrane Library, and Scopus) retrieved 2,524 systematic reviews with meta-analyses (SRMA) after duplicates were removed. SRMA were eligible if they evaluated MetS with ORC incidence or survival, were conducted in an adult population (≥18 years), and included the pre-defined study-specific data. Using Covidence, two reviewers independently screened titles and abstracts (2,524) and then reviewed full text (41), selecting 23 SRMAs for inclusion. Data extraction was then completed independently by two reviewers. The outcomes were pooled using a random-effects model with the package “meta” in R. Sub-group analyses were conducted for a priori chosen factors, as outlined in the protocol. SRMA were appraised using the AMSTAR 2 criteria. Results: 23 SRMA published between 2001 and 2023 met our inclusion criteria, comprising a total of 112 studies, ~52,543,335 total individuals, and ~355,808 ORC cases. After pooled analyses, MetS was associated with a statistically significant 10% increased risk of ORC [RR(95% CI): 1.10(1.06-1.14)]. MetS was also statistically significantly associated with poorer ORC-specific survival [RR(95% CI): 1.10(1.02-1.18)], though there was no association between MetS and overall survival [RR(95% CI): 1.04(0.97-1.11)]. When stratified by sex, both male and female individuals with MetS had a statistically significant higher risk of ORC [RR(95% CI): 1.12(1.06-1.17), 1.10(1.01-1.19), respectively]. When stratified by cancer site, individuals with MetS demonstrated a higher risk of colorectal cancer [RR(95% CI): 1.12(1.06-1.18)]. We also observed suggestive associations between MetS and liver, pancreatic, and postmenopausal breast cancer risk, but these were not statistically significant [RR(95% CI): 1.20(1.00-1.45), 1.20(0.96-1.50), 1.12(0.99-1.27), respectively]. All associations were supported by “critically low” quality evidence according to the AMSTAR2 criteria. This was primarily because these SRMAs either did not follow a pre-specified written and published protocol, or did not provide a list of all potentially relevant studies that were read in full-text form but excluded from the review. Conclusions: These results emphasize the important role that MetS may play in the development of ORC as well as in the survival of patients with ORC. Conducting high-quality reviews is needed to increase the certainty of evidence, reduce potential bias, and improve knowledge in this field. Citation Format: Maci Winn, Prasoona Karra, Ryzen Benson, Svenja Pauleck, Nathorn Chaiyakunapruk, Win Khaing, Tallie Casucci, Mary M. McFarland, Siwen Hu-Lieskovan, Michelle Litchman, Yizhe Xu, Mary Playdon, Sheetal Hardikar. Metabolic syndrome and obesity-related cancer risk and survival: An umbrella review [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB149.

The Predictive Value of Neutrophil Extracellular Trap-Related Risk Score in Prognosis and Immune Microenvironment of Colorectal Cancer Patients.

Colorectal cancer (CRC) has brought great healthy burden for patients. Neutrophil extracellular traps (NETs) have been explored in several tumors, while it remains largely unclear in CRC. CRC-related data were downloaded from Cancer Genome Atlas and Gene Expression Omnibus databases. Then, a NET risk score was built after univariate Cox and LASSO Cox regression analysis. Prognostic value was evaluated via survival analysis, stratification analysis, and ROC analysis. The functional enrichment analysis was conducted basing on bulk and scRNA-seq data. The immune landscape difference was analyzed using CIBERSORT, XCell, and MCPcounter portals. NET risk score was built for CRC patients, basing on G0S2, HIST1H2BC, CRISPLD2, and IL17A. In TCGA-CRC and validation datasets, regardless of age or gender, high-risk CRC patients had significantly worse prognosis, besides higher NET risk score was mainly found in samples with MSI-H and advanced T, N, and M stages. Employing multiple databases, we noticed that M0 and M2 Macrophages infiltrated the most in high-risk CRC patients, besides M2 Macrophages and neutrophils showed positive correlation with NET risk score. A novel reliable prognostic NET risk score was developed for CRC patients, and high-risk patients had unfavorable prognosis with advanced disease status.

Colorectal Cancer Incidence in Iran Based on Sex, Age, and Geographical Regions: A Study of 2014-2017 and Projected Rates to 2025.

While there has been extensive research on colorectal cancer (CRC) incidence and its associated factors in Iran, a significant gap exists in studies predicting its future trends. Our study aimed to thoroughly report CRC incidence across Iran from 2014 to 2017, by sex, age, and geographical regions, and provide a projection for 2025. This retrospective study utilized data from the Iranian National Population-based Cancer Registry (INPCR). Patients with the International Classification of Diseases for Oncology, 3rd Edition (ICD-O-3) codes C18 to C21 were included. The age-standardized incidence rate (ASR), was calculated per 100000 individuals annually, and crude incidence rates were retrieved for various demographic groups and years. Between 2014 and 2017, a total of 43580 new CRC cases (55.96% males) were registered. Men exhibited an ASR of 134.45, while women's ASR was 94.85. The highest ASRs were observed in Tehran, Qom, and Ilam (18.99, 18.26, and 18.06, respectively). Incidence rates surpassed 20 after age 50 for both genders, reaching their peak within the 80-84 age group. Adenocarcinoma was the most frequent histological type of CRC in nearly all provinces. Case numbers and ASRs are projected to continuously rise until 2025, with a predominance of male cases. The anticipated increase in CRC incidence in Iran emphasizes the need for additional studies to better identify risk factors. Furthermore, implementing screening programs is recommended for individuals at a higher risk of CRC, including men, the elderly population, and those residing in regions with a notable prevalence of CRC.

Risk Factors of Early Age Colorectal Cancer among Patients Attending at National Institute of Cancer Research &amp; Hospital

Background: Colorectal cancer (CRC) poses a significant public health burden worldwide, with a notable trend of increasing incidence among individuals aged 20 to 50 years. Understanding the risk factors associated with early-onset CRC is crucial for developing targeted prevention and intervention strategies, particularly in limited-resource settings. Objective: This study aimed to identify and analyze the risk factors contributing to the development of early-onset CRC in a population from a limited-resource country. Method: A comparative study was conducted among 178 CRC patients admitted to the National Institute of Cancer Research &amp; Hospital (NICRH), Dhaka. Patients were divided into two groups: Group-A (age 20-50 years) and Group-B (age &gt;50 years). Demographic and clinical data were collected, and statistical analyses were performed to determine associations between various risk factors and early-onset CRC. Results: The mean age of Group-A subjects was 43.6±7.1 years, significantly younger than Group-B subjects (59.2±9.3 years). Male patients constituted 69.1% of the cohort, with a statistically significant male-to-female ratio of 2.2:1. Higher BMI (≥25) was strongly associated with early-onset CRC (p&lt;0.01). Occupations such as business and middle socioeconomic status were significantly linked to early-onset CRC. Regular exercise (&gt;30 minutes daily) demonstrated a protective effect against CRC development. Consumption of red meat and fast food was associated with a higher risk of CRC, while regular consumption of vegetables was protective. Familial adenomatous polyposis (FAP) presence was significantly associated with early-onset CRC. Conclusions: Male sex, high BMI, specific occupations, dietary factors, and presence of FAP emerged as key risk factors for early-onset CRC. Encouraging regular exercise and promoting healthy dietary habits, particularly reducing red meat and fast-food intake, are crucial in mitigating the risk of early-onset CRC in similar populations.

Abstract 2197: Weight history and colorectal cancer risk in the Cancer Prevention Study-3 cohort

Abstract While the link between obesity and colorectal carcinogenesis is established, limited evidence suggests that early-life overweight/obesity may be an important consideration, particularly in the development of early-onset colorectal cancer (CRC). Using data from the American Cancer Society’s Cancer Prevention Study-3 (CPS-3), we investigated the association of body weight across the life course and risk of CRC. From 2006-13, over 300,000 participants (ages 30-65) enrolled in the CPS-3 cohort and provided a baseline waist circumference (WC) measure, self-reported baseline weight and height, weight at age 18, and weight at each decade of adulthood (20s to current age). Body shape phenotype (apple, pear, other) was self-reported in 2015. Excess body mass index (BMI)-years was calculated by subtracting a reference BMI of 25 from the reported BMI for each decade of life and aggregating excess BMI for the reported years of life. Through 2018, 424 incident cases of colorectal cancer were reported, of which 94 were younger than 50 years. Associations of BMI measures and WC with incident CRC were estimated using multivariable-adjusted Cox proportional hazards regression and stratified by sex and body shape. After exclusions (n=248,804), 78% of participants were women, 85% were non-Hispanic white, 69% were never smokers, and 8% had a family history of CRC. The mean baseline age was 47.8 (women) and 48.5 (men) years. The mean baseline BMI, WC, and age 18 BMI were 27.6 kg/m2, 91.9 cm, and 21.7 kg/m2, respectively, among women and 28.3 kg/m2, 103.8 cm, and 23.1 kg/m2, respectively, among men. Baseline BMI was associated with 8% higher CRC risk (95% confidence interval (CI) 0.99-1.18) per 5 kg/m2 increase. However, apple body shape was associated with higher CRC risk (hazard ratio (HR) per 5 kg/m2 BMI = 1.18, 95% CI 1.02-1.38). WC was associated with higher CRC risk (HR 1.08, 95% CI 1.01-1.15) per 10 cm increase, and the association was higher for apple body shape (HR 1.14, 95% CI 1.01-1.28). BMI at age 18 was associated with 17% higher CRC risk (95% CI 1.03-1.32) per 5 kg/m2 increase, and the association was higher for apple body shape (HR 1.36, 95% CI 1.12-1.65). Associations for non-apple body shapes were not statistically significant across all exposures. For early-onset CRC, associations with baseline BMI, WC, and age 18 BMI were suggestive of higher risk but not statistically significant. Participants in the highest category of excess BMI-years (women ≥35, men ≥81) relative to those in the lowest had 56% higher risk of overall CRC (95% CI 1.19-2.05), but the association with early-onset CRC was not statistically significant (HR 1.92, 95% CI 0.90-4.07). These findings suggest that while obesity is associated with higher CRC risk, excess weight gain around the waist and at younger ages may be of importance. Studies are needed to confirm these findings and further investigate the potential role of early-life obesity in the development of early-onset CRC. Citation Format: Caroline Y. Um, Christina C. Newton, Aparna Parikh, Marjorie L. McCullough, Alpa V. Patel. Weight history and colorectal cancer risk in the Cancer Prevention Study-3 cohort [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 2197.

Abstract 2317: Development and validation of a colorectal cancer prediction model: A nationwide cohort-based study

Abstract Background: Colorectal cancer (CRC) ranks as the third most prevalent cancer globally and is a major cause of cancer-related mortality. Early diagnosis is critical to increase survival rates. While CRC screening has shown significant benefit, adherence remains low, and there is a need for better tools to identify high-risk patients. Risk prediction models were demonstrated to identify such patients. Aim: To establish an individualized risk prediction model for CRC diagnosis based on Electronic Health Records (EHR). Methods: This is a retrospective cohort study utilizing EHR data of Clalit Health Services (CHS) members aged 50-74 that were eligible for CRC screening, from January 2013 to January 2019. The model was trained to predict CRC diagnosis within two years using approximately 20,000 EHR features including socio-demographic information, laboratory results and medical history. Model performance, as a complementary screening method, was evaluated. Results: The study included 2679 subjects with CRC diagnosis and 1,133,713 subjects without CRC diagnosis. The model was trained on subjects from 2013-2017, and performance was validated on subjects from 2019 and a cohort of subjects that underwent fecal occult blood test (FOBT). Incidence values of CRC among subjects in the top 1% risk scores were higher than baseline (2.3% vs. 0.3%; lift 8.38; P-value &amp;lt;0.001). Characteristics of subjects by risk scores percentiles are presented in Table 1. Cumulative event probabilities increased with higher model scores, indicating a correlation between predicted and actual risk of CRC diagnosis. Model-based risk stratification among subjects with a positive FOBT, identified subjects with more than twice the risk for CRC compared to FOBT alone. Conclusions: We developed an individualized risk prediction model for CRC that can be utilized as a complementary decision support tool for healthcare providers to precisely identify patients at high risk for CRC and refer them to confirmatory testing. Citation Format: Samah Hayek. Development and validation of a colorectal cancer prediction model: A nationwide cohort-based 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 2317.

Abstract 3434: Effect modification by levels of sex hormones in the association between adiposity and cancer incidence in the UK Biobank

Abstract Introduction: The association between adiposity and cancer risk differs between sexes for some cancer types. Methods: We prospectively examined adiposity in relation to cancer incidence according to sex hormones in the UK Biobank. Adiposity was assessed by body mass index (BMI) and visceral adipose tissue (VAT), the latter predicted using determinants of age, height, weight, hip circumference, waist circumference, and race. Serum sex hormone binding globulin (SHBG), testosterone, and estradiol were measured using a biochemistry assay and were classified as high or low based on median levels. Cancer incidence was ascertained using ICD-10 codes through cancer registry linkage. For cancer types showing a sex difference in the association between adiposity and cancer incidence, we assessed multiplicative and additive interaction with sex hormones in men and women separately and corrected for multiple testing using false discovery rate. We used Cox regression to calculate the multivariable hazard ratio (HR) of cancer per increase between the 90th to 10th percentile of adiposity (BMI or predicted VAT). Results: During a median follow-up of 13.1 years, we documented 23,964 and 21,045 incident cancer cases among 217,460 men and 256,163 women, respectively. Adiposity showed a much stronger association with higher risk of colorectal, esophageal, and liver cancers in men than women. In men, BMI was more strongly associated with higher risk of colorectal cancer in low vs. high levels of SHBG (HR (95%CI) of 1.47 (1.31-1.64) vs. 1.12 (0.94-1.33) (adjusted Pinteraction = 0.027). In contrast, BMI showed a stronger association in high vs. low levels of SHBG with esophageal (HR = 2.39 vs. 1.62) and liver cancers (HR = 3.24 vs 1.96) in men (adjusted Pinteraction = 0.038 and 0.027, respectively). Among women, BMI was associated with a higher risk of esophageal cancer in those with low SHBG (HR=1.68) but not in those with high SHBG (HR=0.64) (adjusted Pinteraction = 0.025). Similar patterns were observed for predicted VAT. Men with high SHBG levels and high adiposity (BMI and predicted VAT) had 7.63 (5.08-11.46) and 8.92 (5.72 to 13.90), respectively, times higher risk of liver cancer compared to men with low SHBG levels and low adiposity. No effect modification by estradiol or testosterone was detected for any of the cancers studied. Conclusions: The association between adiposity and colorectal, esophageal, and liver cancer differed by sex. SHBG may be an important factor underlying these differences. Citation Format: LeeAnn Lucas, Yujia Lu, Edward L. Giovannucci, Mingyang Song. Effect modification by levels of sex hormones in the association between adiposity and cancer incidence in the UK Biobank [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 3434.

Indoxyl sulfate contributes to colorectal cancer cell proliferation and increased EGFR expression by activating AhR and Akt.

Although patients with chronic kidney disease (CKD) have a higher risk of colorectal cancer (CRC) aggravation, the connection between these two diseases is not well understood. Recent studies have shown that both CKD and CRC aggravation are closely related to an increased abundance of indole-producing Fusobacterium nucleatum in the gut. The indole absorbed from the gut is eventually metabolized to indoxyl sulfate in the liver. Since indoxyl sulfate is involved not only in accelerating CKD progression but also in the initiation and development of its associated complications, the present study aimed to clarify whether indoxyl sulfate induces the proliferation of CRC cells. This study found that indoxyl sulfate induced the proliferation of CRC-derived HCT-116 cells by activating the aryl hydrocarbon receptor (AhR) and the proto-oncogene Akt. The AhR antagonist CH223191 and Akt inhibitor MK2206 suppressed indoxyl sulfate-induced proliferation of HCT-116 cells. We also found that indoxyl sulfate upregulated epidermal growth factor receptor (EGFR) expression, which is associated with poor prognosis of CRC, whereas CH223191 and MK2206 repressed EGFR expression. Furthermore, indoxyl sulfate increased the sensitivity of CRC cells to EGF by upregulating EGFR expression. These findings suggest that indoxyl sulfate may be an important link between CKD and CRC aggravation.

Abstract 7462: Interventional dietary saffron drives antitumor immunity inInterventional dietary saffron drives antitumor immunity in high risk colorectal cancer IBD Patients, A Multisite Clinical Trial Study

Abstract Background: Inflammatory polyps in patients with Inflammatory Bowel Disease (IBD) pose a significant risk for colorectal cancer (CRC). Dietary interventions targeting anti-tumor immunity are crucial in mitigating this risk. Aim: We investigated saffron's anti-inflammatory effects in IBD patients due to the high prevalence of polyps, aiming to prevent CRC. Methods: The study retrospectively evaluated 485 colitis patients (70 IBD, 415 NIC) from Howard University Hospital, through colonoscopy, pathology, and clinical reports evaluations. At Howard University, three UC patients received 50mg of saffron twice daily for 8 weeks, with two cycles. Inflammatory markers, stool calprotectin, and cytokines were assessed. Similar saffron trials were conducted at Yazd University (30 UC patients) and Egypt University (11 UC patients). Results: Patients with inflammatory bowel disease (IBD) were found to have a 15.7% prevalence of polyps compared to 8.2% in Non-inflammatory colitis patients. Among IBD patients, those with ulcerative colitis had more polyps (27%) than those with Crohn's disease (5%). In a multisite clinical trial, Saffron treatment improved various health indicators, including Partial MayoScore and quality of life. In the study (HU site), pro-inflammatory cytokines decreased, anti-inflammatory markers increased, and fecal calprotectin levels dropped significantly after saffron treatment. Saffron also led to changes in gut bacteria composition. Importantly, no adverse events were reported in the study participants. In one group of patients (Yazd study), saffron treatment led to significant improvements in depression scores, disease severity, and inflammation markers. In another site (Egypt study), 50% of saffron-treated patients showed improvement in markers related to disease severity, inflammation, and quality of life. Conclusion: Saffron supplementation, alongside standard treatments, shows promise in reducing local and systemic inflammation in IBD patients and may reduce the risk of developing inflammatory polyps and hence CRC. This safe and feasible intervention warrants further exploration as an inflammation-driven CRC preventive strategy. Citation Format: Hassan Ashktorab, Roham Salmanroghani, Hassan Salmanroghani, Reza Oskrochi, Mudasir Rashid, Adeyinka Laiyemo, Suryanarayana Reddy Challa, Philip Oppong-Twene, Nasrin Farjana, Angesom Kibreab, Holden Maeker, Amr Amin, Amal Ahmed Mohamed, Amr Elsayed, Zaki Mohamed Zaki, Omima Mohamed, Alshymaa Hassnine, Salma Saed, Soha Hassanin, Farshad Aduli, Lakshmi Gayathri Chirumamilla, Hassan Brim. Interventional dietary saffron drives antitumor immunity inInterventional dietary saffron drives antitumor immunity in high risk colorectal cancer IBD Patients, A Multisite Clinical Trial 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 7462.

Prognosis Analysis of Additional Surgical Treatment for High-Risk T1 Colorectal Cancer Patients After Endoscopic Resection

To analyze the effect of additional surgery on the survival and prognosis of high-risk T1 colorectal cancer patients who have undergone endoscopic resection. The clinical data of patients with high-risk T1 colorectal cancer were retrospectively collected. The patients were divided into the endoscopic resection (ER) plus additional surgical resection (SR) group, or the ER+SR group, and the ER group according to whether additional SR were performed after ER. Baseline data of the patients and information on the location, size, and postoperative pathology of the lesions were collected. Patient survival-related information was obtained through the medical record system and patient follow-up. The primary outcome indicators were the overall survival and the colorectal cancer-specific survival. Univariate Cox regression analysis was used to screen survival-related risk factors and hazard ratio (HR) was calculated. Multivariate Cox regression analysis was used to analyze the independent influencing factors. The data of 109 patients with T1 high-risk colorectal cancer were collected, with 52 patients in the ER group and 57 patients in the ER+SR group. The mean age of patients in the ER group was higher than that in the ER+SR group (65.21 years old vs. 60.54 years old, P=0.035), and the median endoscopic measurement of the size of lesions in the ER group was slightly lower than that in the ER+SR group (2.00 cm vs. 2.50 cm, P=0.026). The median follow-up time was 30.00 months, with the maximum follow-up time being 119 months, in the ER+SR group and there were 4 patients deaths, including one colorectal cancer-related death. Whereas the median follow-up time in the ER group was 28.50 months, with the maximum follow-up time being 78.00 months, and there were 4 patient deaths, including one caused by colorectal cancer. The overall 5-year cumulative survival rates in the ER+SR group and the ER group were 94.44% and 81.65%, respectively, and the cancer-specific 5-year cumulative survival rates in the ER+SR group and the ER group were 97.18% and 98.06%, respectively. The Kaplan-Meier analysis showed no significant difference in the overall cumulative survival or cancer-specific cumulative survival between the ER+SR and the ER groups. Univariate Cox regression analysis showed that age and the number of reviews were the risk factors of overall survival (HR=1.16 and HR=0.27, respectively), with age identified as an independent risk factor of overall survival in the multivariate Cox regression analysis (HR=1.10, P=0.045). For T1 colorectal cancer patients with high risk factors after ER, factors such as patient age and their personal treatment decisions should not be overlooked. In clinical practice, additional caution should be exercised in decision-making concerning additional surgery.

Comprehensive analysis of basement membrane-related gene based on single-cell and bulk RNA sequencing data to predict prognosis and evaluate immune characteristics in colorectal cancer.

Basement membrane-related genes (BMs) participate in regulating cell polarity, invasion, metastasis, and survival across different tumor types. Nevertheless, the specific functions of BMs in colorectal cancer (CRC) remain uncertain. To investigate the clinical relevance of BMs in CRC, we retrieved both gene expression and clinical data from The Cancer Genome Atlas (TCGA) datasets for subsequent analysis. The Kaplan-Meier (K-M) survival curve was employed to evaluate prognosis in high- and low-risk groups. Furthermore, additional analyses, including nomogram construction, functional enrichment, examination of the tumor immune microenvironment, prediction of small-molecule drugs, and more, were conducted to delve into the significance of BM-related signatures in CRC. Single-cell data from seven CRC patients were obtained from the TISCH2 database, and expression validation and cell source exploration of BM-related signatures were performed. Lastly, the expression and function of TIMP1, a key gene in BMs that may play a role in the progression of CRC, was validated in vitro through a series of basic experiments. We constructed a seven BMs-based model to categorize CRC patients into high-risk and low-risk groups. K-M survival analysis indicated a poorer prognosis for high-risk CRC patients. Cox regression analysis further identified the risk score as an independent prognostic factor for CRC patients. The nomogram model exhibited superior discrimination and calibration abilities of CRC patients. Based on the results from GO/KEGG and GSEA, genes in the high-risk subgroup were implicated in immune-related pathways and exhibited a positive correlation with immune checkpoints. In single-cell data, we found that TIMP1 is highly expressed in many cells, especially in malignant tumor cells. We also observed up-regulation of TIMP1 in CRC cell lines, promoting cancer invasion and migration in vitro. Our study has discovered a novel prognostic index derived from BM-related genes in CRC patients. Specifically, the new model enables patient stratification, improving the selection of individuals likely to benefit from immunotherapy.

Construction of an immune predictive model and identification of TRIP6 as a prognostic marker and therapeutic target of CRC by integration of single-cell and bulk RNA-seq data

BackgroundInvestigations elucidating the complex immunological mechanisms involved in colorectal cancer (CRC) and accurately predicting patient outcomes via bulk RNA-Seq analysis have been notably limited. This study aimed to identify the immune status of CRC patients, construct a prognostic model, and identify prognostic signatures via bulk RNA sequencing (RNA-seq) and single-cell RNA-seq (scRNA-seq).MethodsThe scRNA-seq data of CRC were downloaded from Gene Expression Omnibus (GEO). The UCSC Xena database was used to obtain bulk RNA-seq data. Differentially expressed gene (DEG), functional enrichment, and random forest analyses were conducted in order to identify core genes associated with colorectal cancer (CRC) that were relevant to prognosis. A molecular immune prediction model was developed using logistic regression after screening features using the least absolute shrinkage and selection operator (LASSO). The differences in immune cell infiltration, mutation, chemotherapeutic drug sensitivity, cellular senescence, and communication between patients who were at high and low risk of CRC according to the predictive model were investigated. The prognostic genes that were closely associated with CRC were identified by random survival forest (RSF) analysis. The expression levels and clinical significance of the hub genes were analyzed in vitro. The LoVo cell line was employed to ascertain the biological role of thyroid hormone receptor-interacting protein 6 (TRIP6).ResultsA total of seven main cell subtypes were identified by scRNA-seq analysis. A molecular immune predictive model was constructed based on the risk scores. The risk score was significantly associated with OS, stage, mutation burden, immune cell infiltration, response to immunotherapy, key pathways, and cell–cell communication. The functions of the six hub genes were determined and further utilized to establish a regulatory network. Our findings unequivocally confirmed that TRIP6 upregulation was verified in the CRC samples. After knocking down TRIP6, cell proliferation, migration, and invasion of LoVo cells were inhibited, and apoptosis was promoted.ConclusionsThe molecular predictive model reliably distinguished the immune status of CRC patients. We further revealed that TRIP6 may act as an oncogene in CRC, making it a promising candidate for targeted therapy and as a prognostic marker for CRC.

Uptake and detection rate of colorectal cancer screening with colonoscopy in China: A population-based, prospective cohort study

BackgroundColorectal cancer is the leading cause of cancer-related death worldwide. Colonoscopy is widely used as a screening test for detecting colorectal cancer in many countries. However, there is little evidence regarding the uptake and diagnostic yields of colonoscopy in population-based screening programs in countries with limited medical resources. ObjectiveWe reported the uptake of colonoscopy and the detection of colorectal lesions and explored related factors based on a colorectal cancer screening program in China. DesignIndividuals aged 45–74 years who were asymptomatic for colorectal cancer and had no history of colorectal cancer were recruited. An established risk score system was used to identify individuals at high risk for colorectal cancer, and they were subsequently recommended for colonoscopy. SettingA population-based, prospective cohort study was implemented in 169 communities, 14 districts of Chongqing, Southwest China. ParticipantsA total of 288,150 eligible participants were recruited from November 2013 to June 2021, and 41,315 participants were identified to be at high risk of colorectal cancer. MethodsGeneralized linear mixed model was used to explore the individual and community structural characteristics associated with uptake of colonoscopy. Additionally, the detection rate of colorectal lesions under colonoscopy screening was also reported, and their associated factors were explored. Results7859 subjects underwent colonoscopy, with an uptake rate of 19.02 % (95 % CI 18.64 %–19.40 %). Lower uptake rates were associated with older age, lower education, more physical activity, and structural characteristics, including residing in developing areas (OR 0.73, 95 % CI 0.69–0.78), residing more than 5 km from screening hospital (5–10 km: OR 0.85, 95 % CI 0.79–0.91; >10 km: OR 0.85, 95 % CI 0.80–0.91), and not being exposed to social media publicity (OR 0.63, 95 % CI 0.53–0.75). Overall, 8 colorectal cancers (0.10 %), 423 advanced adenomas (5.38 %), 820 nonadvanced adenomas (10.43 %), and 684 hyperplastic polyps (8.70 %) were detected, with an adenoma detection rate of 15.92 %. Several factors, including older age, male, current smoking and a family history of colorectal cancer, were positively related to colorectal neoplasms. ConclusionsThe uptake of colonoscopy for colorectal cancer screening was not optimal among a socioeconomically diverse high-risk population. The screening strategy should attempt to ensure equitable access to screening according to regional characteristics, and enhance the uptake of colonoscopy by recommended multifaceted interventions, which focus on individuals with poor compliance, select a closer screening hospital, and strengthen social media publicity at the structural level.