Etiology Of Colorectal Cancer Research Articles

Causal associations between dietary factors and colorectal cancer risk: a Mendelian randomization study.

Previous epidemiological studies have found a link between colorectal cancer (CRC) and human dietary habits. However, the inherent limitations and inevitable confounding factors of the observational studies may lead to the inaccurate and doubtful results. The causality of dietary factors to CRC remains elusive. We conducted two-sample Mendelian randomization (MR) analyses utilizing the data sets from the IEU Open GWAS project. The exposure datasets included alcoholic drinks per week, processed meat intake, beef intake, poultry intake, oily fish intake, non-oily fish intake, lamb/mutton intake, pork intake, cheese intake, bread intake, tea intake, coffee intake, cooked vegetable intake, cereal intake, fresh fruit intake, salad/raw vegetable intake, and dried fruit intake. In our MR analyses, the inverse variance weighted (IVW) method was employed as the primary analytical approach. The weighted median, MR-Egger, weighted mode, and simple mode were also applied to quality control. Heterogeneity and pleiotropic analyses were implemented to replenish the accuracy of the results. MR consequences revealed that alcoholic drinks per week [odds ratio (OR): 1.565, 95% confidence interval (CI): 1.068-2.293, p = 0.022], non-oily fish intake (OR: 0.286; 95% CI: 0.095-0.860; p = 0.026), fresh fruit intake (OR: 0.513; 95% CI: 0.273-0.964; p = 0.038), cereal intake (OR: 0.435; 95% CI: 0.253-0.476; p = 0.003) and dried fruit intake (OR: 0.522; 95% CI: 0.311-0.875; p = 0.014) was causally correlated with the risk of CRC. No other significant relationships were obtained. The sensitivity analyses proposed the absence of heterogeneity or pleiotropy, demonstrating the reliability of the MR results. This study indicated that alcoholic drinks were associated with an increased risk of CRC, while non-oily fish intake, fresh fruit intake, cereal intake, and dried fruit were associated with a decreased risk of CRC. This study also indicated that other dietary factors included in this research were not associated with CRC. The current study is the first to establish the link between comprehensive diet-related factors and CRC at the genetic level, offering novel clues for interpreting the genetic etiology of CRC and replenishing new perspectives for the clinical practice of gastrointestinal disease prevention.

Interactions between folate metabolism-related nutrients and polymorphisms on colorectal cancer risk: a case-control study in the Basque country.

Folate-mediated one-carbon metabolism (FOCM) plays an important role in colorectal carcinogenesis. Previous studies have assessed the role of folate-mediated one-carbon metabolism (FOCM)-related gene-diet interaction in the aetiology of colorectal cancer (CRC), however, the results remained inconclusive. Thus, this study aimed to investigate dietary factors and genetic variants related to FOCM, as well as potential nutrient-gene and nutrient-lifestyle interactions, on CRC risk. This observational study included 229 patients diagnosed with CRC and 229 age- and sex-matched subjects as controls from a population-based bowel cancer screening program. Conditional logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals (95%CI) for CRC risk. A Bonferroni-corrected threshold of α = 0.005 was considered significant, and P values less than 0.05 were considered to be suggestive of an association. After Bonferroni correction, a high dietary intake of betaine was associated with a decreased risk of CRC in the adjusted model (OR, 95% CI: 0.21, 0.10-0.40, P < 0.001). Two SNPs, rs1476413 and rs17824591, exhibited significant gene-diet interactions with total choline ad vitamin B12 intakes, respectively, in adjusted models (total choline, tertile 3 vs. 1, OR, 95% CI: 0.25, 0.11-0.66, Pinteraction = 0.012; vitamin B12, tertile 2 vs. tertile 1, OR, 95% CI: 2.48, 1.04-5.00, Pinteraction = 0.003). These findings suggest that betaine intake and interactions between some dietary factors and variants in MTHFR and MTHFD1 genes have an influence on CRC risk in the population studied. If these results are confirmed, specific nutritional intervention strategies could be designed.

The effects of ANRIL polymorphisms on colorectal cancer, tumor stage, and tumor grade among Iranian population.

Colorectal cancer (CRC) is a type of neoplasm, developing in the colon or rectum. The exact etiology of CRC is not well known, but the role of genetic, epigenetic, and environmental factors are established in its pathogenesis. Therefore, the aim of this research was to explore the effects of ANRIL polymorphisms on the CRC and its clinical findings. The peripheral blood specimens were collected from 142 CRC patients and 225 controls referred to Milad Hospital, Tehran, Iran. PCR- RFLP method was used to analyze ANRIL rs1333040, rs10757274 rs4977574, and rs1333048 polymorphisms. The ANRIL rs1333040 polymorphism was related to a higher risk of CRC in the co-dominant, dominant, and log-additive models. ANRIL rs10757274, rs4977574, and rs1333048 polymorphisms showed no effect on CRC susceptibility. The CGAA and TGGA haplotypes of ANRIL rs1333040/ rs10757274/ rs4977574/rs1333048 polymorphisms were associated with the higher and the lower risk of CRC respectively. The rs1333040 polymorphism was associated with higher TNM stages (III and IV). The frequency of ANRIL rs10757274 polymorphism was lower in CRC patients over 50 years of age only in the dominant model. In addition, the rs10757274 was associated with well differentiation in CRC patients. The ANRIL rs1333040 polymorphism was associated with a higher risk of CRC and higher TNM stages. ANRIL rs10757274 polymorphism was associated with the well-differentiated tumor in CRC.

Abstract 6614: Integrating single-cell RNA-seq and large genome-wide association study data to identify colorectal cancer cell-of-origin populations

Abstract Background: Single-cell RNA sequencing (scRNA-seq) enables the precise identification of distinct cell populations and the measurement of gene expression within each population. Recently, integrating scRNA-seq and genome-wide association study (GWAS) data has shown promise in identifying cell-of-origin populations in human diseases. Colorectal cancer (CRC) progresses through a phenotypic continuum from normal colon to adenoma, and ultimately CRC. However, the specific disease cell-of-origin populations underlying each stage of CRC development at a single-cell resolution have not been well studied. Additionally, while transcriptome-wide association studies (TWAS) have identified more than 200 putative risk genes in CRC, the precise disease cell-of-origin populations associated with these genes remain elusive. Materials and methods: We analyzed scRNA-seq datasets from 31 normal colon, 8 colon serrated polyps, and 15 conventional adenoma tissues of individuals participated the Colorectal Molecular Atlas Project (COLON MAP). We next conducted an integrative analysis of the aforementioned scRNA-seq data, with extensive epigenomics data and summary statistics from a large CRC GWAS conducted among European ancestry populations (78,473 CRC cases and 107,143 controls) using single-cell disease relevance score (scDRS), to investigate cell-of-origin populations underlying the CRC development. We conducted correlation analysis between gene expression and individual cell risk scores derived from scDRS. Additionally, we performed differential expression analysis comparing disease cell-of-origin populations with other cell populations at each stage. Results: We identified multiple cell-of-origin populations associated with CRC, including absorptive cells (ABS) (P &amp;lt; 1 × 10-4) and goblet cells (GOB) (P &amp;lt; 7 × 10-3) in the normal colon, ABS (P &amp;lt; 2 × 10-3), enteroendocrine cells (EE) (P &amp;lt; 0.04), and serrated-specific cells (SSC) (P &amp;lt; 1 × 10-4) in serrated polyps, and ABS (P &amp;lt; 9 × 10-3) and SSC (P &amp;lt; 6 × 10-4) in adenomas. Among the previously reported 205 risk genes from TWAS, a majority show high correlations of their expressions with the risk scores of the single cells (median value R2 = 0.07, 0.14, 0.137 at normal colon, serrated polyps, adenoma, respectively). Moreover, 57 of these TWAS-reported genes (27.8% of 205 genes) exhibited evidence of differential expression in disease cell-of-origin populations compared to other cell populations at a nominal p-value &amp;lt; 0.05 in at least one stage (Binomial test, P &amp;lt; 0.01 for all). Conclusion: This study reveals the cell-of-origin populations that influence the development of CRC, and provides evidence of the role of risk genes in these populations. These findings are crucial for identifying causal genes and understanding the cellular mechanisms that drive the biology and etiology of CRC. Citation Format: Chao Li, Zhishan Chen, Qing Li, Jungyoon Choi, Quanhu Sheng, Wanqing Wen, Xiang Shu, Xiao-ou Shu, Jirong Long, Qiuyin Cai, Bhuminder Singh, Martha J. Shrubsole, Ken Lau, Wei Zheng, Xingyi Guo. Integrating single-cell RNA-seq and large genome-wide association study data to identify colorectal cancer cell-of-origin populations [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 6614.

Abstract 3467: Tumor immune and microbial characteristics of colorectal cancer according to age at diagnosis and detailed anatomical location

Abstract Background: Colorectal cancer is a heterogeneous disease, exhibiting spectra of tumor characteristics that vary across age at diagnosis and anatomical location. We hypothesized that tumor immune and microbial characteristics of colorectal cancer might change with age at diagnosis and detailed anatomical location. Methods: We utilized a pooled dataset of colorectal cancer cases (N= 958 to1413 depending on variables) with available immune cell density or microbial data in the Nurses' Health Study, Health Professionals Follow-up Study, and Ontario Familial Colon Cancer Registry. We examined whether there were statistically significant trends in tumor immune and microbial according to age at diagnosis and detailed primary tumor location (cecum, ascending, hepatic flexure, transverse, splenic flexure, descending, sigmoid, rectosigmoid, rectum) using Spearman’s correlation test. The densities of immune cells were determined by using multiplex immunofluorescence, including T cells (CD3, CD4, CD8, CD45RA, CD45RO, FOXP3) and macrophages (CD68, M1-like, and M2-like) in tumor intraepithelial and stromal regions. We conducted stratified analyses by microsatellite instability (MSI) status. Results: The density of memory (both CD4+ and CD8+) T cells in tumor epithelial areas continuously increased as age at diagnosis increased (P for trend &amp;lt;0.005). Compared to later-onset colorectal cancer, early-onset colorectal cancer had a lower density of memory T-cells. With respect to tumor site, CD3+CD4+ and CD3+CD8+ T densities in tumor epithelial areas were highest in the cecum compared to other subsites, and there was a statistically significant decreasing trend from the cecum to rectum (P for trend &amp;lt;0.005). We also observed significant decreasing trends for CD68+, M1-like, and M2-like macrophage densities in combined tumor (intraepithelial and stromal) regions from the cecum to rectum (P for trend &amp;lt;0.005). The proportion of F. nucleatum-positive colorectal cancers gradually decreased from the cecum to rectum (P for trend &amp;lt;0.005). Similar trends were observed in separate analyses in non-MSI-high cases. Conclusions: This study suggests that certain tumor immune and microbial characteristics in the tumor microenvironment, specifically T cell and macrophage densities and Fusobacterium nucleatum positivity, change gradually according to age at diagnosis and/or detailed anatomical location. Age and anatomical location spectra in tumor immune and microbial characteristics will shed light on the etiology of colorectal cancer (including early-onset colorectal cancer), leading to better-personalized cancer prevention and treatment. Citation Format: Tomotaka Ugai, Yasutoshi Takashima, Yuxue Zhong, Juha P. Väyrynen, Daniel Buchanan, Jeroen Huyghe, Li Hsu, Conghui Qu, Sushma Thomas, Claire Thomas, Steve Gallinger, Robert Grant, Ulrike Peters, Amanda I. Phipps, Jonathan Nowak, Shuji Ogino. Tumor immune and microbial characteristics of colorectal cancer according to age at diagnosis and detailed anatomical location [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 3467.

Abstract 4429: Plasma metabolic profiles in association with subsequent risk of colorectal cancer in the UK Biobank cohort

Abstract Background: Dysregulation of metabolic processes contributes to colorectal cancer (CRC) etiology. We aimed to comprehensively evaluate the prospective associations between pre-diagnostic metabolic biomarkers and CRC risk in 230,420 UK Biobank participants. Methods: A total of 249 metabolic biomarkers were measured by nuclear magnetic resonance spectroscopy from baseline plasma samples. Cox proportional hazard models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for the associations of metabolic biomarkers with CRC risk after adjusting for potential confounders. Subgroup analyses were performed by sex and CRC subsites (i.e., proximal colon, distal colon, rectum). We also conducted factor analyses to identify latent factors and examined their associations with CRC risk. Results: During a median follow-up time of 9.7 years, 2,410 incident primary CRC cases were identified after excluding participants diagnosed with CRC within two years after blood collection. After correcting for multiple testing, 50 metabolic biomarkers, including lipids and lipoproteins, fatty acids, ketone bodies, and inflammation, were significantly associated with incident CRC risk. No statistically significant differences were observed for the biomarker-CRC associations by sex and CRC subsite. In the sensitivity analysis, excluding cholesterol-lowering medication users did not alter the main findings. In factor analyses, we identified a significant association of CRC risk (HR = 1.08; 95% CI = 1.04-1.13; P-value = 6.89×10-5) with a metabolite pattern which was positively correlated with triglycerides and inversely correlated with relative concentrations of omega-6 fatty acids and polyunsaturated fatty acids. Conclusion: We identified multiple metabolic biomarkers and a metabolite pattern associated with CRC risk in a large prospective cohort. These findings suggest lipid metabolism may contribute to carcinogenesis of the colorectum. Citation Format: Fangcheng Yuan, Guochong Jia, Wanqing Wen, Wei Zheng. Plasma metabolic profiles in association with subsequent risk of colorectal cancer in the UK Biobank 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 4429.

Postbiotics in colorectal cancer: intervention mechanisms and perspectives.

Colorectal cancer (CRC) is a common malignancy affecting the gastrointestinal tract worldwide. The etiology and progression of CRC are related to factors such as environmental influences, dietary structure, and genetic susceptibility. Intestinal microbiota can influence the integrity of the intestinal mucosal barrier and modulate intestinal immunity by secreting various metabolites. Dysbiosis of the intestinal microbiota can affect the metabolites of the microbial, leading to the accumulation of toxic metabolites, which can trigger chronic inflammation or DNA damage and ultimately lead to cellular carcinogenesis and the development of CRC. Postbiotics are preparations of inanimate microorganisms or their components that are beneficial to the health of the host, with the main components including bacterial components (e.g., exopolysaccharides, teichoic acids, surface layer protein) and metabolites (e.g., short-chain fatty acids, tryptophan metabolite, bile acids, vitamins and enzymes). Compared with traditional probiotics, it has a more stable chemical structure and higher safety. In recent years, it has been demonstrated that postbiotics are involved in regulating intestinal microecology and improving the progression of CRC, which provides new ideas for the prevention and diagnosis of CRC. In this article, we review the changes in intestinal microbiota in different states of the gut and the mechanisms of anti-tumor activity of postbiotic-related components, and discuss the potential significance of postbiotics in the diagnosis and treatment of CRC. This reviews the changes and pathogenesis of intestinal microbiota in the development of CRC, and summarizes the relevant mechanisms of postbiotics in resisting the development of CRC in recent years, as well as the advantages and limitations of postbiotics in the treatment process of CRC.

Associations of serum trimethylamine N-oxide and its precursors with colorectal cancer risk in the Prostate, Lung, Colorectal, Ovarian Cancer Screening Trial Cohort.

Dietary intake influences gut microbiome composition, which in turn may be associated with colorectal cancer (CRC). Associations of the gut microbiome with colorectal carcinogenesis may be mediated through bacterially regulated, metabolically active metabolites, including trimethylamine N-oxide (TMAO) and its precursors, choline, L-carnitine, and betaine. Prospective associations of circulating TMAO and its precursors with CRC risk were investigated. TMAO, choline, betaine, and L-carnitine were measured in baseline serum samples from 761 incident CRC cases and 1:1 individually matched controls in the prospective Prostate, Lung, Colorectal, Ovarian Cancer Screening Trial Cohort using targeted fully quantitative liquid chromatography tandem mass spectrometry panels. Prospective associations of the metabolites with CRC risk, using multivariable conditional logistic regression, were measured. Associations of a priori-selected dietary exposures with the four metabolites were also investigated. TMAO and its precursors were not associated with CRC risk overall, but TMAO and choline were positively associated with higher risk for distal CRC (continuous ORQ90 vs. Q10 [95% CI] =1.90 [CI, 1.24-2.92; p=.003] and 1.26 [1.17-1.36; p<.0001], respectively). Conversely, choline was inversely associated with rectal cancer (ORQ90 vs. Q10 [95% CI]=0.77 [0.76-0.79; p<.001]). Red meat, which was previously associated with CRC risk in the Prostate, Lung, Colorectal, Ovarian Cancer Screening Trial Cohort , was positively associated with TMAO (Spearman rho=0.10; p=.0003). Serum TMAO and choline may be associated with higher risk of distal CRC, and red meat may be positively associated with serum TMAO. These findings provide insight into a potential microbially mediated mechanism underlying CRC etiology.

Association of Fusobacterium nucleatum infection with the clinicopathological characteristics in colorectal cancer patients.

Colorectal cancer (CRC) is a global health problem. The gut microbiome is now recognized as an important underlying factor to the initiation and progression of CRC. Fusobacterium nucleatum (FN) is one of the most studied bacteria in the aetiology of CRC. This study provided cohort evidence on the association of FN infection with clinicopathologic features in CRC patients. We analysed the cancerous and adjacent non-cancerous formalin-fixed paraffin embedded (FFPE) tissue of 83 CRC patients from a single medical centre in Malaysia. TaqMan probe-based qPCR targeting the 16S rRNA gene was used to detect the presence of FN in the extracted FFPE DNA. The differences in FN expression between cancer and non-cancer tissues were evaluated. Association studies between FN infection in the tumour and relative FN abundance with available clinical data were conducted. FN was more abundant in the cancerous tissue compared to non-cancerous tissue (p = 0.0025). FN infection in the tumour was significantly associated with lymph node metastasis (p = 0.047) and cancer staging (p = 0.032), but not with other clinicopathologic variables. In double-positive patients where FN was detected in both cancerous and non-cancerous tissue, the expression fold-change of FN, calculated using 2-ΔΔCT formula, was significantly higher in patients with tumour size equal to or greater than 5cm (p = 0.033) and in KRAS-mutated patients (p = 0.046). FN is enriched in CRC tumour tissue and is associated with tumour size, lymph node metastasis, cancer staging, and KRAS mutation in this single-centre small cohort study.

Polymorphisms in insulin pathway genes and cancer risk

Background: Insulin is a big hormone (5808 Da) generally produced with the aid of the pancreas. Insulin receptors (IR) are found in neurons and glial cells. Insulin resistance has been related to increased plasma insulin levels, glucose intolerance, elevated insulin-like growth factor-1 (IGF-I), glucose and free fatty acids, body mass index, and an elevated risk for colorectal cancers. Proinflammatory cytokines, boom components, and hormones secreted by adipocytes play a key role in colorectal cancer etiology. Acetyl-CoA acetyltransferase (ACAT1) mediates insulin-precipitated cell proliferation and metastatic outcomes in colorectal cancer cells. Therefore, miRNAs might serve as a biological connection between metabolic changes linked to obesity and the beginning and progression of Colorectal Cancer Cancer (CRC). Furthermore, these findings shed new light on weight problems as a CRC danger component in which miRNA dysregulation may be involved. The function of IGFs in CRC is investigated by examining the association of two genetic polymorphisms in IGFBP-3 (a G → C single nucleotide polymorphism) and IGF-1 (a cytosine-adenosine dinucleotide repeat) with CRC risk in addition to the possibility of the other interventions, including physical activity, body mass index (BMI), and the use of postmenopausal hormones. These factors can exert their effects by modifying IGF-1 and the related binding proteins (IGFBP). Furthermore, the IGFBP-3 genotype can lead to a substantial effect modifier in the association between CRC and risk factors. It has been found that functional polymorphisms in the pathway of insulin genes, including IGFBPI, INSR, INS, and insulin receptor substrates 1 and 2 (IRS1 and IRS2), can be related to CRC.

Greasing the Wheels of Pharmacotherapy for Colorectal Cancer: the Role of Natural Polyphenols.

The main purpose of this review, mainly based on preclinical studies, is to summarize the pharmacological and biochemical evidence regarding natural polyphenols against colorectal cancer and highlight areas that require future research. Typically, colorectal cancer is a potentially preventable and curable cancer arising from benign precancerous polyps found in the colon's inner lining. Colorectal cancer is the third most common cancer, with a lifetime risk of approximately 4 to 5%. Genetic background and environmental factors play major roles in the pathogenesis of colorectal cancer. Theoretically, a multistep process of colorectal carcinogenesis provides enough time for anti-tumor pharmacotherapy of colorectal cancer. Chronic colonic inflammation, oxidative stress, and gut microbiota imbalance have been found to increase the risk for colorectal cancer development by creating genotoxic stress within the intestinal environment to generate genetic mutations and epigenetic modifications. Currently, numerous natural polyphenols have shown anti-tumor properties against colorectal cancer in preclinical research, especially in colorectal cancer cell lines. In this review, the current literature regarding the etiology and epidemiology of colorectal cancer is briefly outlined. We highlight the findings of natural polyphenols in colorectal cancer fromin vitro and in vivo studies. The scarcity of human trials data undermines the clinical use of natural polyphenols as anti-colorectal cancer agents, which should be undertaken in the future.

Hereditary Colorectal Cancer Diagnosis by Next-Generation Sequencing.

Pathogenic germline variants causally contribute to the etiology of colorectal cancer (CRC) and polyposis. The era of massively parallel sequencing, also known as next-generation sequencing (NGS), make it highly possible, effective, and efficient to offer rapid and cost-effective diagnosis for CRC. To aid clinical laboratories in testing the most clinically significant genes, along with the published ACMG CRC technical standard guidelines, this protocol aims to provide a step-by-step technical workflow for carrying out the NGS-panel based CRC molecular diagnosis focusing on the wet lab portion of library preparation and massively parallel sequencing. Using the most popular pull-down-based target enrichment, the chapter particularly encompasses genomic DNA (gDNA) fragmentation, adapter ligation, indexing, hybridization, and capture, which is the most variable and technically challenging part of NGS testing involving at least 3 quality control (QC) checkpoints plus the pre- and post-capture PCR. The gDNA extraction and sequencing is less covered because they are relatively standard technologies with little variations and choices. Although this protocol also introduces pertinent testing algorithms and a brief guideline for pre- and post-testing genetic counselling, the audiences are required to refer to National Comprehensive Cancer Network (NCCN) clinical practice guidelines to determine the most appropriate testing strategies. Since NGS panel-based testing is a highly complex and dynamic platform with multiple choices from different technology and commercial resources, this technical benchtop-based protocol also aims to cover some of the key ramification points for decision-making by each laboratory at the discretion of the directors. © 2023 Wiley Periodicals LLC. Basic Protocol: Hereditary colorectal cancer (CRC) diagnosis by next-generation sequencing.

Abstract B145: Validation of a colorectal cancer risk prediction model in US Black women

Abstract Background: The National Cancer Institute’s Colorectal Cancer Risk Assessment Tool (NCI-CCRAT) estimates an individual's five-year risk of developing colorectal cancer. It was developed by estimating relative risks from a population of US White women and men and incorporating race, gender, and age-specific incidence data from population-based cancer registries. However, the model performance has not been assessed for Black Americans, who have the highest colorectal cancer incidence and mortality rates of any US racial/ethnic group. Methods: The NCI-CCRAT estimates the absolute risk of colorectal cancer based on an individual’s age, sex, family history of colorectal cancer, sigmoidoscopy/colonoscopy, polyps, smoking, physical activity, regular aspirin/nonsteroidal anti-inflammatory drug (NSAID) use, vegetable intake, body mass index, and hormone replacement therapy use. Validation of the NCI-CCRAT was performed using prospective data from 57,558 participants ages 40 to 84 years in the Black Women's Health Study (BWHS). We predicted 5-year absolute risk using data from 2001 through 2015 in three 5-year prediction periods: 2001-2005, 2006-2010, and 2011-2015. To assess model performance, we computed calibration by comparing the expected number of colorectal cancer cases predicted by the model to the observed number of cases (E/O) in the BWHS overall and in subgroups of the population. We assessed discriminatory accuracy by calculating the area under the curve (AUC). Results: During follow-up from 2001 through 2015 (634,512 person-years), 433 BWHS participants developed invasive colorectal cancer. Based on the NCI-CCRAT, 543 cases were expected. The NCI-CCRAT was well-calibrated in the first 5-year prediction period (2001-2005 E/O=1.03, 95% CI: 0.88–1.21), but the model overestimated risk in the subsequent 5-year prediction periods, with E/O=1.30 for 2006-2010 and E/O=1.44 for 2011-2015. The overall E/O ratio was 1.25 (95% confidence interval: 1.14–1.38), indicating that NCI-CCRAT overestimated the number of cases in this population of Black women. Of note, associations with colorectal cancer were weaker in the BWHS than in the development cohort for vigorous physical activity, aspirin/NSAID use, vegetable intake, and body mass index. We estimated discriminatory accuracy only for the first 5-year prediction period (2001-2005, N cases=151) for which the model was well calibrated, and obtained an age-adjusted AUC of 0.61 (95% CI: 0.57–0.66). Conclusions: The NCI-CCRAT overestimated the overall number of colorectal cancer cases by 25% in this prospective cohort of Black women, possibly due to population-specific differences in the relative risks of key factors driving colorectal cancer incidence. Discriminatory accuracy was similar to measures from the original validation cohort of White women and men. Impact: This study suggests that further research is needed to determine the most important predictors of colorectal cancer etiology in Black women and to develop and test a colorectal cancer risk prediction model for Black Americans. Citation Format: Jessica L. Petrick, Nelsy Castro-Webb, Gary R. Zirpoli, Kerrie P. Nelson, Julie R. Palmer, Ruth M. Pfeiffer. Validation of a colorectal cancer risk prediction model in US Black women [abstract]. In: Proceedings of the 16th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2023 Sep 29-Oct 2;Orlando, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2023;32(12 Suppl):Abstract nr B145.

The Possible Preventative Role of Lactate- and Butyrate-Producing Bacteria in Colorectal Carcinogenesis.

: The gut microbiome has emerged as a key player that mechanistically links various risk factors to colorectal cancer (CRC) etiology. However, the role of the gut microbiome in CRC pathogenesis remains unclear. This study aimed to characterize the gut microbiota in healthy controls (HCs) and patients with colorectal adenoma (AD) and CRC in subgroups based on sex and age. : Study participants who visited the hospital for surveillance of CRC or gastrointestinal symptoms were prospectively enrolled, and the gut microbiome was analyzed based on fecal samples. : In terms of HC-AD-CRC sequence, commensal bacteria, including lactate-producing (Streptococcus salivarius) and butyrate-producing (Faecalibacterium prausnitzii, Anaerostipes hadrus, and Eubacterium hallii) bacteria, were more abundant in the HC group than in the AD and CRC groups. In the sex comparison, the female HC group had more lactate-producing bacteria (Bifidobacterium adolescentis, Bifidobacterium catenulatum, and Lactobacillus ruminis) than the male HC group. In age comparison, younger subjects had more butyrate-producing bacteria (Agathobaculum butyriciproducens and Blautia faecis) than the older subjects in the HC group. Interestingly, lactate-producing bacteria (B. catenulatum) were more abundant in females than males among younger HC group subjects. However, these sex- and age-dependent differences were not observed in the AD and CRC groups. : The gut microbiome, specifically lactate- and butyrate-producing bacteria, which were found to be abundant in the HC group, may play a role in preventing the progression of CRC. In particular, lactate-producing bacteria, which were found to be less abundant in healthy male controls may contribute to the higher incidence of CRC in males.

Fecal microbiota transplanted from old mice promotes more colonic inflammation, proliferation, and tumor formation in azoxymethane-treated A/J mice than microbiota originating from young mice

ABSTRACT Aging is a strong risk factor for colorectal cancer (CRC). It is well established that gut microbial dysbiosis can play a role in the etiology of CRC. Although the composition of the gut microbial community changes with age and is reported to become more pro-inflammatory, it is unclear whether such changes are also pro-tumorigenic for the colon. To address this gap, we conducted fecal microbiota transplants (FMT) from young (DY, ~6 wk) and old (DO, ~72 wk) donor mice into young (8 wk) recipient mice that were pre-treated with antibiotics. After initiating tumorigenesis with azoxymethane, recipients were maintained for 19 wk during which time they received monthly FMT boosters. Compared to recipients of young donors (RY), recipients of old donors (RO) had an approximately 3-fold higher prevalence of histologically confirmed colon tumors (15.8 vs 50%, Chi2 P = .03), approximately 2-fold higher proliferating colonocytes as well as significantly elevated colonic IL-6, IL-1β and Tnf-α. Transcriptomics analysis of the colonic mucosa revealed a striking upregulation of mitochondria-related genes in the RO mice, a finding corroborated by increased mitochondrial abundance. Amongst the differences in fecal microbiome observed between DY and DO mice, the genera Ruminoclostridium, Lachnoclostridium and Marvinbryantia were more abundant in DY mice while the genera Bacteroides and Akkermansia were more abundant in DO mice. Amongst recipients, Ruminoclostridium and Lachnoclostridium were higher in RY mice while Bacteroides was higher in RO mice. Differences in fecal microbiota were observed between young and old mice, some of which persisted upon transplant into recipient mice. Recipients of old donors displayed significantly higher colonic proliferation, inflammation and tumor abundance compared to recipients of young donors. These findings support an etiological role for altered gut microbial communities in the increased risk for CRC with increasing age and establishes that such risk can be transmitted between individuals.

Diet-Wide Association, Genetic Susceptibility and Colorectal Cancer Risk: A Prospective Cohort Study.

Both genetic and dietary factors play significant roles in the etiology of colorectal cancer (CRC). To evaluate the relationship between certain food exposures and the risk of CRC, we carried out a large-scale association analysis in the UK Biobank. The associations of 139 foods and nutrients' intake with CRC risk were assessed among 118,210 participants. A polygenic risk score (PRS) of CRC was created to explore any interaction between dietary factors and genetic susceptibility in CRC risk. The hazard ratio (HR) and 95% confidence interval (CI) of CRC risk linked to dietary variables and PRS were estimated using Cox regression models. Multiple comparisons were corrected using the error discovery rate (FDR). During a mean follow-up of 12.8 years, 1466 incidents of CRC were identified. In the UK Biobank, alcohol and white bread were associated with increased CRC risk, and their HRs were 1.08 (95% CI: 1.03-1.14; FDRP = 0.028) and 1.10 (95% CI: 1.05-1.16; FDRP = 0.003), whereas dietary fiber, calcium, magnesium, phosphorus, and manganese intakes were inversely associated. We found no evidence of any PRS-nutrient interaction relationship in relation to CRC risk. Our results show that higher intakes of alcohol and white bread are associated with increased CRC risk, whilst dietary fiber, calcium, magnesium, phosphorus, and manganese are inversely associated.

Heterozygote advantage at HLA class I and II loci and reduced risk of colorectal cancer.

Reduced diversity at Human Leukocyte Antigen (HLA) loci may adversely affect the host's ability to recognize tumor neoantigens and subsequently increase disease burden. We hypothesized that increased heterozygosity at HLA loci is associated with a reduced risk of developing colorectal cancer (CRC). We imputed HLA class I and II four-digit alleles using genotype data from a population-based study of 5,406 cases and 4,635 controls from the Molecular Epidemiology of Colorectal Cancer Study (MECC). Heterozygosity at each HLA locus and the number of heterozygous genotypes at HLA class -I (A, B, and C) and HLA class -II loci (DQB1, DRB1, and DPB1) were quantified. Logistic regression analysis was used to estimate the risk of CRC associated with HLA heterozygosity. Individuals with homozygous genotypes for all loci served as the reference category, and the analyses were adjusted for sex, age, genotyping platform, and ancestry. Further, we investigated associations between HLA diversity and tumor-associated T cell repertoire features, as measured by tumor infiltrating lymphocytes (TILs; N=2,839) and immunosequencing (N=2,357). Individuals with all heterozygous genotypes at all three class I genes had a reduced odds of CRC (OR: 0.74; 95% CI: 0.56-0.97, p= 0.031). A similar association was observed for class II loci, with an OR of 0.75 (95% CI: 0.60-0.95, p= 0.016). For class-I and class-II combined, individuals with all heterozygous genotypes had significantly lower odds of developing CRC (OR: 0.66, 95% CI: 0.49-0.87, p= 0.004) than those with 0 or one heterozygous genotype. HLA class I and/or II diversity was associated with higher T cell receptor (TCR) abundance and lower TCR clonality, but results were not statistically significant. Our findings support a heterozygote advantage for the HLA class-I and -II loci, indicating an important role for HLA genetic variability in the etiology of CRC.

XRCC1 R194W and R399Q Polymorphisms and Colorectal Cancer Risk in a Northeastern Mexican Population.

Colorectal cancer (CRC) is one of the most common cancers worldwide. Its etiopathogenesis is complex, mainly influenced by genetic instability caused by the accumulation of mutations. The XRCC1 gene, which is involved in DNA repair, has been associated with CRC through the R194W (C194T) and R399Q (G399A) polymorphisms, but the results are inconsistent. Here, we analyzed the association of these polymorphisms with sporadic CRC in a northeastern Mexican population, including 155 male CRC patients and 155 male controls. Genotyping was performed using the RFLP method. An association with CRC was found for the 399A allele (G vs A; OR = 1.48 (1.03-2.13), P=0.034) and for the 399AA genotype in a codominant model (AA vs GG; OR = 3.11 (1.06-9.10), P=0.031). In contrast, there were no significant differences between CRC patients and controls for the C194T polymorphism (C vs T; OR = 0.82 (0.52-1.31), P=0.41). These results are consistent with many similar studies, but further research is needed to verify whether the XRCC1 R194W and R399Q polymorphisms play a role in CRC etiology. The functional significance of these polymorphisms is unclear, but some studies suggest that they influence DNA repair capacity and, thus, cancer risk.

Prioritization of risk genes in colorectal cancer by integrative analysis of multi-omics data and gene networks.

Genome-wide association studies (GWASs) have identified over 140 colorectal cancer (CRC)-associated loci; however, target genes at the majority of loci and underlying molecular mechanisms are poorly understood. Here, we utilized a Bayesian approach, integrative risk gene selector (iRIGS), to prioritize risk genes at CRC GWAS loci by integrating multi-omics data. As a result, a total of 105 high-confidence risk genes (HRGs) were identified, which exhibited strong gene dependencies for CRC and enrichment in the biological processes implicated in CRC. Among the 105 HRGs, CEBPB, located at the 20q13.13 locus, acted as a transcription factor playing critical roles in cancer. Our subsequent assays indicated the tumor promoter function of CEBPB that facilitated CRC cell proliferation by regulating multiple oncogenic pathways such as MAPK, PI3K-Akt, and Ras signaling. Next, by integrating a fine-mapping analysis and three independent case-control studies in Chinese populations consisting of 8,039 cases and 12,775 controls, we elucidated that rs1810503, a putative functional variant regulating CEBPB, was associated with CRC risk (OR=0.90, 95%CI=0.86-0.93, P=1.07×10-7). The association between rs1810503 and CRC risk was further validated in three additional multi-ancestry populations consisting of 24,254 cases and 58,741 controls. Mechanistically, the rs1810503 A to T allele change weakened the enhancer activity in an allele-specific manner to decrease CEBPB expression via long-range promoter-enhancer interactions, mediated by the transcription factor, REST, and thus decreased CRC risk. In summary, our study provides a genetic resource and a generalizable strategy for CRC etiology investigation, and highlights the biological implications of CEBPB in CRC tumorigenesis, shedding new light on the etiology of CRC.

Mutational landscape of intestinal crypt cells after long-term in vivo exposure to high fat diet

Obesity is a modifiable risk factor in cancer development, especially for gastrointestinal cancer. While the etiology of colorectal cancer is well characterized by the adenoma-carcinoma sequence, it remains unclear how obesity influences colorectal cancer development. Dietary components of a high fat diet along with obesity have been shown to modulate the cancer risk by perturbing the homeostasis of intestinal stem cells, yet how adiposity impacts the development of genomic instability has not been studied. Mutational signatures are a powerful way to understand how a complex biological response impacts genomic stability. We utilized a mouse model of diet-induced obesity to study the mutational landscape of intestinal crypt cells after a 48-week exposure to an experimental high fat diet in vivo. By clonally enriching single crypt derived cells in organoid culture and obtaining whole genome sequences, we analyzed and compared the mutational landscape of intestinal epithelial cells from normal diet and high fat diet mice. Single nucleotide substitution signatures and indel signatures present in our cohort are found equally active in both diet groups and reflect biological processes of normal aging, cellular replication, and oxidative stress induced during organoid culturing. Thus, we demonstrate that in the absence of activating mutations or chemical exposure, high fat diet alone is not sufficient to increase genomic instability.