Etiology Of Colorectal Cancer Research Articles

Sex hormones and risk of lung and colorectal cancers in women: a Mendelian randomization study

The roles of sex hormones such as estradiol, testosterone, and sex hormone-binding globulin (SHBG) in the etiology of lung and colorectal cancers in women, among the most common cancers after breast cancer, are unclear. This Mendelian randomization (MR) study evaluated such potential causal associations in women of European ancestry. We used summary statistics data from genome-wide association studies on sex hormones and from the Trøndelag Health Study (HUNT) and large consortia on cancers. There was suggestive evidence of 1-standard deviation increase in total testosterone levels being associated with a lower risk of lung non-adenocarcinoma (hazard ratio 0.60, 95% confidence interval 0.37–0.98) in the HUNT Study. However, this was not confirmed by using data from a larger consortium. In general, we did not find convincing evidence to support a causal role of sex hormones on risk of lung and colorectal cancers in women of European ancestry.

Potential use of SCAT1, SCAT2, and SCAT8 as diagnostic and prognosis markers in colorectal cancer

Colorectal cancer (CRC) is the third most common malignancy and the second leading cause of cancer-related deaths worldwide. Despite advancements, the underlying mechanisms controlling CRC's etiology remain unclear, and reliable biomarkers for diagnosis and treatment are still lacking. Long noncoding RNAs (lncRNAs) are increasingly recognized for their role in cancer progression, though many remain unidentified and their functions poorly understood. In this study, we investigated the expression of SCAT1, SCAT2, and SCAT8 lncRNAs in both cancerous and adjacent non-cancerous tissues from CRC patients. Using cDNA synthesized from total RNA extracted from 100 tissue samples, we performed Real-Time PCR to measure the expression levels of these lncRNAs. In addition, their diagnostic potential was evaluated through ROC curve analysis. Our results demonstrate that SCAT1, SCAT2, and SCAT8 are significantly upregulated in CRC tissues, with ROC analysis suggesting SCAT1 as a moderate biomarker and SCAT2 and SCAT8 as promising biomarkers for CRC diagnosis. Moreover, we found strong correlations between SCAT1 and SCAT8, as well as SCAT2 and SCAT8. Collectively, our findings indicate that SCAT1, SCAT2, and SCAT8 may act as oncogenes in CRC, offering potential as novel biomarkers for diagnosis and prognosis.

Circulating tryptophan–kynurenine pathway metabolites are associated with all‐cause mortality among patients with stage I–III colorectal cancer

AbstractAlterations within the tryptophan–kynurenine metabolic pathway have been linked to the etiology of colorectal cancer (CRC), but the relevance of this pathway for prognostic outcomes in CRC patients needs further elucidation. Therefore, we investigated associations between circulating concentrations of tryptophan–kynurenine pathway metabolites and all‐cause mortality among CRC patients. This study utilizes data from 2102 stage I–III CRC patients participating in six prospective cohorts involved in the international FOCUS Consortium. Preoperative circulating concentrations of tryptophan, kynurenine, kynurenic acid (KA), 3‐hydroxykynurenine (HK), xanthurenic acid (XA), 3‐hydroxyanthranilic acid (HAA), anthranilic acid (AA), picolinic acid (PA), and quinolinic acid (QA) were measured by liquid chromatography–tandem mass spectrometry. Using Cox proportional hazards regression, we examined associations of above‐mentioned metabolites with all‐cause mortality, adjusted for potential confounders. During a median follow‐up of 3.2 years (interquartile range: 2.2–4.9), 290 patients (13.8%) deceased. Higher blood concentrations of tryptophan, XA, and PA were associated with a lower risk of all‐cause mortality (per doubling in concentrations: tryptophan: HR = 0.56; 95%CI:0.41,0.76, XA: HR = 0.74; 95%CI:0.64,0.85, PA: HR = 0.76; 95%CI:0.64,0.92), while higher concentrations of HK and QA were associated with an increased risk of death (per doubling in concentrations: HK: HR = 1.80; 95%CI:1.47,2.21, QA: HR = 1.31; 95%CI:1.05,1.63). A higher kynurenine‐to‐tryptophan ratio, a marker of cell‐mediated immune activation, was associated with an increased risk of death (per doubling: HR = 2.07; 95%CI:1.52,2.83). In conclusion, tryptophan–kynurenine pathway metabolites may be prognostic markers of survival in CRC patients.

Diurnal timing of physical activity and risk of colorectal cancer in the UK Biobank

BackgroundPhysical activity reduces colorectal cancer risk, yet the diurnal timing of physical activity in colorectal cancer etiology remains unclear.MethodsThis study used 24-h accelerometry time series from UK Biobank participants aged 42 to 79 years to derive circadian physical activity patterns using functional principal component analysis. Multivariable Cox proportional hazard models were used to examine associations with colorectal cancer risk.ResultsAmong 86,252 participants (56% women), 529 colorectal cancer cases occurred during a median 5.3-year follow-up. We identified four physical activity patterns that explained almost 100% of the data variability during the day. A pattern of continuous day-long activity was inversely associated with colorectal cancer risk (hazard ratio (HR) = 0.94, 95% confidence interval (CI) = 0.89–0.99). A second pattern of late-day activity was suggestively inversely related to risk (HR = 0.93, 95% CI = 0.85–1.02). A third pattern of early- plus late-day activity was associated with decreased risk (HR = 0.89, 95% CI = 0.80–0.99). A fourth pattern of mid-day plus night-time activity showed no relation (HR = 1.02, 95% CI = 0.88–1.19). Our results were consistent across various sensitivity analyses, including the restriction to never smokers, the exclusion of the first 2 years of follow-up, and the adjustment for shift work.ConclusionsA pattern of early- plus late-day activity is related to reduced colorectal cancer risk, beyond the benefits of overall activity. Further research is needed to confirm the role of activity timing in colorectal cancer prevention.

Role of GSTP1 functional polymorphisms in molecular pathogenesis of colorectal cancer

Glutathione S-transferase P1 (GSTP1) plays a crucial role in the detoxification of harmful substances and cancer-causing agents. Single nucleotide polymorphisms (SNPs) in GSTP1 can affect its ability to catalyze reactions and detoxify, thereby influencing the risk of developing colorectal cancer (CRC). This study aimed to investigate the impact of functional SNPs (fSNPs) in GSTP1 on the risk of CRC, as well as their structural and functional consequences. We analyzed a total of 126 selected GSTP1 SNPs, including fSNPs rs1695 A > G (I105V) and rs1138272 C > T (A114V), in CRC patients (n = 103) and controls (n = 107) of south Indian origin using PCR-sequencing analysis with genomic DNA from blood samples. To assess the structural integrity of GSTP1 fSNPs, we conducted in silico analysis using various tools such as Swiss PDB Viewer, pyMOL mutagenesis wizard, ProSA-Web, and Pdbsum. Additionally, we performed functional characterization of GSTP1 fSNPs using cell and molecular biology techniques. Our findings revealed a significant association between the I105V fSNP and CRC risk, while the A114V fSNP did not show any significance. However, both fSNPs exhibited stronger linkage disequilibrium in patients compared to controls. In silico analysis indicated a loss of structural integrity and reduced electrostatic potential energy in the double mutant GSTP1 (V105/V114) compared to the native (I105/A114) or single mutant (V105/A114 and I105/V114) forms. Furthermore, FHC cells transfected with the GSTP1 I105V variant exhibited increased proliferation, invasion, and colony formation, along with decreased GST activity compared to carriers of the wild-type GSTP1. On the other hand, the GSTP1 A114V variant did not show a significant effect. Interestingly, FHC cells transfected with the double mutant GSTP1 variant (V105/V114) demonstrated synergistic and enhanced effects compared to the GSTP1 I105V variant. Consistent with these findings, plasma GST activity was significantly lower in haplogroups carrying both fSNPs compared to haplogroups with single or no fSNPs. To summarize, our findings indicate that while GSTP1 I105V alone contributes to the etiology of CRC, A114V does not; however, their combined presence has a more significant impact.

CD11b/CD86 involved in the microenvironment of colorectal cancer by promoting Wnt signaling activation.

Colorectal cancer (CRC) is a malignancy that arises within the gastrointestinal tract. Despite ongoing research, the etiology and pathogenesis of CRC remain elusive; particularly, the distribution and characteristics of tumor-associated macrophages is currently an active area of investigation in understanding the pathological progression and prevention of CRC. This study utilized CRC patient surgical samples, mouse models of colitis-associated cancer, colonic organoid, and co-culture cell line to examine the changes in CD11b/CD86 at different pathological region and detect the Wnt signaling pathway activity. Our findings revealed a sensitive and increased expression of CD11b from the early to the advanced CRC tissues and correlated with poor prognosis, while CD86 expression was reduced in advanced CRC tissues. CD133 expression was also elevated in advanced CRC tissues and mainly co-localized with CD11b, suggesting a positive regulatory effect of CD11b and CD133 expression that may contribute to CRC progression. In AOM/DSS mouse models, activation of the Wnt signaling pathway was associated with increased CD133 and CD11b expression. Invitro, THP-1 cell was induced to high expression of CD11b, and the above conditional cultural medium enhanced HCT116 cell colony number and CD133 protein expression. Furthermore, colonic crypts from AOM/DSS mouse models were isolated to culture, and the colonic organoids exhibited dilation and significant increases expression of CD133 and β-Catenin/N-P-B-Catenin. CD11b might be an important factor to participate the progress of CRC. And the high CD11b of CRC microenviroment might potentially promote CD133 expression and associate with Wnt signal activation.

Randomized control trial of moderate dose vitamin D alters microbiota stability and metabolite networks in healthy adults.

Preventative measures to reduce the rise in early-onset colorectal cancer are of critical need. Both vitamin D, dietary and serum levels, and the gut microbiome are implicated in the etiology of colorectal cancer. By understanding the intimate relationship between vitamin D, the gut microbiome, and its metabolites, we may be able to identify key mechanisms that can be targeted for intervention, including inflammation and metabolic dysfunction. Furthermore, the similarity of vitamin D to cholesterol, which is metabolized by the gut microbiome, gives precedence to its ability to produce metabolites that can be further studied and leveraged for controlling colorectal cancer incidence and mortality.

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.

Alternative splicing of BAZ1A in colorectal cancer disrupts the DNA damage response and increases chemosensitization

Bromodomain Adjacent to Zinc Finger Domain 1A (BAZ1A) is a critical regulator of chromatin remodeling. We sought to clarify the roles of BAZ1A in the etiology of colorectal cancer, including the mechanisms of its alternatively spliced variants. Public databases were examined and revealed high BAZ1A expression in the majority of colorectal cancer patients, which was corroborated in a panel of human colon cancer cell lines. BAZ1A silencing reduced cell viability and increased markers of DNA damage, apoptosis, and senescence, along with the downregulation of Wnt/β-catenin signaling. The corresponding molecular changes resulted in tumor growth inhibition when BAZ1A-knockout cells were implanted into nude mice. In rescue experiments, a short isoform of BAZ1A that was associated with alternative splicing by the DBIRD complex failed to restore DNA repair activity in colon cancer cells and maintained chemosensitivity to phleomycin treatment, unlike the full-length BAZ1A. A working model proposes that a buried domain in the N-terminus of the BAZ1A short isoform lacks the ability to access linker DNA, thereby disrupting the activity of the associated chromatin remodeling complexes. Given the current interest in RNA splicing deregulation and cancer etiology, additional mechanistic studies are warranted with new lead compounds targeting BAZ1A, and other members of the BAZ family, with a view to improved therapeutic interventions.

Integrated systematic functional screen and fine-mapping decipher the role and genetic regulation of RPS19 in colorectal cancer development.

Despite genome-wide association studies (GWAS) have identified more than 200 risk loci associated with colorectal cancer (CRC), the causal genes or risk variants within these loci and their biological functions remain not fully revealed. Recently, the genomic locus 19q13.2, with the lead SNP rs1800469 was identified as a crucial CRC risk locus in Asian populations. However, the functional mechanism of this region has not been fully elucidated. Here we employed an RNA interfering-based on-chip approach to screen for the genes essential for cell proliferation in the CRC risk locus 19q13.2. Notably, we found that RPS19 exhibited the most significant effect among the identified genes and acted as a critical oncogene facilitating CRC cell proliferation. Subsequently, combining integrative fine-mapping analysis and a large-scale population study consisting of 6027 cases and 6099 controls, we prioritized rs1025497 as a potential causal candidate for CRC risk, demonstrating that rs1025497[A] allele significantly reduced the risk of CRC (OR 0.70, 95% confidence interval = 0.56-0.83, P = 1.12 × 10-6), which was further validated in UK Biobank cohort comprising 5,313 cases and 21,252 controls. Mechanistically, we experimentally elucidated that variant rs1025497 might acted as an allele-specific silencer, inhibiting the expression level of oncogene RPS19 mediated by the transcription suppressive factor HBP1. Taken together, our sturdy unveils the significant role of RPS19 during CRC pathogenesis and delineates its distal regulatory mechanism mediated by rs1025497, advancing our understanding of the etiology of CRC and provided new insights into the personalized medicine of human cancer.

Dietary risk factors for colorectal cancer in Uganda: a case-control study

IntroductionLow-income countries in East Africa have a lower incidence of colorectal cancer (CRC) than high-income countries; however, the incidence has steadily increased in the last few decades. In Uganda, the extent to which genetic and environmental factors, particularly dietary factors, contribute to the aetiology of CRC is unclear. Therefore, the objective of our study was to determine the relationship between dietary factors and CRC in Uganda.MethodsWe conducted a case-control study and recruited 128 cases and 256 controls, matched for age (± 5 years) and sex. Data regarding the frequency of consumption of the dietary factors were obtained from all the participants using an interview-based questionnaire. The potential dietary risk factors and protective factors evaluated included the type and frequency of meat consumed and the type and frequency of high-fibre foods consumed. The frequency was either 4 or more times/week, 2–3 times/week, once/week or never. Conditional logistic regression analyses were used to determine the odds ratios associated with the different risk and protective factors.ResultsThe median age (IQR) for the case participants was 55.5 (43-67.5) years, and that of the control participants was 54 (42–65) years. The male-to-female ratio was 1:1 for all the participants. Factors significantly associated with CRC cases included:- the consumption of boiled beef 2–3 times/week (aOR:3.24; 95% CI: 1.08–9.69; p < 0.035). Consumption of high-fibre foods, including:- millet for ≥ 4 times/week (aOR: 0.23; 95% CI: 0.09–0.62; p = 0.003)), spinach for ≥ 4 times/week (aOR:0.32; 95% CI: 0.11–0.97; p = 0.043), and potatoes 2–3 times/week (aOR: 0.30; 95% CI: 0.09–0.97; p = 0.044), were protective against CRC. Boiled cassava showed a tendency to reduce the likelihood of CRC when consumed ≥ 4 times/week (aOR:0.38; 95% CI: 0.12–1.18) however this did not reach statistical significance (p = 0.093).ConclusionsThe consumption of boiled beef increases the risk of CRC, while the intake of high-fibre foods may reduce the risk of CRC among Ugandans. We recommend nutritional educational programmes to increase public awareness regarding the protective role of a high-fibre diet and to limit the intake of cooked meat in our Ugandan population.

Management of Cancer in the Digestive System

Cancer is a non-communicable disease characterized by the presence of abnormal cells/tissues that are malignant, grow quickly and uncontrollably and can spread to other places in the patient's body. Cancer cells are malignant and can invade and damage the function of the tissue. Digestive cancer, also called gastrointestinal cancer, attacks the organs of the digestive system. Digestive cancer also includes gastrointestinal cancer, liver cancer, stomach cancer, colorectal cancer, and pancreatic cancer. Risk factors for digestive cancers are varied because many different organs can be affected. Some factors that contribute to cancer throughout the digestive system include age, heavy drinking (alcohol), smoking, and diabetes sufferers. This type of liver cancer is cancer that grows in liver cells. Liver cancer is a type of cancer that ranks second as the cancer that causes the most deaths in the world. Gastric cancer is a group of malignant diseases that have multifactorial causes, namely genetic, lifestyle and environmental factors. The symptoms caused by stomach cancer are initially not as typical as the symptoms of general digestive complaints. The diagnosis of colorectal cancer can be carried out in stages, including through an appropriate history, physical examination, and supporting examinations in the form of laboratory examinations, both from clinical laboratories and anatomical pathology laboratories. The etiology of colorectal cancer is currently still unknown. Symptoms of colorectal cancer are varied and non-specific. The main complaints of patients with colorectal cancer relate to the size and location of the tumor. Tumors in the right colon, where the contents of the colon are fluid, tend to remain hidden until they are very advanced.

ATG16L1 in myeloid cells limits colorectal tumor growth in ApcMin/+ mice infected with colibactin-producing Escherichia coli via decreasing inflammasome activation

ABSTRACT Escherichia coli strains producing the genotoxin colibactin, designated as CoPEC (colibactin-producing E. coli), have emerged as an important player in the etiology of colorectal cancer (CRC). Here, we investigated the role of macroautophagy/autophagy in myeloid cells, an important component of the tumor microenvironment, in the tumorigenesis of a susceptible mouse model infected with CoPEC. For that, a preclinical mouse model of CRC, the Apc Min/+ mice, with Atg16l1 deficiency specifically in myeloid cells (Apc Min/+ /Atg16l1[∆MC]) and the corresponding control mice (Apc Min/+ ), were infected with a clinical CoPEC strain 11G5 or its isogenic mutant 11G5∆clbQ that does not produce colibactin. We showed that myeloid cell-specific Atg16l1 deficiency led to an increase in the volume of colonic tumors in Apc Min/+ mice under infection with 11G5, but not with 11G5∆clbQ. This was accompanied by increased colonocyte proliferation, enhanced inflammasome activation and IL1B/IL-1β secretion, increased neutrophil number and decreased total T cell and cytotoxic CD8+ T cell numbers in the colonic mucosa and tumors. In bone marrow-derived macrophages (BMDMs), compared to uninfected and 11G5∆clbQ-infected conditions, 11G5 infection increased inflammasome activation and IL1B secretion, and this was further enhanced by autophagy deficiency. These data indicate that ATG16L1 in myeloid cells was necessary to inhibit colonic tumor growth in CoPEC-infected Apc Min/+ mice via inhibiting colibactin-induced inflammasome activation and modulating immune cell response in the tumor microenvironment. Abbreviation: AOM, azoxymethane; APC, APC regulator of WNT signaling pathway; ATG, autophagy related; Atg16l1[∆MC] mice, mice deficient for Atg16l1 specifically in myeloid cells; CASP1, caspase 1; BMDM, bone marrow-derived macrophage; CFU, colony-forming unit; CoPEC, colibactin-producing Escherichia coli; CRC, colorectal cancer; CXCL1/KC, C-X-C motif chemokine ligand 1; ELISA, enzyme-linked immunosorbent assay; IL, interleukin; MC, myeloid cell; MOI, multiplicity of infection; PBS, phosphate-buffered saline; pks, polyketide synthase; qRT-PCR, quantitative real-time reverse-transcription polymerase chain reaction; siRNA, small interfering RNA; TME, tumor microenvironment; TNF/TNF-α, tumor necrosis factor.

Microbiome signature, immune landscape and global methylation in early onset colorectal cancer.

3580 Background: The incidence of colorectal cancer (CRC) in young adults (age at diagnosis &lt; 50 years old) has been rapidly increasing. Approximately 20% of early-onset (EO) CRC cases are due to germline gene mutations. However, the etiology of sporadic EO CRC remains poorly understood. Research suggests that environmental factors such as Western diet may be associated with increased incidence of sporadic EO CRC. The gut microbiota decomposes and ferments dietary fibers to produce microbial metabolites, which play important roles in maintaining the intestinal epithelium integrity. A high-fat, low-fiber diet has been associated with intestinal dysbiosis, which disrupts intestinal bacterial homeostasis. An increased inflammation state characterizes dysbiosis and may promote an immunosuppressive tumor microenvironment (TME) and suppress antitumor immune surveillance. In addition, epigenetic modifications are influenced by environmental changes and therefore epigenetics may bridge the knowledge gap in understanding the development of sporadic EOCRC. Methods: We obtained RNA sequencing data from the Cancer Genome Atlas (TCGA) and the Oncology Research Information Exchange Network (ORIEN) from the Ohio State University biospecimen services to characterize intra-tumor microbiota composition, tumor-infiltrating lymphocytes (TILs) and differential pathways in EO CRC. We used Infinium HM450 methylation array in The Cancer Genome Atlas (TCGA) and performed genome-wide analyses using reduced representation bisulfite sequencing (RRBS) method to identify differentially methylated regions (DMRs) in EO CRC. Results: Gene expression analysis is consistent with Fusobacterium promoting inflammation in EO CRC. Intra-tumor microbes are positively correlated with M2 macrophages. Compared to late onset (LO) CRC, EO CRC patients have unique gene signatures of phagosome formation, S100 family signaling pathway and CREB signaling in neurons by using ingenuity pathway analysis (IPA). In addition, we found that methylation ages predicted by epigenetic clocks in EO CRC patients were 15 years older on average than their chronological ages, whereas methylation ages in late onset (LO) CRC patients were comparable with chronological ages. The enriched pathways based on DMRs associated with EO CRC have significant overlap with canonical pathways based on differentially expressed genes (DEGs), including CREB signaling in neurons and S100 family signaling pathways. Conclusions: These data suggest that pathogenic microbes may induce inflammation, which leads to accelerated aging in EO CRC.

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.