Risk Of Colorectal Cancer Research Articles

Unraveling colorectal cancer prevention: The vitamin D - gut flora - immune system nexus.

Colorectal cancer (CRC) is one of the most common cancers diagnosed in the world. Although environmental and genetic factors play a major role in the pathogenesis of CRC, extensive research has suggested that vitamin D may play a pivotal role in the development of CRC. Vitamin D, primarily obtained through sunlight exposure, dietary sources, and supplements, has long been recognized for its essential functions in maintaining health, including immune regulation. This article delves into the intricate relationship between vitamin D, the immune system, gut flora, and the prevention of CRC. It presents a synthesis of epidemiological data, experimental studies, and clinical trials, highlighting the mechanisms by which vitamin D influences immune cell function, cytokine production, and inflammation. By enhancing the immune system's surveillance and anti-tumor activity, vitamin D may offer a promising avenue for CRC prevention. Furthermore, this comprehensive review delves into the prospective clinical applications of vitamin D supplementation and delineates the forthcoming avenues of research in this dynamic domain. Additionally, the paper tentatively outlines a spectrum of prophylactic impacts of vitamin D on CRC, emphasizing its significant potential in reducing CRC risk through shedding light on its mechanisms, encompassing antineoplastic mechanisms, influences on the immune system, and modulation of the gut microbiome.

Cigarettes and waterpipe use and risk of colorectal cancer in Iran: the IROPICAN study.

We aimed to investigate the association between cigarettes and waterpipe use and colorectal cancer (CRC) in an Iranian population. We analyzed data from a multicenter hospital-based case-control study in Iran (IROPICAN). Data on tobacco smoking, including cigarettes, and waterpipe smoking, were collected in detail. Multivariate logistic regressions estimated the odds ratios (ORs) and 95% confidence intervals (CIs) for the association between cigarette and waterpipe smoking and CRC, accounting for confounders including age, sex, socioeconomic status, opium use, marital status, family history of cancer, red meat, fiber, body shape at age 15 and perceived physical workload, and each other of the two exposures. The study population consisted of 3215 controls and 848 cases, including 455 colon and 393 rectum cancers. We found no association between CRC and cigarette smoking (OR, 0.8; 95% CI, 0.6-1.0) or waterpipe smoking (OR, 1.1; 95% CI, 0.9-1.5). Analysis by categories of cigarette pack-year and frequency of waterpipe smoking (head-year) did not show associations. We observed an inverse association between colon cancer and cigarette smoking (OR, 0.6; 95% CI, 0.5-0.9). There was, however, no significant association by pack-year categories. Cigarette and waterpipe smoking was not associated with CRC in the Iranian population. Further studies are needed to better understand the role of waterpipe on CRC.

Investigating the causal effect of previously reported therapeutic agents for colorectal cancer prevention: protocol for a Mendelian randomization analysis.

Colorectal cancer (CRC) is the third most common cancer worldwide, with 1.9 million new cases in 2020 and a predicted rise to 3.2 million in 2040. Screening programmes are already in place to aid early detection and secondary prevention of CRC, but the rising prevalence means additional approaches are required in both primary and secondary prevention settings. Preventive therapy, whereby natural or synthetic agents are used to prevent, reverse or delay disease development, could be an effective strategy to further reduce cancer risk and potential agents have already been identified in conventional observational studies. However, as such studies are vulnerable to confounding and reverse causation, we aim to evaluate these observed relationships using Mendelian randomization (MR), an alternative causal inference approach which should be less susceptible to these biases. We will use two-sample MR, which uses two independent samples for the exposure and outcome data, to investigate previously reported observational associations of multiple potential preventive agents with CRC risk. We define preventive agents as any synthetic (e.g. approved medication) or natural (e.g. micronutrient, endogenous hormone) molecule used to reduce the risk of cancer. We will first extract potential preventive agents that have been previously linked to CRC risk in observational studies from reviews of the literature. We will then evaluate whether we can develop a genetic instrument for each preventive agent from previously published genome-wide association studies (GWASs) of direct measures of molecular traits (e.g. circulating levels of protein drug targets, blood-based biomarkers of dietary vitamins). The summary statistics from these GWASs, and a large GWAS of CRC, will be used in two-sample MR analyses to investigate the causal effect of putative preventive therapy agents on CRC risk. Sensitivity analyses will be conducted to evaluate the robustness of findings to potential violations of MR assumptions.

Developing an optimal stratification model for colorectal cancer screening and reducing racial disparities in multi-center population-based studies

BackgroundEarly detection of colorectal neoplasms can reduce the colorectal cancer (CRC) burden by timely intervention for high-risk individuals. However, effective risk prediction models are lacking for personalized CRC early screening in East Asian (EAS) population. We aimed to develop, validate, and optimize a comprehensive risk prediction model across all stages of the dynamic adenoma-carcinoma sequence in EAS population.MethodsTo develop precision risk-stratification and intervention strategies, we developed three trans-ancestry PRSs targeting colorectal neoplasms: (1) using 148 previously identified CRC risk loci (PRS148); (2) SNPs selection from large-scale meta-analysis data by clumping and thresholding (PRS183); (3) PRS-CSx, a Bayesian approach for genome-wide risk prediction (PRSGenomewide). Then, the performance of each PRS was assessed and validated in two independent cross-sectional screening sets, including 4600 patients with advanced colorectal neoplasm, 4495 patients with non-advanced adenoma, and 21,199 normal individuals from the ZJCRC (Zhejiang colorectal cancer set; EAS) and PLCO (the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial; European, EUR) studies. The optimal PRS was further incorporated with lifestyle factors to stratify individual risk and ultimately tested in the PLCO and UK Biobank prospective cohorts, totaling 350,013 participants.ResultsThree trans-ancestry PRSs achieved moderately improved predictive performance in EAS compared to EUR populations. Remarkably, the PRSs effectively facilitated a thorough risk assessment across all stages of the dynamic adenoma-carcinoma sequence. Among these models, PRS183 demonstrated the optimal discriminatory ability in both EAS and EUR validation datasets, particularly for individuals at risk of colorectal neoplasms. Using two large-scale and independent prospective cohorts, we further confirmed a significant dose–response effect of PRS183 on incident colorectal neoplasms. Incorporating PRS183 with lifestyle factors into a comprehensive strategy improves risk stratification and discriminatory accuracy compared to using PRS or lifestyle factors separately. This comprehensive risk-stratified model shows potential in addressing missed diagnoses in screening tests (best NPV = 0.93), while moderately reducing unnecessary screening (best PPV = 0.32).ConclusionsOur comprehensive risk-stratified model in population-based CRC screening trials represents a promising advancement in personalized risk assessment, facilitating tailored CRC screening in the EAS population. This approach enhances the transferability of PRSs across ancestries and thereby helps address health disparity.Graphical

Colon Age: A Metric for Whether and How to Screen Male Veterans for Early-Onset Colorectal Cancer.

We aimed to develop a metric for estimating risk for early-onset colorectal cancer (EOCRC) to help decide whether and how to screen persons < age 50. We used risk prediction models derived and validated on male veterans to calculate the RRs for six scenarios: one low-risk scenario (no risk factors present), four intermediate risk scenarios (some risk factors present), and one high-risk scenario (all risk factors present) for three age groups (35-39, 40-44, and 45-49 years). For each scenario, we estimated absolute colorectal cancer risk using Surveillance Epidemiology and End Results colorectal cancer incidence rates and each scenario's RR. We identified the current Surveillance Epidemiology and End Results 5-year age group to which the revised estimate was closest and refer to the midpoint of this group as the "colon age." When the revised estimate equals or exceeds that for 50- to 54-year-olds and for 70- to 74-year-olds, respective recommendations were made for (any) colorectal cancer screening and screening with colonoscopy. Among the scenarios, there was inconsistency between the two models for the 35 to 39 and 40 to 44 age groups, with only the 15-variable model recommending screening for the higher-risk 35- to 39-year-olds. Both models recommended screening for some intermediate risk and high-risk 40- to 44-year-olds. The models were well aligned on whether and how to screen most 45- to 49-year-olds. Using risk factors for EOCRC with colorectal cancer incidence rates, "colon age" may be useful for shared decision-making about whether and how to screen male veterans <50 years. For 45- to 49-year-olds, the 7-variable model may be preferred by patients, providers, and health systems. Prevention Relevance: A new metric known as "colon age" expresses risk of EOCRC based on biological risk and may be useful for providers to explain and for patients to understand colorectal cancer risk when considering whether and how to be screened for colorectal cancer prior to age 45 or 50.

Levels of 5α-reductase gene in intestinal lavage fluid decrease with progression of colorectal cancer.

Introduction. Colorectal cancer (CRC) is a leading cause of cancer deaths, closely linked to the intestinal microbiota and bile acid metabolism. Secondary bile acids, like deoxycholic and lithocholic acid, are associated with increased CRC risk due to their disruption of vital cellular functions. In contrast, isoallolithocholic acid (isoalloLCA) shows potential health benefits, highlighting the complex role of bile acids in CRC. A specific primer set was previously developed to amplify homologs of the 5α-reductase gene (5ar), which are involved in the biosynthesis of isoalloLCA, thereby enabling the estimation of abundance of 5ar (5ar levels) in the intestine.Hypothesis/Gap Statement. We hypothesized that 5ar levels in the intestine are associated with CRC.Aim. This study aimed to investigate intestinal 5ar levels and compare them across different stages of the adenoma-carcinoma sequence, providing insights into novel strategies for monitoring CRC risk.Methodology. DNA was extracted from intestinal lavage fluids (ILF) collected during 144 colonoscopies. Next-generation sequencing (NGS) was employed to examine the sequence of 5ar homologues, using a specific primer set on DNA from seven selected ILFs - four from carcinoma patients and three from individuals with non-neoplastic mucosa. Additionally, we used quantitative PCR (qPCR) to measure 5ar levels in all 144 DNA samples.Results. We conducted 144 colonoscopies and categorized patients according to the adenoma-cancer sequence: 52 with non-neoplastic mucosa, 69 with adenomas and 23 with carcinoma. Analysis of 292,042 NGS-derived 5ar sequences revealed the seven most prevalent amplicon sequence variants, each 254 base pairs in length. These closely matched or were identical to 5ar sequences in Bacteroides uniformis, Phocaeicola vulgatus and Phocaeicola dorei. Furthermore, qPCR analysis demonstrated significantly lower 5ar levels in the carcinoma group compared to those in the non-neoplastic mucosa group (P = 0.0004). A similar, though not statistically significant, trend was observed in the adenoma group (P = 0.0763), suggesting that 5ar levels decrease as CRC progresses.Conclusion. These findings indicate that PCR-based monitoring of 5ar levels in intestinal samples over time could provide a non-invasive, rapid and cost-effective method for assessing an increased risk of CRC.

Development and evaluation of a risk prediction tool for risk-adapted screening of colorectal cancer in China

Risk prediction tools for colorectal cancer (CRC) have potential to improve the efficiency of population-based screening by facilitating risk-adapted strategies. However, such an applicable tool has yet to be established in the Chinese population. In this study, a risk score was created using data from the China Kadoorie Biobank (CKB), a nationwide cohort study of 409,854 eligible participants. Diagnostic performance of the risk score was evaluated in an independent CRC screening programme, which included 91,575 participants who accepted colonoscopy at designed hospitals in Zhejiang Province, China. Over a median follow-up of 11.1 years, 3136 CRC cases were documented in the CKB. A risk score was created based on nine questionnaire-derived variables, showing moderate discrimination for 10-year CRC risk (C-statistic = 0.68, 95 % CI: 0.67–0.69). In the CRC screening programme, the detection rates of CRC were 0.25 %, 0.82 %, and 1.93 % in low-risk (score <6), intermediate-risk (score: 6–19), and high-risk (score >19) groups, respectively. The newly developed score exhibited a C-statistic of 0.65 (95 % CI: 0.63–0.66), surpassing the widely adopted tools such as the Asia-Pacific Colorectal Screening (APCS), modified APCS, and Korean Colorectal Screening scores (all C-statistics = 0.60). In conclusion, we developed a novel risk prediction tool that is useful to identify individuals at high risk of CRC. A user-friendly online calculator was also constructed to encourage broader adoption of the tool.

History of Infertility and Risk of Colorectal Cancer.

There has been limited prior research on the association between infertility and risk of colorectal cancer. Data from postmenopausal women in the Women's Health Initiative were used to estimate the association between self-reported infertility (12 months of trying to get pregnant without achieving a pregnancy) and the risk of colorectal cancer using Cox proportional hazard models. No association was observed between infertility and risk of postmenopausal colorectal cancer [RR, 0.97; 95% confidence interval (CI), 0.87-1.08], invasive colorectal cancer (RR, 0.99; 95% CI, 0.88-1.10), or colorectal cancer mortality (RR, 0.89; 95% CI, 0.71-1.12). Infertility was not found to be associated with colorectal cancer risk among postmenopausal women. Risk did not vary by specific infertility diagnoses. Infertility may not be associated with colorectal cancer risk.

Relationship between menopausal hormone therapy and colorectal cancer: a cohort study utilizing the health insurance database in South Korea (HISK)-II.

Many studies have demonstrated that menopausal hormone therapy is associated with a reduced risk for colorectal cancer. This study investigated the relationship between specific hormone therapy regimens and colorectal cancer risk in postmenopausal women in South Korea using national insurance claims data. This population-based, retrospective cohort study used insurance data provided by the Health Insurance Review and Assessment Service between 2007 and 2020. The hormone therapy group comprised women ≥40 years of age who underwent hormone therapy for the first time between 2011 and 2014. The control group included women ≥40 years of age who visited medical institutions for menopause-related issues during the same period but did not undergo hormone therapy. After 1:1 propensity score matching, 153,736 women were grouped into either the hormone therapy or nonhormone therapy groups. The incidence of colorectal cancer was 46 and 53 per 100,000 person-years in the nonhormone therapy and hormone therapy groups, respectively. Hormone therapy was associated with an increased risk for colorectal cancer (hazard ratio 1.124 [95% confidence interval 1.002-1.261]). Subgroup analysis, according to hormone therapy type, revealed no significant differences in the risk of colorectal cancer for estrogen plus progestogen or estrogen therapy alone; however, tibolone was associated with an increased risk of colorectal cancer compared to nonhormone therapy (hazard ratio, 1.178 [95% confidence interval, 1.021-1.359]). This study found an increased risk of colorectal cancer in women receiving hormone therapy, and tibolone was significantly associated with an increased risk of colorectal cancer. However, the magnitude of the increase was small and unlikely to be of clinical significance.

Genome-wide enhancer RNA profiling adds molecular links between genetic variation and human cancers

BackgroundDysregulation of enhancer transcription occurs in multiple cancers. Enhancer RNAs (eRNAs) are transcribed products from enhancers that play critical roles in transcriptional control. Characterizing the genetic basis of eRNA expression may elucidate the molecular mechanisms underlying cancers.MethodsInitially, a comprehensive analysis of eRNA quantitative trait loci (eRNAQTLs) was performed in The Cancer Genome Atlas (TCGA), and functional features were characterized using multi-omics data. To establish the first eRNAQTL profiles for colorectal cancer (CRC) in China, epigenomic data were used to define active enhancers, which were subsequently integrated with transcription and genotyping data from 154 paired CRC samples. Finally, large-scale case-control studies (34,585 cases and 69,544 controls) were conducted along with multipronged experiments to investigate the potential mechanisms by which candidate eRNAQTLs affect CRC risk.ResultsA total of 300,112 eRNAQTLs were identified across 30 different cancer types, which exert their influence on eRNA transcription by modulating chromatin status, binding affinity to transcription factors and RNA-binding proteins. These eRNAQTLs were found to be significantly enriched in cancer risk loci, explaining a substantial proportion of cancer heritability. Additionally, tumor-specific eRNAQTLs exhibited high responsiveness to the development of cancer. Moreover, the target genes of these eRNAs were associated with dysregulated signaling pathways and immune cell infiltration in cancer, highlighting their potential as therapeutic targets. Furthermore, multiple ethnic population studies have confirmed that an eRNAQTL rs3094296-T variant decreases the risk of CRC in populations from China (OR = 0.91, 95%CI 0.88–0.95, P = 2.92 × 10−7) and Europe (OR = 0.92, 95%CI 0.88–0.95, P = 4.61 × 10−6). Mechanistically, rs3094296 had an allele-specific effect on the transcription of the eRNA ENSR00000155786, which functioned as a transcriptional activator promoting the expression of its target gene SENP7. These two genes synergistically suppressed tumor cell proliferation. Our curated list of variants, genes, and drugs has been made available in CancereRNAQTL (http://canernaqtl.whu.edu.cn/#/) to serve as an informative resource for advancing this field.ConclusionOur findings underscore the significance of eRNAQTLs in transcriptional regulation and disease heritability, pinpointing the potential of eRNA-based therapeutic strategies in cancers.

Integrated multi-omics analyses revealed the association between rheumatoid arthritis and colorectal cancer: MYO9A as a shared gene signature and an immune-related therapeutic target

BackgroundOur study aims to explore the relationship, shared gene signature, and the underlying mechanisms that connect rheumatoid arthritis (RA) to colorectal cancer (CRC).MethodsMendelian randomization (MR) analysis was conducted to assess the causality between RA and CRC. Summary statistic data-based Mendelian randomization (SMR) leveraging eQTL data was employed to identify the CRC-related causal genes. Integrated analyses of single-cell RNA sequencing and bulk RNA sequencing were employed to comprehensively investigate the shared gene signature and potential mechanisms underlying the pathogenesis of both RA and CRC. Predictive analysis of the shared hub gene in CRC immunotherapy response was performed. Pan-cancer analyses were conducted to explore the potential role of MYO9A in 33 types of human tumors.ResultsMR analysis suggested that RA might be associated with a slight increased risk of CRC (Odds Ratio = 1.04, 95% Confidence Interval = 1.01–1.07, P = 0.005). SMR analysis combining transcriptome analyses identified MYO9A as a causal gene in CRC and a shared gene signature in both RA and CRC. MYO9A may contribute to tumor suppression, while downregulation of MYO9A may impact CRC tumorigenesis by disrupting epithelial polarity and architecture, resulting in a worse prognosis in CRC. Additionally, MYO9A shows promise as a powerful predictive biomarker for cancer prognosis and immunotherapy response in CRC. Pan-cancer analyses demonstrated MYO9A may have a protective role in the occurrence and progression of various human cancers.ConclusionRA might be associated with a slight increased risk of CRC. MYO9A is a shared gene signature and a potential immune-related therapeutic target for both CRC and RA. Targeting the MYO9A-mediated loss of polarity and epithelial architecture could be a novel therapeutic approach for CRC.

Investigating the Effects of AL049796.1 Silencing in Inhibiting High Glucose-Induced Colorectal Cancer Progression.

Patients with colorectal cancer (CRC) and diabetes share many risk factors. Despite a strong association between diabetes and CRC being widely studied and confirmed, further genetic research is needed. This study found higher AL049796.1 and TEA domain transcription factor 1 (TEAD1) levels (both mRNA and protein) in CRC tissues of diabetic patients compared with nondiabetics, but no significant difference in miR-200b-3p levels. A positive correlation between AL049796.1 and TEAD1 protein existed regardless of diabetes status, whereas miR-200b-3p was only negatively correlated with TEAD1 protein in nondiabetic CRC tissues. In vitro experiments have shown that high glucose (HG) treatment increased AL049796.1 in CRC cells, and AL049796.1 silencing reduced HG-induced proliferation, migration and invasion, as well as connective tissue growth factor, cysteine-rich angiogenic inducer 61, and epidermal growth factor receptor protein expression. Mechanistic investigations indicated that AL049796.1 could mitigate suppression of miR-200b-3p on TEAD1 posttranscriptionally by acting as a competitive binder. In vivo, subcutaneous CRC tumors in streptozotocin (STZ)-induced mice grew significantly faster; AL049796.1 silencing did not affect the growth of subcutaneous CRC tumors but significantly reduced that of STZ-induced mice. Our study suggests that AL049796.1 independently contributes to the risk of CRC in diabetic patients, highlighting its potential as both a therapeutic target and a novel biomarker for CRC among individuals with diabetes.

Sessile serrated lesion prevalence and factors associated with their detection: a post-hoc analysis of a multinational randomized controlled trial from Asia.

Sessile serrated lesions (SSLs) are associated with an increased risk of colorectal cancer. Data on the prevalence of SSLs in Asia are limited. We performed this study to estimate the prevalence of SSLs in Asia and to explore endoscopic factors that are associated with SSL detection. This is a post-hoc analysis of a multicenter randomized controlled trial from four Asian countries/regions that compared adenoma detection rates using linked-color imaging (LCI) and white-light imaging. Colonoscopies were performed in an average-risk population for screening, diagnostic examination, or polyp surveillance. Patients with SSLs were compared against those without SSLs to evaluate for possible predictors of SSL detection using Firth's logistic regression. 2898 participants (mean age 64.5 years) were included in the analysis. The estimated prevalence of SSLs was 4.0% (95%CI 3.4%-4.8%), with no sex or age group differences. On multivariable analysis, use of LCI (adjusted odds ratio [aOR] 1.63, 95%CI 1.10-2.41), experienced endoscopists (aOR 1.94, 95%CI 1.25-3.00), use of transparent cap (aOR 1.75, 95%CI 1.09-2.81), and longer withdrawal time (aOR 1.06, 95%CI 1.03-1.10) were independently associated with SSL detection. Synchronous adenoma detection (aOR 1.89, 95%CI 1.20-2.99) was also predictive of SSL detection. The prevalence of SSLs in Asia is 4.0%. Use of LCI or a transparent cap, greater endoscopist experience, and longer withdrawal time were all associated with increased SSL detection.

No association between hepatitis C virus infection and risk of colorectal cancer: a systematic review and meta-analysis of cohort studies.

There is still uncertainty regarding whether hepatitis C virus (HCV) infection is associated with colorectal cancer (CRC). This study aims to investigate the potential association between HCV infection and CRC through a systematic review and meta-analysis of cohort studies. PubMed, Embase, and Web of Science were systematically searched from the beginning of their inception to October 2023 to find relevant cohort studies on the association between HCV infection and CRC risk. The random-effect, generic inverse variance method was used to calculate the hazard ratios (HRs) and 95% confidence intervals (CIs) for CRC outcome among individuals with HCV infection. We also performed subgroup and sensitivity analysis. A total of 8 cohort studies involving 1,939,164 participants were included in this meta-analysis. The result from the meta-analysis suggested that there was no statistically significant association between HCV and the risk of developing CRC (HR = 0.99, 95% CI: 0.82-1.88, p = 0.88) with low statistical heterogeneity (I2 = 28%, p = 0.20). Subgroup analyses that were conducted based on study design, diagnosis of HCV infection, and publication year yielded similar results. Analyses of subgroups based on study areas revealed that there was no significant association between HCV infection and CRC risk in Asia (n = 2, HR = 0.96, 95% CI: 0.71-1.29, p = 0.79; I2 = 26%), Europe (n = 3, HR = 1.06, 95% CI: 0.83-1.37, p = 0.63; I2 = 0%), and North America (n = 2, HR = 1.10, 95% CI: 0.87-1.38, p = 0.44; I2 = 0%); however, a negative correlation was found in Oceania (n = 1, HR = 0.43, 95% CI: 0.22-0.84, p = 0.01). Sensitivity analysis further reinforce the stability of our conclusion. Our cohort-based meta-analysis showed insufficient evidence to support the association between HCV infection and an increased risk of CRC. To gain a clearer insight into the potential association between these two conditions, it would be beneficial to conduct large, well-designed, high-quality prospective cohort studies that consider different ethnic populations and potential confounding factors.Systematic review registration: PROSPERO, identifier [CRD42023472688], https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42023472688.

The association between ambient air pollution and colorectal cancer: a Mendelian randomization study

ABSTRACT Mounting epidemiology studies have reported the potential associations between ambient air pollution exposure and colorectal cancer (CRC). However, the genetic association between ambient air pollution and CRC remains unclear. Using the Genome-wide association study (GWAS) data from UK biobank, we explored the genetic association of CRC (5,657 cases and 372,016 controls) with four ambient air pollutants (PM2.5, PM10, NO2, NOx; n = 423,796 to 456,380) under the framework of Mendelian randomization (MR). Our results revealed a significant association between long-term NO2 exposure (per 10 µg/m3) and increased CRC risk, with an odds ratio (OR) of 1.02 (95% confidence interval [CI]: 1.00–1.03), while no statistical association was found between CRC risk and the other air pollutants. Sensitivity analysis confirmed the robustness of the results. It is imperative to consider the impact of air pollution, particularly NO2, in mitigating the risk of CRC.

Impact of hormone replacement therapy on all-cause and cancer-specific mortality in colorectal cancer: A systematic review and dose‒response meta-analysis of observational studies.

The effect of hormone replacement therapy (HRT) on colorectal cancer (CRC) mortality and all-cause mortality remains unclear. We conducted a systematic review and dose-response meta-analysis to determine the effects of HRT on CRC mortality and all-cause mortality. We searched the electronic databases of PubMed, Embase, and The Cochrane Library for all relevant studies published until January 2024 to investigate the effects of HRT exposure on survival rates for patients with CRC. Two reviewers independently extracted individual study data and evaluated the risk of bias between the studies using the Newcastle‒Ottawa Scale. We performed a two-stage random-effects dose-response meta-analysis to examine a possible nonlinear relationship between the year of HRT use and CRC mortality. Ten cohort studies with 480,628 individuals were included. HRT was inversely associated with the risk of CRC mortality (hazard ratios (HR)=0.77, 95% CI (0.68, 0.87), I2=69.5%, p<0.05). The pooled results of seven cohort studies revealed a significant association between HRT and the risk of all-cause mortality (HR=0.71, 95% CI (0.54, 0.92), I2=89.6%, p<0.05). A linear dose-response analysis (p for nonlinearity=0.34) showed a 3% decrease in the risk of CRC for each additional year of HRT use; this decrease was significant (HR=0.97, 95% CI (0.94, 0.99), p<0.05). An additional linear (p for nonlinearity=0.88) dose-response analysis showed a nonsignificant decrease in the risk of all-cause mortality for each additional year of HRT use. This study suggests that the use of HRT is inversely associated with all-cause and colorectal cancer mortality, thus causing a significant decrease in mortality rates over time. More studies are warranted to confirm this association.

Acceptability of stool-based DNA colorectal cancer (CRC) screening among Black/African American patients served by a Federally Qualified Health Center (FQHC).

10530 Background: CRC has an increased burden among Black/African American populations in the United States. Following the COVID-19 pandemic, home-based CRC screening options are being used more frequently. We conducted focus groups to understand the acceptability of stool-based DNA testing for CRC screening in this population. Methods: 10 Focus group sessions were conducted at 2 FQHCs in Milwaukee, WI from 06/22/2023-10/30/2023. Participants were paid $40 for participation. Groups were categorized by gender and age (younger [40-50] vs. older [over 50]). Participants were recruited by fliers and direct text from the FQHC. Eligibility was verified by FQHC staff. Each session was 90 minutes, held at the FQHC, and led by the same facilitator. Participants were given an overview of CRC screening tests and shown a video about stool DNA tests before beginning the focus groups. Thematic analysis was carried out using NVivo. Results: Across 10 groups, there were 79 participants, 32 younger (40.5%) and 47 older (59.5%), with 42 males (53.2%) and 37 (46.8%) females. In the overall study population, there was minimal knowledge of one’s risk for CRC, including the concept of average versus high-risk. Also, there was limited awareness of CRC screening options among younger patients and widespread lack of knowledge about stool-based DNA testing. None of the participants had personal experience with stool-based DNA screening. Most participants were open to the idea of stool-based DNA testing for screening. Examination of DNA was not a pervasive concern in the groups. Most preferred colonoscopy as their first-choice screening test. Reasons for colonoscopy preference included: definitive removal of polyps, direct visualization of the colon, increased confidence level in effectiveness, potential longer periods between screenings, and no need for confirmatory evaluation. Conclusions: Study findings reveal that stool-based DNA testing was acceptable among our study population, however, colonoscopy was identified as the preferred screening modality among this population of Black/African American patients served by an FQHC. Given the low awareness/knowledge of screening modalities identified in our study, educational interventions and shared decision making by primary care providers are needed to promote patient awareness of CRC screening options within the population.

Blood-based colorectal cancer (CRC) screening implementation into clinical practice in the outpatient clinical setting in the Appalachian highlands.

TPS10622 Background: Maximizing colorectal cancer (CRC) screening participation relies on tests that are acceptable, accessible, and patient-centered. While colonoscopy or stool-based tests have traditionally been the standard of care (SOC), they often present challenges related to timely completion and patient adherence. Blood-based tests (BBTs) detecting circulating tumor DNA (ctDNA) offer a quicker, less invasive alternative to previous methods of screening. While the BBTs exhibit comparable sensitivity and specificity to the existing noninvasive SOC, their user-friendly nature holds the potential to enhance adherence. This study aims to explore the implementation of a BBT and its impact on patient acceptability and adherence to CRC screening. The study focuses on the Appalachian population, known for higher CRC incidence1 and mortality rates2 compared to the general US population. Methods: The trial is being conducted at two primary care clinics. It consists of two phases over a 6-month period, aiming to enroll over 300 patients. Participants aged 45-84 years, identified as average risk for CRC according to USPSTF guidelines, and who have opted to be screened for CRC and are willing to participate in the study will be eligible. Exclusion criteria consist of higher-than-average risk for CRC according to the USPSTF standards. During Phase 1 (control period), patients meeting inclusion criteria will be offered SOC (colonoscopy and/or stool-based test) for 3 months followed by Phase 2 (intervention period) where a BBT in addition to SOC will be offered for another 3 months. Informed consent will be obtained prior to any study procedures. The BBT used for the study has a sensitivity of 83% and specificity of 90%. Patients who agree to BBT will undergo a single blood draw of 40 mL. Phase 1 has concluded with enrollment of 75 patients, while Phase 2 is currently ongoing and actively recruiting participants. Upon completion of study, an EMR review will be conducted on participants to evaluate screening rates before and after implementing the BBT and to assess adherence. The primary endpoint of the study involves calculating the total number of consented patients who opted for and completed either BBT or SOC during the interventional period compared to the total number of patients who opted for SOC during the control period. Final data analysis is expected by July 2024.

Genetic Evidence for a Causal Relationship Between Innate Leukocytes and the Risk of Digestive System Cancers in East Asians and Europeans.

Peripheral traditional immune cell disorder plays an important role in cancer onset and development. The causal relationships between leukocytes prior to cancer and the risk of digestive system cancer remain unknown. This study assesses the causal correlations between leukocytes and digestive system cancer risk in East Asians and Europeans. Summary-level data on leukocyte-related genetic variation were extracted from Biobank Japan (107,964 participants) and a recent large-scale meta-analysis (563,946 participants). Summary-level data for the cancers were obtained from Biobank Japan (212,978 individuals) and the FinnGen consortium (178,802 participants). Univariable and multivariable Mendelian randomization (MR) analyses were performed on East Asians and Europeans separately. Univariable MR analysis demonstrated the significant association between circulating eosinophil counts and risk of colorectal cancer (CRC) in East Asians (odds ratio (OR) = 0.80, 95% confidence interval (CI): 0.69 - 0.92, P = 0.002) and a suggestive relationship in the European population (OR = 0.86, 95% CI: 0.77 - 0.97, P = 0.013). An inverse suggestive association was observed between levels of basophils and the risk of gastric cancer (GC) in East Asians (OR = 0.83, 95% CI: 0.72 - 0.97, P = 0.019). The multivariable MR analysis showed the independent causal effect of eosinophil count on CRC risk in East Asians (OR = 0.72, 95% CI: 0.57 - 0.92, P = 0.009) and Europeans (OR = 0.80, 95% CI: 0.70 - 0.92, P = 0.002). Circulating basophils served as the negative causal factor in GC risk in East Asians (OR = 0.80, 95% CI: 0.67 - 0.94, P = 0.007). Our MR analyses revealed a genetic causal relationship between reduced blood eosinophils and an increased CRC risk in both Europeans and East Asians. Furthermore, our results suggested a causal association between decreased basophils and an elevated GC risk specifically in East Asians.

Identification and validation of a novel 17 coagulation-related genes signature for predicting prognostic risk in colorectal cancer

BackgroundPatients with colorectal cancer commonly experience disturbances in coagulation homeostasis. Activation of the coagulation system contributes to cancer-associated thrombosis as the second risk factor for death in cancer patients. This study intended to discover coagulation-related genes and construct a risk model for colorectal cancer patients' prognosis. MethodsCoagulation-related genes were identified by searching coagulation-related pathways in the Molecular Signatures Database. Transcriptomic data and clinical data were downloaded from the Cancer Genome Atlas and Gene Expression Omnibus datasets. Univariate Cox and backward stepwise regression were utilized to identify prognosis-related genes and construct a predictive risk model for the training cohort. Next, survival analysis determines the risk model's predictive power, correlation with clinicopathological characteristics, and nomogram. Additionally, we characterized the variances in immune cell infiltration, somatic mutations, immune checkpoint molecules, biological functions, and drug sensitivity between the high- and low-score patients. ResultEight hundred forty-five genes were obtained by searching the theme term "coagulation" after de-duplication. After univariate regression analysis, 69 genes correlated with prognosis were obtained from the Cancer Genome Atlas dataset. A signature consisting of 17 coagulation-related genes was established through backward stepwise regression. The Kaplan-Meier curve indicated a worse prognosis for high-score patients. Time-dependent receiver operating characteristic curve analysis demonstrated high accuracy in predicting overall survival. Further, the results were validated by two independent datasets (GSE39582 and GSE17536). Combined with clinicopathological characteristics, the risk model was proven to be an independent prognostic factor to predict poor pathological status and worse prognosis. Furthermore, high-score patients had significantly higher stromal cell infiltration. Low-score patients were associated with high infiltration of resting memory CD4+ T cells, activated CD4+ T cells, and T follicular helper cells. The low-score patients exhibited increased expression of immune checkpoint genes, and this might be relevant to their better prognosis. High-score patients exhibited lower IC50 values of Paclitaxel, Rapamycin, Temozolomide, Cyclophosphamide, etc. The differential signaling pathways mainly involve the calcium signaling pathway and the neuroactive ligand-receptor interaction. Lastly, a nomogram was constructed and showed a good prediction. ConclusionThe prognostic signature of 17 coagulation-related genes had significant prognostic value for colorectal cancer patients. We expect to improve treatment modalities and benefit more patients through research on molecular features.