Increased Risk Of Colon Cancer Research Articles

Obesity Promotes Marrow-Derived Myeloid Cell Accumulation while Exercise Reduces Proliferative Signaling in Colon Cancer.

Obesity increases colon cancer risk that has been previously linked to marrow-derived myeloid cells. We previously demonstrated that exercise training (EX) prevents colon cancer initiation, potentially through reduced myelopoiesis. However, it remains unknown whether early myeloid cell accumulation and inflammation in the colon precedes carcinogenesis with high-fat diet (HFD)-induced obesity, and if EX can attenuate these effects. We hypothesized that obesity would promote colon carcinogenesis that was preceded by myeloid cell accumulation and inflammation that would be attenuated by EX. C57BL/6 mice were randomized to a HFD or control (CON) diet for 8 weeks. The HFD mice switched to CON diet and all mice were given intraperitoneal injections of azoxymethane (AOM) to induce colon cancer and randomized into EX or sedentary (SED) conditions. HFD mice developed more aberrant crypt foci (ACF), a marker for early carcinogenesis, compared to CON (p < 0.01), and EX developed fewer ACF compared to SED (p < 0.0001). Marrow-derived (p < 0.001) CD206+ macrophages were elevated in HFD compared to CON at study week 16 (p < 0.01). Marrow-derived CD206- macrophages (p < 0.05) and marrow-derived (p < 0.05) CD206+ macrophages were more abundant in HFD compared to CON at study week 42. EX did not alter colon immune cell populations. β-Catenin protein was higher in HFD compared to CON at study week 42 (p < 0.05), and STAT3 protein content was lower at study week 28 with EX compared to SED (p < 0.05). The results suggest that obesity promotes colon ACF formation, potentially through early inflammatory myeloid cell accumulation. Despite attenuating ACF, EX did not alter myeloid cell accumulation in the colon, suggesting that EX inhibits ACF formation through alternative mechanisms which may include reduced β-Catenin and STAT3 signaling.

Integrative analysis of causal associations between neurodegenerative diseases and colorectal cancer

BackgroundObservational studies have shown that the correlation between neurodegenerative diseases and colorectal cancer (CRC) remains controversial. Therefore, this study aimed to verify the causal association between these two diseases. MethodsMendelian randomization (MR) analysis was used to assess the causal relationships between five major neurodegenerative diseases and CRC. Multivariable MR (MVMR) analysis was conducted to assess the direct causal effect of neurodegenerative diseases on CRC. Colocalization and pathway enrichment analyses were conducted to further elucidate our results. Sensitivity analysis was conducted to assess the robustness of the results. ResultsGenetically predicted Alzheimer's disease (AD) nominally increased CRC risk (OR = 1.0620, 95%CI = 1.0127–1.1136, P = 0.013). There was no causal effect of genetically predicted CRC on neurodegenerative diseases. Furthermore, we demonstrated that genetically predicted AD marginally increased colon cancer risk (OR = 1.1621, 95%CI = 1.0267–1.3153, P = 0.017). Genetically predicted Lewy body dementia (LBD) had a significant causal effect on the increasing risk of colon cancer (IVW OR = 1.1779, 95%CI = 1.0694–1.2975, P = 0.001). MVMR indicated that effect of AD on colon cancer was driven by LBD, type 2 diabetes, body mass index, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, triglyceride, total cholesterol (TC), processed meat consumption, smoking, alcohol consumption, and educational attainment, whereas the effect of LBD on colon cancer was only influenced by TC. Colocalization and pathway enrichment analysis suggested that LBD and colon cancer possibly shared causal variants (nearby gene APOE), and ERBB4 signaling and lipid metabolism may mediate the causal association between LBD and colon cancer. Sensitivity analysis confirmed the reliability of our findings. ConclusionsOur study demonstrated that genetic vulnerabilities to AD nominally increased the overall risk of CRC and colon cancer. Genetically predicted LBD indicated an elevated risk of colon cancer, potentially linked to ERBB4 signaling and lipid metabolism.

Glycemic Control Impacts the Quality of Bowel Preparation in Patients Undergoing Elective Colonoscopy: A Multicenter Retrospective Cohort Study

Introduction: Diabetes Mellitus has been linked to poor quality of bowel preparation (BP) but the impact of various glycemic control levels remains unclear. The primary objective of this study was to investigate the relationship between the quality of BP and the glycemic control in patients with diabetes. Methods: Data was collected retrospectively to identify adults who underwent elective colonoscopy from March 2020-December 2022. The patient population was subdivided into two groups based on the quality of BP. Univariate and multivariate analyses were used to assess associations between glycemic control, medications, sociodemographic factors, and BP quality. Results: A total of 1458 patients who met the inclusion criteria were included in the final analysis. Of these, 6.3% of patients had suboptimal BP. Non-diabetics, prediabetics, and well-controlled diabetics had lower odds (0.28, 0.20, and 0.32;p&lt;0.001) of having suboptimal BP as compared to poorly controlled diabetics. Insulin users had higher odds (5.39;p&lt;0.01), non-smokers and former smokers had lower odds (0.54, 0.40;p&lt;0.04), and medicare and commercial insurance holders had lower odds (0.49, 0.28;p&lt;0.001) of suboptimal BP. Gender, body mass index, and the use of glucagon-like peptide-1 (GLP-1) agonists were not shown to impact the quality of BP. Conclusions: This study shows that poorly controlled and insulin-dependent diabetics have higher rates of suboptimal QBP, leading to missed lesions and increased colon cancer risk. Limited access to healthcare due to low socioeconomic status indirectly contributes to poorly controlled DM and higher rates of suboptimal QBP. Identifying poor preparation risks allows targeted interventions to enhance QBP in high-risk patients. By prioritizing bowel preparation optimization, we can enhance the overall quality of colonoscopy screening, leading to earlier detection of colorectal malignancies, improved patient outcomes, and a reduction in the burden of colorectal cancer.

The relationship between caffeine consumption and colon cancer prevalence in a nationally representative population.

This study examines the correlation between caffeine consumption and the prevalence of colon cancer. Utilizing data from the National Health and Nutrition Examination Survey (NHANES) for the years 2001 to 2014, we applied weighted logistic regression to evaluate the association between caffeine consumption and the prevalence of colon cancer. This analysis accounted for variables including age, gender, race, education, poverty income ratio, smoking status, alcohol consumption, and diabetes. The findings were expressed as weighted odds ratios (ORs) with accompanying 95% confidence intervals (CIs). The restricted cubic spline analysis was performed to exam the dose-dependent relationship. The study included 27,637 participants, of which 144 were diagnosed with colon cancer and 27,493 served as controls. Individuals in the highest quartile (Q4) of caffeine consumption (Q4) displayed a significantly increased risk of colon cancer compared to those in the lowest quartile (Q1), with a weighted OR of 2.00 (95% CI: 1.11-3.59; p = 0.022). Additionally, restricted cubic spline analysis indicated a significant correlation between higher caffeine intake and increased colon cancer risk, with an overall association p-value of 0.007. These findings suggest a potential relationship between higher levels of caffeine consumption and an increased risk of colon cancer. The dose-response relationship suggests a notable correlation at higher caffeine intake levels. Further investigations are warranted to confirm these results and elucidate potential underlying mechanisms.

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

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

Abstract 3406: Transcriptomic analysis reveals differentially expressed pathways in colon tumors of cancer patients with vs without obesity: Results from the ColoCare Study

Abstract Despite the rise of global obesity rates and obesity’s implication in increased colon cancer risk, the understanding of mechanisms underlying these associations and opportunities for interception are limited. This work leveraged transcriptomic data from colon tumors to identify pathways and biologically relevant functions that characterize the tumors among obese vs nonobese individuals. Fresh-frozen colon tumor samples were collected from 155 patients who underwent surgery without neoadjuvant treatment as part of the ColoCare Study at Huntsman Cancer Institute, Utah, and Heidelberg University Hospital, Germany. RNA was sequenced using the NovaSeq X. The DESeq2 R package identified differentially expressed genes stratified by body mass index (BMI) at diagnosis (&amp;gt;30 kg/m2 vs &amp;lt;30 kg/m2) adjusting for age, sex, study site, and tumor stage. Genes with padj &amp;lt; 0.2 were entered into Ingenuity Pathway Analysis (IPA) software for pathway and expression analyses. Significant pathways were identified using Fischer’s Exact Test as the probability of molecules’ association with canonical pathways due to chance. The analysis was also repeated testing a median BMI categorization of &amp;gt;27.7 kg/m2 vs &amp;lt;27.7 kg/m2 using padj &amp;lt; 0.1 for IPA entry. Patients were 49% female, 63±14 years old, 47% stage III with a mean baseline BMI of 28.8±6.0 kg/m2. In colon tumors of those with &amp;gt;BMI 30 kg/m2, 213 genes were differentially expressed compared to BMI &amp;lt;30 kg/m2. IPA identified five upregulated pathways (neurovascular coupling signaling, adrenergic receptor signaling, activation of N-methyl-D-aspartate receptors and postsynaptic events, response to elevated platelet cytosolic Ca2+, docosahexaenoic acid signaling) and one downregulated pathway (WNT/B-catenin signaling) in patients with vs without obesity (p &amp;lt;0.05). The top predicted functional pathways, based on activation z-scores, identified in expression analysis included significant activation in chromosomal instability and aberration, size of body, phosphorylation of L-tyrosine, protein kinase cascade, and cell death and survival categories among colon tumors in obese patients. Using a median BMI categorization, 458 genes and 35 pathways were differentially expressed in those with BMI &amp;gt; 27.7 kg/m2 vs &amp;lt; 27.7 kg/m2. Both BMI models had good agreement with 5 pathways consistently significantly (z-score &amp;gt; |2|) up- or down-regulated, including predicted downregulation of organismal death and increased body size and phosphorylation of L-tyrosine in the higher BMI group. Colon tumors from patients with a higher BMI had pathways associated with more aggressive tumors, such as increased chromosomal instability and decreased cell death. Our ongoing work investigates the role of the adipose-tissue tumor microenvironment among patients, and the potential for interception using parallel mouse models. Citation Format: Victoria M. Bandera, Tengda Lin, Caroline Himbert, Elaine M. Glenny, Aik Choon Tan, Jennifer Ose, Christy Warby, Olena Aksonova, Alessandro Carpanese, Chris Stubben, David Nix, Kenneth Boucher, Peter Schirmacher, Ildiko Strehli, Jolanta Jedrzkiewicz, Lyen C. Huang, Jessica N. Cohan, Alexander Brobeil, Martin A. Schneider, Christoph Kahlert, Erin M. Siegel, Adetunji T. Toriola, David Shibata, Christopher I. Li, Jane C. Figueiredo, Biljana Gigic, Jatin Roper, Stephen Hursting, Cornelia M. Ulrich. Transcriptomic analysis reveals differentially expressed pathways in colon tumors of cancer patients with vs without obesity: Results from the ColoCare Study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3406.

Dietary Folate and Cofactors Accelerate Age-dependent p16 Epimutation to Promote Intestinal Tumorigenesis.

Our study demonstrates that dietary folate and cofactors modulate tumor-suppressor gene methylation to increase intestinal tumorigenesis. Our findings highlight the need for monitoring the long-term safety of folate fortification in high-risk individuals.

Abstract 644: Gut microbiota-derived metabolites as regulators of immunity in pre-cancer

Abstract Introduction: Tryptophan (Trp) as an essential amino acid that can only be obtained through diet and is a precursor of serotonin and melatonin and required for protein and niacin biosynthesis. In addition, Trp is appreciated for its influence on both host and microbial metabolism. Trp is shunted into the Kyn pathway (mostly) and indolic pathway (bacterial degradation), especially in the immune cells. Both Kyn and Indole/indole derivatives, in part by activating the ligand-dependent transcription factor aryl hydrocarbon receptor (AHR), can become dysfunctional in cancer. Most individuals with cancer such as colon cancer, exhibit increased L-kynurenine levels, which in part is explained by progression of immunosuppressive phenotype and excessive inflammatory signaling molecules. To date, studies in mice and humans have linked Kyn and AHR as potent modulators of host immunity to colon cancer (CRC). Nothing is yet known about their role in pre-cancer, during the development of adenomatous polyps. We hypothesized that increases in plasma Kyn and I3A and their receptor AHR on immune cells would be detected in patients with pre-malignant polyps, suggesting dysbiosis and increased colon cancer risk due to immune modulation. Methods: We measured with mass spectrometry Kyn and I3A in plasma samples of 88 polyp patients and compared to 22 colon cancer patients. We analyzed by flow cytometry PBMCs from 64 newly diagnosed advanced polyp patients (40-70 years old) and 9 age-matched colon cancer patients in order to evaluate AHR expression in different subsets of T cells, NKT cells and NK cells, and their possible association with exhaustion markers Tim-3, LAG-3 and PD-1, as well as Granzyme K, and the presence of immunosuppressive Treg and MDSC. Results: We showed high level of expression of gut microbiota-derived metabolites in plasma of colon pre-cancer compared to cancer patients. We identified CD8+ T effector memory cells (TEM) as primary T cell population expressing their receptor AHR in polyp patients, which had a statistically significant association with Granzyme K expression, which is a hallmark of inflammaging. Conclusions: Our results suggest gut microbiota-derived metabolites as potential mediators of immunosuppression in the setting of premalignancy, which could increase cancer risk and be targets of cancer-preventing strategies. Citation Format: Amir Hossein Mohseni, Sedigheh Taghinezhad-S, Pamela L. Beatty, Olivera J. Finn. Gut microbiota-derived metabolites as regulators of immunity in pre-cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 644.

65 Gene-specific risk of syndrome-associated cancers in first-degree relatives of pancreatic cancer patients with pathogenic/likely pathogenic variants

This abstract is based on unpublished data. OBJECTIVES/GOALS: The estimates of unbiased first-degree relatives (FDRs) risk of cancers would enhance genetic counseling of at-risk FDRs in families where the pancreatic cancer (PC) proband carrying a germline variant. This study aims at quantifying gene-specific risks of six cancers among FDRs of PC patients with germline variants in cancer-associated genes. METHODS/STUDY POPULATION: In the prospective, clinic-based Mayo Clinic Biospecimen Resource for Pancreas Research registry, 4,562 PC patients had previously undergone germline genetic testing for pancreatic cancer-associated genes through either research studies or clinical testing. Of these, 234 PC probands were found to carry germline pathogenic/likely pathogenic variants (PLPV) among 9 genes of interest and had provided detailed demographic and cancer data on their FDRs by questionnaire. We focused on six cancer types (ovary, breast, uterus, pancreas, colon, and malignant melanoma) in FDRs as reported by the probands. Standardized incidence ratios were calculated to estimate risk of six cancers among FDRs of PC patients carrying PLPV by gene. RESULTS/ANTICIPATED RESULTS: 1,670 FDRs (mean age 58.1+17.8SD; 48.9% female) were included in the study. We found significantly increased risk of ovarian cancer in female FDRs of PC probands who carry PLPV in BRCA1 (SIR 9.49, 95%CI:3.06-22.14) or BRCA2 (3.72, 95%CI:1.36-8.11), and breast cancer risks were higher with BRCA2 (2.62, 95%CI:1.89-3.54). Uterine cancer risk was increased in FDRs of PC probands who carry PLPV for Lynch Syndrome mismatch repair (MMR) (6.53, 95%CI:2.81-12.86). PC risk was also increased (ATM 4.53, 95% CI:2.69-7.16; BRCA2 3.45, 95%CI:1.72-6.17; CDKN2A 7.38, 95%CI:3.18-14.54; PALB2 5.39, 95%CI:1.45-13.79). Increased colon cancer risk was observed in FDRs of probands who carried MMR PLPV (5.83, 95%CI:3.70-8.75), while melanoma risk was elevated for FDRs of probands with CDKN2A PLPV (7.47, 95%CI:3.97-12.77). DISCUSSION/SIGNIFICANCE: PLPV in nine syndrome-associated genes in PC probands are associated with increased risk of six cancers in FDRs. The findings underscore the importance of risk estimation of various other cancers in PC families for screening, early detection, intervention, and cascade genetic testing.

Low-Carbohydrate Diet Score and the Risk of Colorectal Cancer: Findings from the Singapore Chinese Health Study.

Colorectal cancer is common cancer with a high mortality rate. Low-carbohydrate diet (LCD) score holistically evaluates the LCD pattern from carbohydrate, protein, and fat intake. Epidemiologic data of LCD-colorectal cancer association are sparse. We evaluated the associations between LCD (i.e., total, animal- and plant-based) and colorectal cancer risk in the Singapore Chinese Health Study, a population-based prospective cohort study including 61,321 Chinese in Singapore who were 45 to 74 years old at baseline. Cox proportional hazard regression model was used to determine the HRs and respective 95% confidence intervals (CI) for colorectal cancer associated with LCD after adjusting for potential confounders, including age, sex, BMI, physical activity, family history of colorectal cancer, etc. After an average of 19.5 years of follow-up, 2,520 participants developed colorectal cancer (1,608 colon cancer and 912 rectal cancer). Overall, the association between total or plant-based LCD scores with the risk of colorectal, colon, or rectal cancer was null (all Ptrend ≥ 0.28). The animal-based LCD was modestly associated with colon cancer risk (Ptrend = 0.02), but not with rectal cancer. Compared with the lowest quartile, HRs (95% CIs) of colon cancer for quartiles 2, 3, and 4 of animal-based LCD were 1.12 (0.98-1.29), 1.27 (1.10-1.46), and 1.14 (0.99-1.31), respectively. A low-level carbohydrate diet with a high level of animal protein and fat was associated with a moderate increase in the risk of colon cancer among Chinese Singaporeans. High consumption of animal protein/fat and low consumption of carbohydrates may increase colon cancer risk.

Long-term exposure to traffic noise and risk of incident colon cancer: A pooled study of eleven Nordic cohorts

BackgroundColon cancer incidence is rising globally, and factors pertaining to urbanization have been proposed involved in this development. Traffic noise may increase colon cancer risk by causing sleep disturbance and stress, thereby inducing known colon cancer risk-factors, e.g. obesity, diabetes, physical inactivity, and alcohol consumption, but few studies have examined this.ObjectivesThe objective of this study was to investigate the association between traffic noise and colon cancer (all, proximal, distal) in a pooled population of 11 Nordic cohorts, totaling 155,203 persons.MethodsWe identified residential address history and estimated road, railway, and aircraft noise, as well as air pollution, for all addresses, using similar exposure models across cohorts. Colon cancer cases were identified through national registries. We analyzed data using Cox Proportional Hazards Models, adjusting main models for harmonized sociodemographic and lifestyle data.ResultsDuring follow-up (median 18.8 years), 2757 colon cancer cases developed. We found a hazard ratio (HR) of 1.05 (95% confidence interval (CI): 0.99–1.10) per 10-dB higher 5-year mean time-weighted road traffic noise. In sub-type analyses, the association seemed confined to distal colon cancer: HR 1.06 (95% CI: 0.98–1.14). Railway and aircraft noise was not associated with colon cancer, albeit there was some indication in sub-type analyses that railway noise may also be associated with distal colon cancer. In interaction-analyses, the association between road traffic noise and colon cancer was strongest among obese persons and those with high NO2-exposure.DiscussionA prominent study strength is the large population with harmonized data across eleven cohorts, and the complete address-history during follow-up. However, each cohort estimated noise independently, and only at the most exposed façade, which may introduce exposure misclassification. Despite this, the results of this pooled study suggest that traffic noise may be a risk factor for colon cancer, especially of distal origin.

Abstract A033: Gene-specific risk of syndrome-associated cancers in first-degree relatives of pancreatic cancer patients with pathogenic/likely pathogenic variants

Abstract Increased pancreatic cancer (PC) risk in first-degree relatives (FDRs) of PC patients with germline pathogenic/likely pathogenic variants (PLPV) is a motivator for cascade genetic testing. To date, unbiased FDR risk estimates for gene-specific risks of genetic cancer syndrome-associated cancers are unknown. These estimates would enhance genetic counseling of at-risk FDRs in families where the PC proband has been found to carry a PLPV. Study Aim: To objectively quantify gene-specific risks of six relevant cancers among FDRs of PC patients with germline PLPV in ATM, BRCA1, BRCA2, CDKN2A, MLH1, MSH2, MSH6, PALB2, and PMS2. Methods: In the prospective, clinic-based Mayo Clinic Biospecimen Resource for Pancreas Research registry, 4,562 PC patients had previously undergone germline genetic testing for pancreatic cancer-associated genes through either research studies or clinical testing. Of these, 234 PC probands were found to carry PLPV among 9 genes of interest and had provided detailed demographic and cancer data on their FDRs by questionnaire. We focused on six cancer types (ovary, breast, uterus, pancreas, colon, and malignant melanoma) in FDRs as reported by the probands. Standardized incidence ratios estimated risk by gene of six cancers among FDRs of PC patients carrying PLPV. Results: 1,670 FDRs (mean age 58.1+17.8SD; 48.9% female) were included in the study. We found significantly increased risk of ovarian cancer in female FDRs of PC probands who carry PLPV in BRCA1 (SIR 9.49, 95%CI:3.06-22.14) or BRCA2 (3.72, 95%CI:1.36-8.11), and breast cancer risks were higher with BRCA2 (2.62, 95%CI:1.89-3.54). Uterine cancer risk was increased in FDRs of PC probands who carry PLPV for Lynch Syndrome mismatch repair (MMR) (6.53, 95%CI:2.81-12.86). PC risk was also increased (ATM 4.53, 95% CI:2.69-7.16; BRCA2 3.45, 95%CI:1.72-6.17; CDKN2A 7.38, 95%CI:3.18-14.54; PALB2 5.39, 95%CI:1.45-13.79). Increased colon cancer risk was observed in FDRs of probands who carried MMR PLPV (5.83, 95%CI:3.70-8.75), while melanoma risk was elevated for FDRs of probands with CDKN2A PLPV (7.47, 95%CI:3.97-12.77). Conclusion: PLPV in nine syndrome-associated genes in PC probands are associated with increased risk of six cancers in FDRs in PC families. The findings underscore the importance of risk estimation of various other cancers in PC families for screening, early detection, and intervention. The gene-specific quantified cancer risks for FDRs of PC patients with syndrome-associated germline PLPV can inform counseling regarding extra-PC risks when considering cascade genetic testing. Citation Format: Xuan Chen, Kari Rabe, Margaret Meyer, Jennnifer Kemppainen, Masayasu Horibe, Shruti Chandra, Shounak Majumder, Gloria Petersen. Gene-specific risk of syndrome-associated cancers in first-degree relatives of pancreatic cancer patients with pathogenic/likely pathogenic variants [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr A033.

Genetic Variation in DEAD-Box Helicase 20 as a Putative Marker of Recurrence in Propensity-Matched Colon Cancer Patients.

Variants of the DEAD-Box Helicase 20 (DDX20), one of the microRNAs (miRNAs) machinery genes, can modulate miRNA/target gene expressions and, hence, influence cancer susceptibility and prognosis. Here, we aimed to unravel the association of DDX20 rs197412 T/C variant with colon cancer risk and/or prognosis in paired samples of 122 colon cancer and non-cancer tissue specimens by TaqMan allelic discrimination analysis. Structural/functional bioinformatic analyses were carried out, followed by a meta-analysis. We found that the T allele was more frequent in cancer tissues compared to control tissues (60.2% vs. 35.7%, p < 0.001). Furthermore, the T variant was highly frequent in primary tumors with evidence of recurrence (73% vs. 47.5%, p < 0.001). Genetic association models, adjusted by age and sex, revealed that the T allele was associated with a higher risk of developing colon cancer under heterozygote (T/C vs. C/C: OR = 2.35, 95%CI = 1.25–4.44, p < 0.001), homozygote (T/T vs. C/C: OR = 7.6, 95%CI = 3.5–16.8, p < 0.001), dominant (T/C-T/T vs. C/C: OR = 3.4, 95%CI = 1.87–8.5, p < 0.001), and recessive (T/T vs. C/C-T/C: OR = 4.42, 95%CI = 2.29–8.54, p = 0.001) models. Kaplan–Meier survival curves showed the shift in the C > T allele to be associated with poor disease-free survival. After adjusting covariates using a multivariate cox regression model, patients harboring C > T somatic mutation were 3.5 times more likely to develop a recurrence (p < 0.001). A meta-analysis of nine studies (including ours) showed a higher risk of CRC (81%) in subjects harboring the T/T genotype than in T/C + C/C genotypes, supporting the potential clinical utility of the specified study variant as a biomarker for risk stratification in CRC cases. However, results were not significant in non-colorectal cancers. In conclusion, the DDX20 rs197412 variant is associated with increased colon cancer risk and a higher likelihood of recurrence in the study population.

Dietary Intakes of Animal and Plant Proteins and Risk of Colorectal Cancer: The EPIC-Italy Cohort.

Simple SummaryAfter breast and prostate cancer, colorectal (CRC) is the third most frequent cancer in men and women. It is unclear if protein-rich diets other than red meat elevate risk or even lower CRC occurrence at specific colon locations. The aim of this study is to assess the associations of animal and plant protein intakes with CRC risk in middle-aged Italian men and women. Our findings show that replacing animal proteins with plant proteins was associated with a lower risk of rectal cancer but not of colon cancer, while replacing animal proteins with plant-based proteins from high-glycemic-index (GI) foods was associated with an increased colon cancer risk. These results have important public health implications as they suggest that both refined high-GI foods and meat might have site-specific roles in the pathogenesis of CRC.We prospectively investigated the associations of protein intake with colorectal cancer (CRC) risk in middle-aged Italian men and women. Food consumption was assessed by validated Epic semiquantitative food-frequency questionnaires. Multivariable Cox models stratified by center, age, and sex, adjusted for confounders, estimated the associations of animal and plant protein consumption with CRC risk by subsite. Among 44,824 men and women, we identified 539 incident CRCs after a median follow-up of 14 years. Replacing animal proteins with plant proteins was associated with a decreased risk of rectal (HR, 0.71; 95% CI, 0.55–0.92) but not colon cancer. By contrast, replacing animal proteins with plant proteins from high-glycemic-index (GI) foods was associated with an increased risk of proximal and distal (including sigma) colon cancer (HR, 1.23; 95% CI, 1.07–1.40) but not when animal proteins were replaced with plant proteins from low-GI foods (HR, 0.93; 95% CI, 0.79–1.11). Further evaluation revealed that the increased colon cancer risk was limited to the substitution of proteins from red and processed meat, as well as dairy and eggs, with vegetable proteins from high-GI foods. Participants in the highest quintile of animal protein intake had higher plasma glucose and cholesterol levels than those in the lowest quintile. By contrast, higher intake of plant proteins from low-GI foods was inversely associated with fasting insulin and HOMA-IR levels. In conclusion, replacing animal proteins with plant proteins from high-GI foods was associated with an increased risk of colon cancer.

An evolutionary explanation for antibiotics' association with increased colon cancer risk.

More than 10 studies have confirmed the association of antibiotic overuse with colorectal cancer. The exact cause is unknown, but most authors hypothesize that disturbance of colon microbiota is the main culprit. In this commentary, an evolutionary explanation is proposed. It is well known that antibiotics can induce antibiotic resistance in bacteria through selection of mutators—DNA mismatch repair deficient (dMMR) strains. Mutators have an increased survival potential due to their high mutagenesis rate. Antibiotics can also cause stress in human cells. Selection of dMMR colon cells may be advantageous under this stress, mimicking selection of bacterial mutators. Concomitantly, mismatch repair deficiency is a common cause of cancer, this may explain the increased cancer risk after multiple cycles of oral antibiotics. This proposed rationale is described in detail, along with supporting evidence from the peer-reviewed literature and suggestions for testing hypothesis validity. Treatment schemes could be re-evaluated, considering toxicity and somatic selection mechanisms.Lay SummaryThe association of antibiotics with colon cancer is well established but of unknown cause. Under an evolutionary framework, antibiotics may select for stress-resistant cancerous cells that lack mechanisms for DNA mismatch repair (MMR). This mimics the selection of antibiotic resistant ‘mutators’—MMR-deficient micro-organisms—highly adaptive due to their increased mutagenesis rate.

Metabolic Dysfunction-Associated Fatty Liver Disease Increases Colon Cancer Risk: A Nationwide Cohort Study.

INTRODUCTION:The association between nonalcoholic fatty liver disease (NAFLD) and colorectal cancer (CRC) has been controversial. Using the new consensus-driven definition, we evaluated the association of metabolic dysfunction–associated fatty liver disease (MAFLD) with the risk of developing CRC.METHODS:From a nationwide health screening database, we included 8,933,017 participants (48.6% male) aged 40–64 years between 2009 and 2010. Participants were categorized by the presence of fatty liver disease (FLD)—NAFLD and MAFLD, separately—and by the combination of the 2 definitions: neither FLD, NAFLD only, MAFLD only, or both FLD. The primary outcome was the development of CRC.RESULTS:Among the participants, 2,517,330 (28.2%) had NAFLD, and 3,337,122 (37.4%) had MAFLD, whereas 2,465,151 (27.6%) met both NAFLD and MAFLD definitions. Over a median follow-up period of 10.1 years, 60,888 new CRC cases developed. NAFLD and MAFLD were each associated with a significantly higher risk of developing CRC. When the neither FLD group was the reference, multivariable-adjusted hazard ratios (95% confidence interval) for CRC were 1.16 (1.06–1.28) in the NAFLD only group, 1.18 (1.16–1.20) in the both FLD group, and 1.32 (1.28–1.35) in the MAFLD only group. The presence of advanced liver fibrosis further increased CRC risk in each FLD group.DISCUSSION:FLD was associated with a higher risk of CRC development. CRC risk was higher in the presence of MAFLD, especially when accompanied by liver fibrosis.

Long-Term Statin Use, Total Cholesterol Level, and Risk of Colorectal Cancer: A Prospective Cohort Study.

Statin use has been examined as a potential chemopreventive strategy against colorectal cancer (CRC). Previous studies have not been able to investigate this topic with adequate follow-up time or disentangle the effects of statin use and total cholesterol level. We investigated prospectively this topic. Eligible participants (100,300 women and 47,991 men) in the Nurses' Health Study and Health Professionals Follow-Up Study were followed for up to 24 years. Cox proportional hazards models were used to estimate hazard ratios and 95% confidence intervals. We documented 2,924 incident CRC cases during follow-up. In fully adjusted analyses, longer duration of statin use was associated with higher risk of colon cancer (hazard ratios, the 95% confidence interval was 1.09, 0.95-1.25 for 1-5 years; 1.16, 0.99-1.36 for 6-10 years; 1.08, 0.81-1.44 for 11-15 years; 1.85, 1.30-2.61 for >15 years; vs never users, P = 0.004 for trend) rather than rectal cancer. The risk elevation was driven by proximal colon cancer (1.16, 0.98-1.38 for 1-5 years; 1.19, 0.98-1.45 for 6-10 years; 1.25, 0.89-1.74 for 11-15 years; 2.17, 1.46-3.24 for >15 years; vs never users, P = 0.001 for trend) rather than distal colon cancer. The results remained robust in analyses among participants with hypercholesterolemia or who never received screening. Total cholesterol level was not associated with CRC risk. This study does not support benefit of statin use in CRC chemoprevention or any association between total cholesterol level and CRC risk. On the contrary, long-term statin use may be associated with increased colon cancer risk (driven by proximal colon cancer).

Insulin-Like Growth Factor 1 (IGF-1) Signaling in Glucose Metabolism in Colorectal Cancer.

Colorectal cancer (CRC) is one of the most common aggressive carcinoma types worldwide, characterized by unfavorable curative effect and poor prognosis. Epidemiological data re-vealed that CRC risk is increased in patients with metabolic syndrome (MetS) and its serum components (e.g., hyperglycemia). High glycemic index diets, which chronically raise post-prandial blood glucose, may at least in part increase colon cancer risk via the insulin/insulin-like growth factor 1 (IGF-1) signaling pathway. However, the underlying mechanisms linking IGF-1 and MetS are still poorly understood. Hyperactivated glucose uptake and aerobic glycolysis (the Warburg effect) are considered as a one of six hallmarks of cancer, including CRC. However, the role of insulin/IGF-1 signaling during the acquisition of the Warburg metabolic phenotypes by CRC cells is still poorly understood. It most likely results from the interaction of multiple processes, directly or indirectly regulated by IGF-1, such as activation of PI3K/Akt/mTORC, and Raf/MAPK signaling pathways, activation of glucose transporters (e.g., GLUT1), activation of key glycolytic enzymes (e.g., LDHA, LDH5, HK II, and PFKFB3), aberrant expression of the oncogenes (e.g., MYC, and KRAS) and/or overexpression of signaling proteins (e.g., HIF-1, TGF-β1, PI3K, ERK, Akt, and mTOR). This review describes the role of IGF-1 in glucose metabolism in physiology and colorectal carcinogenesis, including the role of the insulin/IGF system in the Warburg effect. Furthermore, current therapeutic strategies aimed at repairing impaired glucose metabolism in CRC are indicated.

Carrying asymptomatic gallstones is not associated with changes in intestinal microbiota composition and diversity but cholecystectomy with significant dysbiosis

Gallstone disease affects up to twenty percent of the population in western countries and is a significant contributor to morbidity and health care expenditure. Intestinal microbiota have variously been implicated as either contributing to gallstone formation or to be affected by cholecystectomy. We conducted a large-scale investigation on 404 gallstone carriers, 580 individuals post-cholecystectomy and 984 healthy controls with similar distributions of age, sex, body mass index, smoking habits, and food-frequency-score. All 1968 subjects were recruited from the population-based Study-of-Health-in-Pomerania (SHIP), which includes transabdominal gallbladder ultrasound. Fecal microbiota profiles were determined by 16S rRNA gene sequencing. No significant differences in microbiota composition were detected between gallstone carriers and controls. Individuals post-cholecystectomy exhibited reduced microbiota diversity, a decrease in the potentially beneficial genus Faecalibacterium and an increase in the opportunistic pathogen Escherichia/Shigella. The absence of an association between the gut microbiota and the presence of gallbladder stones suggests that there is no intestinal microbial risk profile increasing the likelihood of gallstone formation. Cholecystectomy, on the other hand, is associated with distinct microbiota changes that have previously been implicated in unfavorable health effects and may not only contribute to gastrointestinal infection but also to the increased colon cancer risk of cholecystectomized patients.

Colon Cancer Risk of a Westernized Diet Is Reduced in Mice by Feeding Cruciferous or Apiaceous Vegetables at a Lower Dose of Carcinogen but Not a Higher Dose.

Western-style diets (WD) are associated with greater risk of colon cancer. Exposure to 2-amino-1-methyl-6-phenylimidazo(4,5-b)pyridine (PhIP), a food-borne carcinogen, is linked to increased colon cancer risk. In contrast, intake of apiaceous and cruciferous vegetables (APIs and CRUs) is associated with reduced risk. Here we evaluated effects of a WD alone or a WD containing API or CRU, relative to a purified diet (basal), on colon cancer risk in mice. All diets were fed at one of two concentrations of PhIP (100 or 400 ppm). The activity of the hepatic PhIP-activating enzyme, cytochrome P450 (CYP) 1A2, was examined at week 4 and colonic precancerous lesions (aberrant crypt foci, ACF) were enumerated at week 12. In low PhIP-fed groups, CYP1A2 activity was greater for CRU than all other groups, which did not differ from one another. WD had a significantly greater effect on the formation of ACF than the basal diet. In groups fed API or CRU, the ACF number was reduced to the level observed in the basal diet-fed group. In high PhIP-fed groups, all WD-based diets had greater CYP1A2 activity than the basal diet-fed group. Surprisingly, the basal diet group had more ACF than the WD group, and API and CRU groups did not differ from the WD alone group. Thus, at the lower dose of PhIP, the WD increased colon cancer risk in mice, compared to a purified diet, and APIs and CRUs reduced the risk of the WD. However, at the higher dose of PhIP, the enhancement of colon cancer risk by the WD was not evident, nor was the chemopreventive effect of these vegetables.