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Interrogating the mechanistic link between neighborhood deprivation and colorectal cancer risk through gene expression analysis of normal colorectal biopsies

ABSTRACT: Importance: Neighborhood socioeconomic status has been associated with increased colorectal cancer (CRC) risk, particularly among different racial groups, yet the biological mechanisms underlying this association remain unclear. Objective: To investigate whether neighborhood deprivation, as assessed by Neighborhood Deprivation Index (NDI), is associated with differential gene expression in normal colorectal biopsies; to explore molecular links to CRC risk and to identify potential chemoprevention targets. Design: A cross-sectional study involving transcriptomic analysis of normal colorectal tissues and meta-analysis of gene expression data between African Americans (AA) and European Americans (EA), and an experimental study exposing colon organoids derived from healthy colon biopsies to metformin. Setting: Participants were enrolled in the Cleveland Colon Screening and Risk Factors Study (2012-2018) in metropolitan Cleveland, Ohio. Organoids were derived from colon biopsies of patients undergoing colonoscopy in Charlottesville, Virginia. Participants: Normal colorectal biopsies from AA (n = 34) and EA (n = 23) adults undergoing colonoscopy were analyzed. Colon organoids were derived from AA (n = 4) and EA (n = 6) individuals. RNA-seq data was generated from each participant. Main Outcome(s) and Measures: Differentially expressed genes (DEGs) associated with NDI in normal colorectal biopsies and overlap with DEGs identified in CRC tumor tissues; and association of metformin on NDI-associated, CRC risk gene expression. Results: A total of 237 DEGs were found to be commonly associated with NDI across individual-matched biopsy triplets (right and left colon, and rectum) in both racial groups. Cellular metabolism pathways were amongst the most significantly enriched within identified DEGs. Of the 237 NDI associated DEGs, 82 overlapped with CRC tumor DEGs from a publicly available dataset (TCGA-COADREAD; P=2.21×10⁻⁵; OR=1.83), and nine were prioritized as therapeutic targets, including MYC overexpression (BH=2.48E-12). Metformin exposure in colon organoids also altered the expression of 28 of these genes, with ~79% showing opposite direction, including reduced MYC expression (BH=0.095). Conclusion and Relevance: NDI is associated with CRC-related transcriptional differences. These findings suggest potential molecular mechanisms linking neighborhood deprivation to CRC risk. The observed reversal of gene expression by metformin suggests a potential role for metformin in reducing CRC risk in high NDI-populations, who face greater than average risk of developing CRC.

ORGANISM(S): Homo sapiens

PROVIDER: GSE319878 | GEO | 2026/04/10

REPOSITORIES: GEO

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Project description:Background: An increasing body of evidence has linked fructose intake to colorectal cancer (CRC). African Americans (AAs) consume greater quantities of fructose and are more likely to develop right-side colon cancer than European Americans. Objective: We examined the hypothesis that fructose consumption leads to genomic differences associated with CRC tumor biology. Methods: DNA methylation data from this study was obtained using the Illumina Infinium MethylationEPIC kit (GSE151732). Right and left colon differentially methylated regions (DMRs) were identified using DMRcate through analysis of fructose consumption in normal AA colon biopsies (n=79) undergoing screening colonoscopy. Secondary analysis of CRC tumors was carried out using data derived from TCGA-COAD, GSE101764 and GSE193535. Right colon organoids derived from AA normal colon tissues were exposed to 4.4mM of fructose for 72 hours. Fructose-associated differentially expressed genes (DEGs) were identified using DESeq2. This package was also used to identify DEGs in CRC tumors from TCGA-COAD. Results: We identified 4,263 right colon fructose-associated DMRs (FDR<0.05). In contrast, only 24 DMRs survived multiple testing corrections (FDR<0.05) in matched, left colon. Almost 50% of right colon fructose-associated DMRs overlapped regions implicated in CRC in at least one of three datasets. A highly significant enrichment was also observed between genes corresponding to right colon fructose-associated DMRs and DEGs associated with fructose exposure in AA right colon organoids (P=3.28E-30). Further, overlapping and significant enrichments for a number of fatty acid metabolism, glycolysis and cell proliferation pathways were also found. By further examining the overlap of genes within these pathways that were also differentially expressed in TCGA-COAD, our analysis reveals potential role for PFKP and ANKRD23 in fructose-mediated CRC risk. Conclusions: Our data support that dietary fructose exerts a greater CRC risk-related effect in right than left colon among AAs, alluding to its potential role in contributing to racial disparities in CRC.

Project description:Study 1: Transcriptomic profiles in colon tissue from inflammatory bowel diseases patients in relation to N-nitroso compound exposure and colorectal cancer risk Study 1: N-nitroso compounds (NOC) have been suggested to play a role in human cancer development but definitive evidence is still lacking. In this study we investigated gene expression modifications induced in human colon tissue in relation to NOC exposure to gain insight in the relevance of these compounds in human colorectal cancer (CRC) development. Since there are indications that inflammation stimulates endogenous NOC formation, the study population consisted of patients with inflammatory bowel disease (IBD) and irritable bowel syndrome patients as controls without inflammation. Strong transcriptomic differences were identified in colonic biopsies from IBD patients and compared to controls that enhance the understanding of IBD pathophysiology. However, fecal NOC levels were not increased in IBD patients, suggesting that inflammation did not stimulate NOC formation. By relating gene expression changes of all subjects to fecal NOC levels, we did, however, identify a NOC exposure-associated transcriptomic response that suggests that physiological NOC concentrations may induce genotoxic responses and chromatin modifications in human colon tissue, both of which are linked to carcinogenicity. In a network analysis, chromatin modifications were linked to 11 significantly modulated histone genes, pointing towards a possible epigenetic mechanism that may be relevant in comprehending the molecular basis of NOC-induced carcinogenesis. We conclude that NOC exposure is associated with gene expression modifications in the colon that may increase CRC risk in humans. Study 2: Red meat intake-induced increases in fecal water genotoxicity correlate with pro-carcinogenic gene expression changes in the human colon Study 2: Red meat consumption is associated with an increased colorectal cancer (CRC) risk, which may be due to an increased endogenous formation of genotoxic N-nitroso compounds (NOCs). To assess the impact of red meat intake on potential risk factors of CRC, we investigated the effect of a 7-day dietary red meat intervention in human subjects on endogenous NOC formation and fecal water genotoxicity in relation to transcriptomic changes induced in colonic tissue. In order to evaluate the potential effect of an inflamed colon on endogenous nitrosation, the study population consisted of inflammatory bowel disease (IBD) and irritable bowel syndrome (IBS) control subjects without inflammation. The intervention had no effect on fecal NOC formation but fecal water genotoxicity significantly increased in response to red meat intake. Since IBD patients showed no difference in fecal NOC formation or fecal water genotoxicity levels as compared to IBS controls, for transcriptomic analyses, all subjects were grouped together. Genes significantly correlating with the increase in fecal water genotoxicity were involved in biological pathways indicative of genotoxic effects, including modifications in DNA damage, cell cycle, and apoptosis pathways. Moreover, WNT signaling and nucleosome remodeling pathways were modulated that are known to play a part in the carcinogenic process in the human colon. These results are in line with a possible oxidative effect of dietary heme. We conclude that the gene expression changes identified in this study corroborate the genotoxic potential of diets high in red meat and point towards a possible risk of CRC development in humans. The study investigated transcription levels in human colon biopsies obtained during a colonoscopic exam in 32 subjects suffering from either inflammatory bowel disease (IBD) or irritable bowel syndrome (IBS). IBS patients served as control patients for comparison with IBD patients (see Study 1). 12 of these patients (6 IBD and 6 IBS) also followed a 7-day diet high in red meat (300 grams/day) after which a second colonscopic exam was performed to obtain colon biopsies to investigate the effect of the red meat intervention (Study 2). For each subject, cRNA copies of mRNA isolated from the colon biopsies were labeled with one dye (Cy3) and each sample was hybridized on a separate array. One replicate per subject or before/after red meat intervention (so 44 arrays in total, i.e. 20 before patients and 12 before and after patients).

Project description:Background: Low socioeconomic status (SES) has been linked to chronic stress and poorer health outcomes for marginalized communities in the U.S. The biological processes mediating the impact of SES on health to promote chronic diseases, such as cancer, remain poorly understood. Here, we aim to determine how changes in DNA methylation are linked to neighborhood-level socioeconomic deprivation, thereby promoting cancer initiation and progression through cancer- and immune-related pathways. Methods: We extracted DNA from 402 fresh frozen tissues from 289 women in the NCI-Maryland Breast Cancer Cohort, including 185 tumor samples, 113 additional paired adjacent normal samples, and 104 normal tissues from reduction mammoplasty. Census-tract level socioeconomic deprivation was measured via a Neighborhood Deprivation Index (NDI) using the geocoded addresses from our study participants. DNA methylation values were acquired using the Illumina Infinium MethylationEPIC 850K Beadchip. We conducted a differentially methylated probe (DMP) analysis between tumor and adjacent normal tissue to characterize methylation profiles by NDI status. We also used methylCIBERSORT to estimate immune cell subpopulation differences by tissue type and NDI status. Results: NDI was significantly associated with self-reported race in our cohort in both normal (p<0.0001, 95% CI -4.32, -2.58) and tumor (p<0.0001, 95% CI -4.22, -2.79) tissue. Our DMP analysis showed more significant methylation events (hypo- or hyper- methylation of the tumor tissue compared to adjacent normal tissue) in the NDI high group compared to the NDI low group. We also identified five CpG sites that were significantly hypomethylated in the tumors of the NDI high group, including two tumor suppressor genes, LRIG1 (p=1.99 x10-10) and WWOX (p=6.47 x 10-9). These methylation changes translated to an inverse relationship between gene expression for these tumor suppressor genes and NDI. We also identified significantly lower neutrophils in the NDI high tumors compared to NDI low tumors (p=0.001, 95% CI -0.112, -0.028). Conclusions: Overall, our analysis provides evidence that high neighborhood deprivation can lead to pro-tumorigenic changes in DNA methylation and gene expression that may impact the immune microenvironment, breast cancer progression, and overall survival.

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Interrogating the mechanistic link between neighborhood deprivation and colorectal cancer risk through gene expression analysis of normal colorectal biopsies

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