Biomarkers Of Colorectal Cancer Risk Research Articles

Polyketide synthase positive Escherichia coli one-time measurement in stool is not informative of colorectal cancer risk in a screening setting.

Environmental factors like the pathogenicity island polyketide synthase positive (pks+) Escherichia coli (E. coli) could have potential for risk stratification in colorectal cancer (CRC) screening. The association between pks+ E. coli measured in fecal immunochemical test (FIT) samples and the detection of advanced neoplasia (AN) at colonoscopy was investigated. Biobanked FIT samples were analyzed for both presence of E. coli and pks+ E. coli and correlated with colonoscopy findings; 5020 CRC screening participants were included. Controls were participants in which no relevant lesion was detected because of FIT-negative results (cut-off ≥15 μg Hb/g feces), a negative colonoscopy, or a colonoscopy during which only a nonadvanced polyp was detected. Cases were participants with AN [CRC, advanced adenoma (AA), or advanced serrated polyp (ASP)]. Existing DNA isolation and quantitative polymerase chain reaction (qPCR) procedures were used for the detection of E. coli and pks+ E. coli in stool. A total of 4542 (90.2%) individuals were E. coli positive, and 1322 (26.2%) were pks+ E. coli positive. The prevalence of E. coli in FIT samples from individuals with AN was 92.9% compared to 89.7% in FIT samples of controls (p = 0.010). The prevalence of pks+ E. coli in FIT samples from individuals with AN (28.6%) and controls (25.9%) was not significantly different (p = 0.13). The prevalences of pks+ E. coli in FIT samples from individuals with CRC, AA, or ASP were 29.6%, 28.3%, and 32.1%, respectively. In conclusion, the prevalence of pks+ E. coli in a screening population was 26.2% and did not differ significantly between individuals with AN and controls. These findings disqualify the straightforward option of using a snapshot measurement of pks+ E. coli in FIT samples as a stratification biomarker for CRC risk. © 2024 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Fibre-rich Foods to Treat Obesity and Prevent Colon Cancer trial study protocol: a randomised clinical trial of fibre-rich legumes targeting the gut microbiome, metabolome and gut transit time of overweight and obese patients with a history of noncancerous adenomatous polyps

IntroductionRecently published studies support the beneficial effects of consuming fibre-rich legumes, such as cooked dry beans, to improve metabolic health and reduce cancer risk. In participants with overweight/obesity and a...

Fecal Microbiota and Associated Volatile Organic Compounds Distinguishing No-Adenoma from High-Risk Colon Adenoma Adults.

Microbiota and the metabolites they produce within the large intestine interact with the host epithelia under the influence of a range of host-derived metabolic, immune, and homeostatic factors. This complex host-microbe interaction affects intestinal tumorigenesis, but established microbial or metabolite profiles predicting colorectal cancer (CRC) risk are missing. Here, we aimed to identify fecal bacteria, volatile organic compounds (VOC), and their associations that distinguish healthy (non-adenoma, NA) from CRC prone (high-risk adenoma, HRA) individuals. Analyzing fecal samples obtained from 117 participants ≥15 days past routine colonoscopy, we highlight the higher abundance of Proteobacteria and Parabacteroides distasonis, and the lower abundance of Lachnospiraceae species, Roseburia faecis, Blautia luti, Fusicatenibacter saccharivorans, Eubacterium rectale, and Phascolarctobacterium faecium in the samples of HRA individuals. Volatolomic analysis of samples from 28 participants revealed a higher concentration of five compounds in the feces of HRA individuals, isobutyric acid, methyl butyrate, methyl propionate, 2-hexanone, and 2-pentanone. We used binomial logistic regression modeling, revealing 68 and 96 fecal bacteria-VOC associations at the family and genus level, respectively, that distinguish NA from HRA endpoints. For example, isobutyric acid associations with Lachnospiraceae incertae sedis and Bacteroides genera exhibit positive and negative regression lines for NA and HRA endpoints, respectively. However, the same chemical associates with Coprococcus and Colinsella genera exhibit the reverse regression line trends. Thus, fecal microbiota and VOC profiles and their associations in NA versus HRA individuals indicate the significance of multiple levels of analysis towards the identification of testable CRC risk biomarkers.

Association between the methylation of CpG islands in JAK-STAT pathway-related genes and colorectal cancer

BackgroundAberrant promoter methylation of CpG islands plays an important role in carcinogenesis. However, the association between the DNA methylation of JAK-STAT pathway-related genes in peripheral blood leukocytes and colorectal cancer (CRC) susceptibility remains unclear. MethodsWe conducted a case-control study of 403 patients with CRC and 419 cancer free controls, and the DNA methylation levels of JAK2, STAT1, STAT3, and SOCS3 in peripheral blood samples from all subjects were assessed using a methylation-sensitive high-resolution melting (MS-HRM) analysis. ResultsCompared with controls, the methylation of the JAK2, STAT1 and SOCS3 genes increased the CRC risk (ORadjusted=1.96, 95% CI, 1.12–3.41, P=0.01; ORadjusted=5.37, 95% CI, 3.74–7.71, P<0.01; ORadjusted=3.30, 95% CI, 1.58–6.87, P<0.01). In the multiple CpG site methylation (MCSM) analysis, a high MCSM value denoted an increased CRC risk (ORadjusted=4.97, 95% CI, 3.34–7.37, P<0.01). ConclusionIn peripheral blood, the methylation of JAK2, STAT1, and high levels of MCSM are promising biomarkers for CRC risk.

Prospective Proteomic Study Identifies Potential Circulating Protein Biomarkers for Colorectal Cancer Risk.

Simple SummaryStudies on circulating protein for colorectal cancer risk in a prospective study design is lacking. The aim of the present study was to scan and identify the protein markers by using proteomics technologies in a two-stage case-control study nested within the Shanghai Women’s Health Study (SWHS), a population-based prospective cohort study. In the discovery set, we found 27 circulating proteins with a nominally significant association. Six of them, including CD79B, DDR1, EFNA4, FLRT2, LTA4H, and NCR1, were validated in the validation phase of the study. This study is the first to evaluate over 1000 circulating proteins in prediagnostic blood samples for their associations with CRC risk in East Asians.Background: Proteomics-based technologies are emerging tools used for cancer biomarker discovery. Limited prospective studies have been conducted to evaluate the role of circulating proteins in colorectal cancer (CRC) development. Methods: A two-stage case-control proteomics study nested in the Shanghai Women’s Health Study was conducted. A total of 1104 circulating proteins were measured in the discovery phase, consisting of 100 incident CRC cases and 100 individually matched controls. An additional 60 case-control pairs were selected for validation. Protein profiling at both stages was completed using the Olink platforms. Conditional logistic regression was used to evaluate the associations between circulating proteins and CRC risk. The elastic net method was employed to develop a protein score for CRC risk. Results: In the discovery set, 27 proteins showed a nominally significant association with CRC risk, among which 22 were positively and 5 were inversely associated. Six of the 27 protein markers were significantly associated with CRC risk in the validation set. In the analysis of pooled discovery and validation sets, odds ratios (ORs) per standard deviation (SD) increase in levels of these proteins were 1.54 (95% confidence interval (CI): 1.15–2.06) for CD79B; 1.71 (95% CI: 1.24–2.34) for DDR1; 2.04 (95% CI: 1.39–3.01) for EFNA4; 1.54 (95% CI: 1.16–2.02) for FLRT2; 2.09 (95% CI: 1.47–2.98) for LTA4H and 1.88 (95% CI: 1.35–2.62) for NCR1. Sensitivity analyses showed consistent associations for all proteins with the exclusion of cases diagnosed within the first two years after the cohort enrollment, except for CD79B. Furthermore, a five-protein score was developed based on the six proteins identified and showed significant associations with CRC risk in both discovery and validation sets (Discovery: OR1-SD = 2.46, 95% CI: 1.53–3.95; validation: OR1-SD = 4.16, 95% CI: 1.92–8.99). Conclusions: A panel of five protein markers was identified as potential biomarkers for CRC risk. Our findings provide novel insights into the etiology of CRC and may facilitate the risk assessment of the malignancy.

Inhibitory immune checkpoints PDCD-1 and LAG-3 hypermethylation may reduce the risk of colorectal cancer

BackgroundChanges in DNA methylation of immunosuppressive checkpoints may impact express and consequently affect antigen processing and presentation by tumor cells and facilitates evasion of immunosurveillance and lead to colorectal cancer (CRC). This study is to investigate the effect of PDCD-1, LAG-3 methylation statuses in peripheral blood leukocytes on CRC risk.MethodsGSE51032 dataset from Gene Expression Omnibus comprised of 166 CRC patients and 424 normal samples was used to identify significantly differentially methylated CpG sites of the two genes. A case–control study with 390 CRC patients and 397 cancer-free controls was carried out to validate the relationship between the methylation levels of the two genes and CRC susceptibility and then estimated their interactions with environmental factors on CRC risk.ResultsIn the GSE51032 dataset, cg06291111 (PDCD-1) and cg10191002 (LAG-3) were screened as the candidate CpG sites for the following study. There were significant associations between hypermethylation of PDCD-1 and LAG-3 and lower risk of CRC (ORadj = 0.322, 95% CI 0.197–0.528; ORadj = 0.666, 95% CI 0.446–0.5996, respectively). Moreover, the results in case–control study showed similar trend, that hypermethylation of PDCD-1 and LAG-3 were associated with lower CRC risk (ORadj = 0.448, 95% CI 0.322–0.622; ORadj = 0.417, 95% CI 0.301–0.578, respectively). A synergistic interaction between LAG-3 hypermethylation and intake of eggs on CRC risk was observed. There were combination effects between hypermethylation of PDCD-1 and LAG-3 and environmental factors on CRC risk.ConclusionsPDCD-1 and LAG-3 may potentially serve as blood-based predictive biomarkers for CRC risk.

Methylation of three genes encoded by X chromosome in blood leukocytes and colorectal cancer risk.

X chromosome change has been proved to be associated with carcinogenesis and related to gender differences in cancer risk. If aberrant methylation of genes encoded by X chromosome involve in the risk and prognosis of cancers, including colorectal cancer (CRC), remain unclear. We conducted a case–control study consisted of 432 CRC cases and 434 controls, detecting the methylation levels of FAM156B, PIH1D3, and PPP1R3F in the X chromosome in blood leukocytes using methylation‐sensitive high‐resolution melting (MS‐HRM). We analyzed the relationship between the methylation levels and CRC susceptibility and then explored the interactions with environmental factors on CRC risk with logistics regression. Moreover, we conducted a follow‐up study containing 225 CRC patients to explore the associations between the methylation of FAM156B, PPP1R3F, and PIH1D3 and CRC prognosis. The hypermethylation of FAM156B, PPP1R3F, and PIH1D3 was related to increased CRC risk (ORPS‐adj = 2.932, 95% confidence interval [CI]: 2.029–4.237; ORPS‐adj = 1.602, 95% CI: 1.078–2.382; ORPS‐adj = 1.628, 95% CI: 1.065–2.490, respectively). In the multiple CpG site methylation (MCSM) analysis, compared with non‐MCSM, a significant relationship between MCSM and increased CRC risk was found (ORPS‐adj = 2.202, 95% CI: 1.512–3.208). We observed synergistic interaction between PPP1R3F hypermethylation and fried food consumption on CRC risk (ORi = 2.682, 95% CI: 1.321–5.446). However, there were no associations between the methylation of FAM156B, PPP1R3F, and PIH1D3 and CRC prognosis (p > 0.05). In conclusion, the methylation of FAM156B, PPP1R3F, and PIH1D3 genes in blood leukocytes is significantly related to CRC risk and may be potential biomarkers for CRC risk but not prognosis.

Pre-Diagnostic Circulating Metabolites and Colorectal Cancer Risk in the Cancer Prevention Study-II Nutrition Cohort.

Untargeted metabolomic studies have identified potential biomarkers of colorectal cancer risk, but evidence is still limited and broadly inconsistent. Among 39,239 Cancer Prevention Study II Nutrition cohort participants who provided a blood sample between 1998–2001, 517 newly diagnosed colorectal cancers were identified through 30 June 2015. In this nested case–control study, controls were matched 1:1 to cases on age, sex, race and date of blood draw. Mass spectroscopy-based metabolomic analyses of pre-diagnostic plasma identified 886 named metabolites, after quality control exclusions. Conditional logistic regression models estimated multivariable-adjusted odds ratios (OR) and 95% confidence intervals (CI) for 1 standard deviation (SD) increase in each metabolite with risk of colorectal cancer. Six metabolites were associated with colorectal cancer risk at a false discovery rate < 0.20. These metabolites were of several classes, including cofactors and vitamins, nucleotides, xenobiotics, lipids and amino acids. Five metabolites (guanidinoacetate, 2’-O-methylcytidine, vanillylmandelate, bilirubin (E,E) and N-palmitoylglycine) were positively associated (OR per 1 SD = 1.29 to 1.32), and one (3-methylxanthine) was inversely associated with CRC risk (OR = 0.79, 95% CI, 0.69–0.89). We did not replicate findings from two earlier prospective studies of 250 cases each after adjusting for multiple comparisons. Large pooled prospective analyses are warranted to confirm or refute these findings and to discover and replicate metabolites associated with colorectal cancer risk.

A two-tiered targeted proteomics approach to identify pre-diagnostic biomarkers of colorectal cancer risk

Colorectal cancer prognosis is dependent on stage, and measures to improve early detection are urgently needed. Using prospectively collected plasma samples from the population-based Northern Sweden Health and Disease Study, we evaluated protein biomarkers in relation to colorectal cancer risk. Applying a two-tiered approach, we analyzed 160 proteins in matched sequential samples from 58 incident colorectal cancer case–control pairs. Twenty-one proteins selected from both this discovery phase and the literature were then analyzed in a validation set of 450 case–control pairs. Odds ratios were estimated by conditional logistic regression. LASSO regression and ROC analysis were used for multi-marker analyses. In the main validation analysis, no proteins retained statistical significance. However, exploratory subgroup analyses showed associations between FGF-21 and colon cancer risk (multivariable OR per 1 SD: 1.23 95% CI 1.03–1.47) as well as between PPY and rectal cancer risk (multivariable OR per 1 SD: 1.47 95% CI 1.12–1.92). Adding protein markers to basic risk predictive models increased performance modestly. Our results highlight the challenge of developing biomarkers that are effective in the asymptomatic, prediagnostic window of opportunity for early detection of colorectal cancer. Distinguishing between cancer subtypes may improve prediction accuracy. However, single biomarkers or small panels may not be sufficient for effective precision screening.

XPF expression and its relationship with the risk and prognosis of colorectal cancer

BackgroundXPF (xeroderma pigmentosum complementation group F) is a key factor contributing to DNA damage excision of nucleotide excision repair pathway. The relationship between XPF expression and the risk and prognosis of colorectal cancer (CRC) is unclear.MethodsIn this experiment, a total of 824 cases of colorectal tissue were collected. XPF protein expression was detected by immunohistochemical staining. We conducted a Mann–Whitney U test in order to explore the differential expression of XPF between CRC and non-cancer controls, and the correlation between XPF expression and CRC clinicopathological parameters. Univariate and multivariate Cox regression analyses were conducted to investigate the relationship between XPF expression and CRC prognosis. The Java based software GSEA as well as STRING, David, GO, KEGG were used to explore the function and regulation network of XPF.ResultsThe results demonstrated that the XPF expression in CRC was significantly up-regulated compared with non-tumor controls (P < 0.001) and adenoma tissue (P < 0.001). XPF protein was increased in the dynamic sequence of anal diseases to adenoma tissue to CRC. Expression of XPF was related to tumor location (P = 0.005) and tumor growth pattern (P = 0.009). The results of prognosis analysis suggested that in patients with stage T1-T2, XPF low expression may be significantly associated with better overall survival (HR = 7.978, 95% CI 1.208–52.673, P = 0.031). XPF and its interacting genes played a vital role in different processes of nucleotide excision repair pathway. XPF expression was related with Ubiquitin like protein specific protease activity.ConclusionsXPF might be a promising biomarker for CRC risk, and also showed potential as a prognostic predictor in CRC patients.

Abstract 2353: A two-tiered targeted proteomics approach to identify biomarkers of colorectal cancer risk

Abstract Colorectal cancer (CRC) mortality is highly dependent on stage at diagnosis, and measures to increase the likelihood of early detection are urgently needed. Many countries have ongoing screening programs, but the addition of blood-based pre-screening biomarkers for risk stratification could reduce costs and increase compliance. In this study, we used prospectively collected plasma samples from the population-based Northern Sweden Health and Disease Study (NSHDS) to evaluate panels of protein biomarkers in relation to CRC risk. Using a two-tiered approach, we first included a unique set of 58 CRC cases and 58 matched controls with time-matched, repeated, prediagnostic samples (10 years apart, with the second sample collected three months to five years before diagnosis). Relative plasma concentrations of 161 proteins were analyzed by multiplex immunoassay (Olink proteomics, inflammation panel and oncology II panel). In the second tier, 15 of these proteins were selected for further analysis, together with six promising early detection protein markers from the literature. The second sample set included prediagnostic samples from 450 CRC cases and 450 matched controls, of which 33 case/control pairs had repeated samples. Conditional logistic regression and linear mixed models were used to estimate odds ratios for CRC risk. In the second-tier analyses, Lasso regression was used to develop multi-marker models, and the resulting protein combinations were tested using ROC analysis. Of the 15 proteins showing promise as predictive biomarkers in the first phase, none retained statistical significance in the second phase. The most promising marker candidate was FGF-21 (multivariable OR: 1.14 95% CI: 0.99-1.30), a metabolic hormone involved in stimulation of glucose uptake that has been associated with body mass index. FGF-21 was also the only protein consistently selected by the Lasso algorithm. Sensitivity analysis for FGF-21 in subgroups based on tumor site, stage and molecular subtypes including BRAF and KRAS mutations did not reach statistical significance. Our findings highlight the challenge of identifying cancer biomarkers that can be used in the prediagnostic window of opportunity for early detection. For early risk stratification, with the vision of achieving effective precision screening, single biomarkers or small marker panels may not be sufficient. Large studies using prospectively collected samples and machine learning to identify biomarker risk patterns may be a more promising approach. Citation Format: Sophia Harlid, Justin Harbs, Robin Myte, Carl Brunius, Marc Gunter, Xijia Liu, Richard Palmqvist, Bethany Van Guelpen. A two-tiered targeted proteomics approach to identify biomarkers of colorectal cancer risk [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2353.

Design and baseline characteristics of the Biomarkers Of Risk In Colorectal Cancer (BORICC) Follow-Up study: A 12+ years follow-up.

Colorectal cancer (CRC) is the third most common cancer worldwide. Age is the strongest non-modifiable risk factor but it is estimated that over half of CRC cases are linked with lifestyle factors such as diet. The Biomarkers Of RIsk of Colorectal Cancer (BORICC) Study recruited 363 participants in 2005 to investigate the effects of lifestyle factors on biomarkers of CRC risk. In the present BORICC Follow-Up (BFU) Study, we are using a longitudinal study design to investigate the effects of ageing (12+ years) and lifestyle factors on biomarkers of CRC risk and on healthy ageing. BFU Study participants attended a study visit at North Tyneside General Hospital (UK) for collection of biological samples, including blood and rectal biopsies, and information collected included anthropometric measurements, a Health & Medications Questionnaire, physical activity and sedentary behaviour, and habitual diet. Furthermore, musculoskeletal function was assessed by heel bone densitometry, timed up and go and hand grip strength as markers of healthy ageing. The BFU Study outcomes will be similar to those measured at baseline in the BORICC Study, such as DNA methylation and mitochondrial function, with additional measurements including the gut microbiome, faecal short-chain fatty acid concentrations and expression of genes associated with CRC. Participants' recruitment to BFU Study and all sample and data collection have been completed. Forty-seven of the original BORICC participants were re-recruited to the BFU Study (mean age 67 years, 51% female). The recruits included 37 initially healthy participants and 10 participants who had adenomatous polyps at baseline. Approximately 70% of participants were over-weight or obese. Ultimately, identifying lifestyle factors that can reduce CRC risk, and understanding the underlying mechanisms for the effects of lifestyle and ageing on CRC risk, could lead to early prevention strategies.

LncRNA-PCAT1 rs2632159 polymorphism could be a biomarker for colorectal cancer susceptibility.

Background: Single-nucleotide polymorphisms (SNPs) in lncRNAs could be biomarkers for susceptibility to colorectal cancer (CRC), but the association of PCAT1 polymorphisms and CRC susceptibility is yet to be studied. Methods: Five tagSNPs covering the PCAT1 gene were detected through Kompetitive Allele-Specific PCR among 436 CRC patients and 510 controls. An expression quantitative trait locus (eQTL) bioinformatic analysis was then performed. Results: In the present study, PCAT1 rs2632159 polymorphism increased CRC risk by 1.37-fold and 2.19-fold in the dominant and recessive models, respectively (P=0.040 and 0.041). When the CRC cases were divided into colon cancer and rectal cancer, we found that this polymorphism affected colon cancer risk under the dominant model (P=0.022, OR = 1.51) and affected rectal cancer susceptibility under the recessive model (P=0.009, OR = 3.03). A more pronounced effect was observed in the male subgroup in that PCAT1 rs2632159 SNP increased rectal cancer risk by 3.97-fold (P=0.017). When PCAT1 rs2632159 was present, epistatic effects were observed with rs1902432 and rs785005 (P=0.011 and 0.008, respectively). eQTL analysis showed that rs2632159 could influence binding with the transcription factors EBF, LUN-1, and TCF12. Conclusion: PCAT1 rs2632159 SNP could be a biomarker for CRC risk. And the rs1902432 SNP might only have potential to be a biomarker for colon cancer risk.

Abstract 2685: Identification of circulating protein biomarkers for colorectal cancer risk: A genetic instrument analysis

Abstract Colorectal cancer (CRC) is one of the most common cancers in United States and many countries in the world. There is an urgent need to better understand its etiology and identify novel biomarkers to facilitate the early detection of CRC. Previous studies either lacked sufficient power to identify novel biomarkers or provided inconsistent results. In the current study, we attempted to uncover novel protein biomarkers for CRC through an integrated analysis of genomics and proteomics data. We first constructed study instruments using genetic variants identified from a large-scale protein quantitative trait loci (pQTL) analysis for over 1,400 circulating proteins. We used beta coefficients and standard errors for these pQTL variants from two large consortia of European-ancestry populations, the Colorectal Transdisciplinary (CORECT) Study (11,895 cases and 14,659 controls) and the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO) (22,974 cases and 14,392 controls) for association analyses for genetically predicted protein levels with CRC risk using an inverse-variance weighted method. The genetically predicted levels of six proteins were associated with CRC risk after accounting for multiple comparisons (Benjamini-Hochberg FDR &amp;lt; 0.05). Among them, genetically predicted levels of VCAM-1, MIP-3b and LPH were inversely associated with CRC risk (VCAM-1: odds ratio [OR] per unit of increase = 0.65, Pmeta = 6.2 ×10-11; MIP-3b: OR = 0.68, Pmeta = 5.5×10-7; LPH: OR = 0.93, Pmeta = 8.0×10-5), while BMP-6, CRDL2 and laminin were positively associated (BMP-6: OR = 1.57, Pmeta = 3.0 ×10-9; CRDL2: OR = 1.36, Pmeta = 3.0 ×10-9; laminin: OR = 1.13, Pmeta = 6.7 ×10-5). Except for VCAM-1 (rs3184504, 12q24.12-SH2B3), other associations are not accounted for by any known CRC susceptibility variants. We observed a possible biological link connecting the genetic variants of LAMC1, LAMC1 expression, and laminin concentrations to CRC risk. Our study identifies potential novel biomarkers for CRC risk and provides novel insight into the disease etiology. Citation Format: Xiang Shu, Xiao-ou Shu, Jirong Long, Qiuyin Cai, Conghui Qu, Stephanie L. Schmit, Chenxu Qu, Sonja I. Berndt, Peter T. Campbell, Andrew T. Chan, Graham G. Giles, Andrea Gsur, Michael Hoffmeister, Mark A. Jenkins, Sanford D. Markowitz, Li Li, Gad Rennert, Kenneth Offit, David Conti, Annika Lindblom, Graham Casey, Stephen B. Gruber, Ulrike Peters, Wei Zheng. Identification of circulating protein biomarkers for colorectal cancer risk: A genetic instrument analysis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2685.

Analysis of MIR155HG variants and colorectal cancer susceptibility in Han Chinese population.

Background MIR155HG plays an important role in malignant tumors, but it is rarely reported in the occurrence and development of colorectal cancer (CRC). This study investigated the effects of MIR155HG polymorphisms on CRC susceptibility from the perspective of molecular genetics.MethodsEight SNPs in MIR155HG were selected and genotyped among 514 CRC cases and 510 healthy controls using the Agena MassARRAY platform. The associations between these SNPs and the CRC risk were evaluated under genetic models using conditional logistic regression analysis. The HaploReg v4.1 database was used for SNPs functional prediction.ResultsThe allele “C” of rs12482371 (p = 0.047), allele “C” of rs1893650 (p = 0.025), and the allele “A” of rs928883 (p = 0.037) in MIR155HG were significantly associated with CRC risk. Genetic model analysis revealed that rs12482371 and rs1893650 increased CRC risk; whereas rs928883 was associated with reduced CRC risk. Stratification analysis showed that rs9383938 was a protective factor in CRC patients under 60 years old. Rs12482371 and rs1893650 were associated with the CRC risk in females. Rs11911469 and rs34904192 may affect the clinical stage and lymph node metastasis. Moreover, the haplotypes CTT and GTC of LD block rs4143370|rs77218221|rs12482371, and the haplotypes CATGA and CACGG of LD block rs77699734|rs11911469|rs1893650|rs34904192|rs928883 were significantly associated with CRC risk.ConclusionThis study revealed that MIR155HG SNPs were associated with CRC susceptibility and could be predictive biomarkers for CRC risk.

Four novel polymorphisms in long non-coding RNA HOTTIP are associated with the risk and prognosis of colorectal cancer.

Background: The role of long non-coding RNA (lncRNA) HOXA transcript at the distal tip (HOTTIP) as an oncogene in varieties of human cancer including colorectal cancer (CRC) has been extensively researched. The expression and function of lncRNAs could be affected by single nucleotide polymorphisms (SNPs), which are associated with cancer susceptibility and prognosis. However, no investigation has focused on the association between HOTTIP SNPs and CRC. The aim of the present study was to explore the association of polymorphisms in the lncRNA HOTTIP gene with CRC risk and prognosis. Methods: A total of 1848 subjects were enrolled in our study, including 884 CRC cases and 964 controls. Genotyping for five HOTTIP tagSNPs (rs3807598, rs17501292, rs2067087, rs17427960, and rs78248039) was performed by applying Kompetitive allele specific PCR (KASP). Results: The results showed three SNPs (rs3807598, rs2067087, and rs17427960) were associated with enhanced CRC risk both in overall and stratified analysis. One polymorphism, rs17501292, could improve the overall survival (OS) of CRC patients in the tumor of ulcerative/invasive-type subgroup. Conclusion: These findings suggest HOTTIP SNPs could potentially be predictive biomarkers for CRC risk and prognosis. The present study provides clues for further exploration of novel lncRNA-based genetic biomarkers to predict CRC susceptibility as well as clinical outcome.

CHST7 Gene Methylation and Sex-Specific Effects on Colorectal Cancer Risk.

X chromosome aberrations are involved in carcinogenesis and are associated with gender differences in cancer development. Abnormal DNA methylation also contributes to cancer. Carbohydrate Sulfotransferase 7 (CHST7), encoded by the X chromosome, is abnormally expressed during tumor development. However, its impact on colorectal cancer (CRC) and the effect of CHST7 methylation on sex-specific CRC risk remain unclear. To investigate the effect of CHST7 methylation in white blood cells on CRC risk and to evaluate its impact on gender-specific differences. CHST7 methylation in white blood cells was determined using methylation-sensitive high-resolution melting. A propensity score analysis was performed to control potential confounders. Furthermore, extensive sensitivity analyses were applied to assess the robustness of our findings. In addition, we validated the initial findings with a GEO dataset (GSE51032). CHST7 hypermethylation in white blood cells was associated with an increased CRC risk [odds ratio (OR)adj = 4.447, 95% confidence interval (CI) 2.662-7.430; p < 0.001]. The association was validated with the GEO dataset (ORadj = 2.802, 95% CI 1.235-6.360; p = 0.014). In particular, CHST7 hypermethylation significantly increased the CRC risk in females (ORadj = 7.704, 95% CI 4.222-14.058; p < 0.001) and younger patients (≤ 60years) (ORadj = 5.755, 95% CI 2.540-13.038; p < 0.001). Subgroup analyses by tumor location and Duke's stage also observed these associations. CHST7 methylation in white blood cells is positively associated with CRC risk, especially in females, and may potentially serve as a blood-based predictive biomarker for CRC risk.

The Impact of Diet-Induced Weight Loss on Biomarkers for Colorectal Cancer: An Exploratory Study (INTERCEPT).

ObjectiveThe aim of this study was to explore the potential effects of diet‐induced weight loss on molecular biomarkers of colorectal cancer risk in serum and colorectal tissue.MethodsThis single‐arm exploratory study included 20 adults with BMI ≥ 30 kg/m2 completing an 8‐week, complete, low‐energy liquid diet. Pre‐ and postintervention anthropometric measurements, fasting blood draws, and endoscopic examinations to procure colorectal biopsies were performed. Fasting insulin, glucose, insulinlike growth factor 1 (IGF‐1), C‐reactive protein (CRP), and blood lipids were measured in serum, and tissue markers of apoptosis (M30), colonocyte proliferation (Ki‐67), and insulin signaling (phospho‐mTOR) were assessed using immunohistochemical staining.ResultsParticipants achieved substantial weight loss (mean = 13.56%). Mean concentrations of insulin, glucose, and cholesterol were significantly reduced (P < 0.05), but IGF‐1 and CRP were not. Colorectal tissue expression of Ki‐67 was significantly reduced (preintervention mean score = 7, postintervention mean score = 3.9, mean % change −43.8; P = 0.027). There were no significant changes in M30 or phospho‐mTOR.ConclusionsWeight loss in individuals with obesity was associated with improvements in insulin sensitivity and blood lipid profiles and a significant reduction in tissue Ki‐67 expression. This is one of the first studies to demonstrate potential cancer‐relevant changes in colorectal tissue following weight loss achieved through diet.

Genome-wide DNA methylation profiling reveals cancer-associated changes within early colonic neoplasia.

Colorectal cancer (CRC) is characterized by genome-wide alterations to DNA methylation that influence gene expression and genomic stability. Less is known about the extent to which methylation is disrupted in the earliest stages of CRC development. In this study we have combined laser-capture microdissection (LCM) with reduced representation bisulfite sequencing (RRBS) to identify cancer-associated DNA methylation changes in human aberrant crypt foci (ACF), the earliest putative precursor to CRC. Using this approach, methylation profiles have been generated for 10 KRAS-mutant ACF and 10 CRCs harboring a KRAS mutation, as well as matched samples of normal mucosa. Of 811 differentially methylated regions (DMRs) identified in ACF, 537 (66%) were hypermethylated and 274 (34%) were hypomethylated. DMRs located within intergenic regions were heavily enriched for AP-1 transcription factor binding sites and were frequently hypomethylated. Furthermore, gene ontology (GO) analysis demonstrated that DMRs associated with promoters were enriched for genes involved in intestinal development, including homeobox genes and targets of the Polycomb repressive complex 2 (PRC2). Consistent with their role in the earliest stages of colonic neoplasia, 75% of the loci harboring methylation changes in ACF were also altered in CRC samples, though the magnitude of change at these sites was lesser in ACF. While aberrant promoter methylation was associated with altered gene expression in CRC, this was not the case in ACF, suggesting the insufficiency of methylation changes to modulate gene expression in early colonic neoplasia. Together, these data demonstrate that DNA methylation changes, including significant hypermethylation, occur more frequently in early colonic neoplasia than previously believed, and identify epigenomic features of ACF that may provide new targets for cancer chemoprevention or lead to the development of new biomarkers for CRC risk.

Higher Order Chromatin Modulator Cohesin SA1 Is an Early Biomarker for Colon Carcinogenesis: Race-Specific Implications.

Alterations in high order chromatin, with concomitant modulation in gene expression, are one of the earliest events in the development of colorectal cancer. Cohesins are a family of proteins that modulate high-order chromatin, although the role in colorectal cancer remains incompletely understood. We, therefore, assessed the role of cohesin SA1 in colorectal cancer biology and as a biomarker focusing in particular on the increased incidence/mortality of colorectal cancer among African-Americans. Immunohistochemistry on tissue arrays revealed dramatically decreased SA1 expression in both adenomas (62%; P = 0.001) and adenocarcinomas (75%; P = 0.0001). RT-PCR performed in endoscopically normal rectal biopsies (n = 78) revealed a profound decrease in SA1 expression in adenoma-harboring patients (field carcinogenesis) compared with those who were neoplasia-free (47%; P = 0.03). From a racial perspective, colorectal cancer tissues from Caucasians had 56% higher SA1 expression than in African-Americans. This was mirrored in field carcinogenesis where healthy Caucasians expressed more SA1 at baseline compared with matched African-American subjects (73%; P = 0.003). However, as a biomarker for colorectal cancer risk, the diagnostic performance as assessed by area under ROC curve was greater in African-Americans (AUROC = 0.724) than in Caucasians (AUROC = 0.585). From a biologic perspective, SA1 modulation of high-order chromatin was demonstrated with both biophotonic (nanocytology) and chromatin accessibility [micrococcal nuclease (MNase)] assays in SA1-knockdown HT29 colorectal cancer cells. The functional consequences were underscored by increased proliferation (WST-1; P = 0.0002, colony formation; P = 0.001) in the SA1-knockdown HT29 cells. These results provide the first evidence indicating a tumor suppressor role of SA1 in early colon carcinogenesis and as a risk stratification biomarker giving potential insights into biologic basis of racial disparities in colorectal cancer. Cancer Prev Res; 9(11); 844-54. ©2016 AACR.