Much of the genetic risk of colorectal cancer is likely to be mediated through susceptibility to adenomas.
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ABSTRACT:
SUBMITTER: Carvajal-Carmona LG
PROVIDER: S-EPMC3572711 | biostudies-literature | 2013 Jan
REPOSITORIES: biostudies-literature
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Much of the genetic risk of colorectal cancer is likely to be mediated through susceptibility to adenomas.
Carvajal-Carmona Luis G LG Zauber Ann G AG Jones Angela M AM Howarth Kimberley K Wang Jiping J Cheng Timothy T Riddell Robert R Lanas Angel A Morton Dion D Bertagnolli Monica M MM Tomlinson Ian I
Gastroenterology 20120919 1
Several single-nucleotide polymorphisms (SNPs) have been associated with colorectal cancer (CRC) susceptibility. Most CRCs arise from adenomas, and SNPs therefore might affect predisposition to CRC by increasing adenoma risk. We found that 8 of 18 known CRC-associated SNPs (rs10936599, rs6983267, rs10795668, rs3802842, rs4444235, rs1957636, rs4939827, and rs961253) were over-represented in CRC-free patients with adenomas, compared with controls. Ten other CRC-associated SNPs (rs6691170, rs668775 ...[more]
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Project description:Our study aimed to evaluate the relevance of genetic susceptibility in the development of colorectal adenomas (CRA) and its relationship with the presence of family history of colorectal cancer (CRC). Genomic DNA from 750 cases (first degree relatives of patients with CRC) and 750 controls (subjects with no family history of CRC) was genotyped for 99 single nucleotide polymorphisms (SNPs) previously associated with CRC/CRA risk by GWAS and candidate gene studies by using the MassArray™ (Sequenom) platform. Cases and controls were matched by gender, age and histological lesion. Eight hundred and fifty-eight patients showed no neoplastic lesions, whereas 288 patients showed low-risk adenomas, and 354 patients presented high-risk adenomas. Two SNPs (rs10505477, rs6983267) in the CASC8 gene were associated with a reduced risk of CRA in controls (log-additive models, OR: 0.67, 95%CI:0.54-0.83, and OR:0.66, 95%CI:0.54-0.84, respectively). Stratified analysis by histological lesion revealed the association of rs10505477 and rs6983267 variants with reduced risk of low- and high-risk adenomas in controls, being this effect stronger in low-risk adenomas (log-additive models, OR:0.63, 95%CI:0.47-0.84 and OR:0.64, 95%CI:0.47-0.86, respectively). Moreover, 2 SNPs (rs10795668, rs11255841) in the noncoding LINC00709 gene were significantly associated with a reduced risk of low-risk adenomas in cases (recessive models, OR:0.22, 95%CI:0.06-0.72, and OR:0.08, 95%CI:0.03-0.61) and controls (dominant models, OR:0.50, 95%CI:0.34-0.75, and OR:0.52, 95%CI:0.35-0.78, respectively). In conclusion, some variants associated with CRC risk (rs10505477, rs6983267, rs10795668 and rs11255841) are also involved in the susceptibility to CRA and specific subtypes. These associations are influenced by the presence of family history of CRC.
| S-EPMC6587859 | biostudies-literature
Project description:Colorectal cancer is the second most common type of cancer both in Europe and Poland. During the last 30 years more than a 3-fold increase has been observed in Poland due to environmental and genetic factors. Almost all colorectal malignancies are related to the formation and malignant transformation of colorectal dysplasia and adenoma. Efforts aiming to decrease the number of colorectal cancer deaths are focused on the disease early detection. Genetic diagnosis for hereditary syndromes predisposing to colorectal cancer has been developed and is a part of the routine treatment. Most cancers are sporadic. They often develop from polyps in the colon. In addition to the genetic events described in the 1990s, showing the adenoma transformation into carcinoma that has been a prime example of malignant transformation for a long time, there are also other possibilities of neoplastic transformation. The recognition of colorectal cancer risk factors make sense as their nature is lifestyle- and diet-related. In this review paper those risk factors are presented and the prevention of colorectal cancer is discussed taking into account genetic factors.
| S-EPMC5814382 | biostudies-literature
Project description:BackgroundIncreasing evidence suggests that conventional adenomas (CAs) and serrated polyps (SPs) represent two distinct groups of precursor lesions for colorectal cancer (CRC). The influence of common genetic variants on risk of CAs and SPs remain largely unknown.MethodsAmong 27 426 participants within three prospective cohort studies, we created a weighted genetic risk score (GRS) based on 40 CRC-related single nucleotide polymorphisms (SNPs) identified in previous genome-wide association studies; and we examined the association of GRS (per one standard deviation increment) with risk of CAs, SPs and synchronous CAs and SPs, by multivariable logistic regression. We also analysed individual variants in the secondary analysis.ResultsDuring 18-20 years of follow-up, we documented 2952 CAs, 1585 SPs and 794 synchronous CAs and SPs. Higher GRS was associated with increased risk of CAs [odds ratio (OR) = 1.17, 95% confidence interval (CI): 1.12-1.21] and SPs (OR = 1.09, 95% CI: 1.03-1.14), with a stronger association for CAs than SPs (Pheterogeneity=0.01). An even stronger association was found for patients with synchronous CAs and SPs (OR = 1.32), advanced CAs (OR = 1.22) and multiple CAs (OR = 1.25). Different sets of variants were associated with CAs and SPs, with a Spearman correlation coefficient of 0.02 between the ORs associating the 40 SNPs with the two lesions. After correcting for multiple testing, three variants were associated with CAs (rs3802842, rs6983267 and rs7136702) and two with SPs (rs16892766 and rs4779584).ConclusionsCommon genetic variants play a potential role in the conventional and serrated pathways of CRC. Different sets of variants are identified for the two pathways, further supporting the aetiological heterogeneity of CRC.
| S-EPMC7426026 | biostudies-literature
Project description:IntroductionEpidemiological studies estimate that having a first-degree relative (FDR) with colorectal cancer (CRC) increases 2-fold to 3-fold the risk of developing the disease. Because FDRs of CRC patients are more likely to co-inherit CRC risk variants, we aimed to evaluate potential differences in genotype distribution of single nucleotide polymorphisms (SNPs) related to CRC risk between FDRs of patients with nonsyndromic CRC (cases) and individuals with no family history of CRC (controls).MethodsWe designed a case-control study comprising 750 cases and 750 Spanish Caucasian controls matched by sex, age, and histological findings after colonoscopy. Genomic DNA from all participants was genotyped for 88 SNPs associated with CRC risk using the MassArray (Sequenom) platform.ResultsTen of the 88 SNPs analyzed revealed significant associations (P < 0.05) with a family history of CRC in our population. The most robust associations were found for the rs17094983G>A SNP in the long noncoding RNA LINC01500 (odds ratio = 0.72; 95% confidence interval: 0.58-0.88, log-additive model), and the rs11255841T>A SNP in the long noncoding RNA LINC00709 (odds ratio = 2.04; 95% confidence interval: 1.19-3.51, dominant model). Of interest, the observed associations were in the same direction than those reported for CRC risk.DiscussionFDRs of CRC patients show significant differences in genotype distribution of SNPs related to CRC risk as compared to individuals with no family history of CRC. Genotyping of CRC risk variants in FDRs of CRC patients may help to identify subjects at risk that would benefit from stricter surveillance and CRC screening programs.
| S-EPMC7861964 | biostudies-literature
Project description:Colorectal cancer is the second leading cause of cancer-related death, and most colorectal cancer usually arises from colorectal adenomas. Removal of polyps reduces mortality from colorectal cancer. Colorectal adenomas are known to aggregate in families; however, the genetic determinants for risk of polyps are largely unknown.In this study, we used data from the Tennessee Colorectal Polyp Study and the Tennessee-Indiana Adenoma Recurrence Study to conduct a GWAS of adenoma cases and controls. Our design consisted of discovery and replication phases for a total of 2,551 Caucasian adenoma cases and 3,285 Caucasian controls. We carried out logistic regression to test for association in both the discovery and replication phase and further examined the results with meta-analysis.No single nucleotide polymorphism (SNP) achieved a genome-wide significant P value; however, the most significantly associated SNPs were either previously associated with colorectal cancer in GWAS, such as rs10505477 in the gene POU5F1 [odds ratio (OR) = 0.87; 95% confidence interval (CI) 0.81-0.94; P = 4.4 × 10(-4)), or have been biologically linked to benign growths in other tissues, such as rs1919314 in the gene histone deacetylase 9 (OR = 1.32; 95% CI, 1.18-1.47; P = 1.1 × 10(-6)).This study suggests that several SNPs may be related to adenoma risk and provides clues for future studies.These results suggest that some known genetic risk factors of colorectal cancer are necessary but not sufficient for carcinogenesis.
| S-EPMC3716448 | biostudies-literature
Project description:Background & aimsRisk for colorectal cancer (CRC) can be greatly reduced through screening. To aid in the development of screening strategies, we refined models designed to determine risk of CRC by incorporating information from common genetic susceptibility loci.MethodsBy using data collected from more than 12,000 participants in 6 studies performed from 1990 through 2011 in the United States and Germany, we developed risk determination models based on sex, age, family history, genetic risk score (number of risk alleles carried at 27 validated common CRC susceptibility loci), and history of endoscopic examinations. The model was validated using data collected from approximately 1800 participants in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial, conducted from 1993 through 2001 in the United States.ResultsWe identified a CRC genetic risk score that independently predicted which patients in the training set would develop CRC. Compared with determination of risk based only on family history, adding the genetic risk score increased the discriminatory accuracy from 0.51 to 0.59 (P = .0028) for men and from 0.52 to 0.56 (P = .14) for women. We calculated age- and sex-specific 10-year CRC absolute risk estimates based on the number of risk alleles, family history, and history of endoscopic examinations. A model that included a genetic risk score better determined the recommended starting age for screening in subjects with and without family histories of CRC. The starting age for high-risk men (family history of CRC and genetic risk score, 90%) was 42 years, and for low-risk men (no family history of CRC and genetic risk score, 10%) was 52 years. For men with no family history and a high genetic risk score (90%), the starting age would be 47 years; this is an intermediate value that is 5 years earlier than it would be for men with a genetic risk score of 10%. Similar trends were observed in women.ConclusionsBy incorporating information on CRC risk alleles, we created a model to determine the risk for CRC more accurately. This model might be used to develop screening and prevention strategies.
| S-EPMC4446193 | biostudies-literature
Project description:The risk of sporadic colorectal cancer (CRC) is mainly associated with lifestyle factors, particularly dietary factors. Diets high in red meat and fat and low in fruit and vegetables are associated with an increased risk of CRC. The dietary effects may be modulated by genetic polymorphisms in biotransformation genes. In this study we aimed to evaluate the role of dietary factors in combination with genetic factors in the different stages of colorectal carcinogenesis in a Norwegian population.We used a case-control study design (234 carcinomas, 229 high-risk adenomas, 762 low-risk adenomas and 400 controls) to test the association between dietary factors (meat versus fruit, berries and vegetables) genetic polymorphisms in biotransformation genes (GSTM1, GSTT1, GSTP1 Ile105Val, EPHX1 Tyr113His and EPHX1 His139Arg), and risk of colorectal carcinomas and adenomas. Odds ratio (OR) and 95% confidence interval (95% CI) were estimated by binary logistic regression.A higher ratio of total meat to total fruit, berry and vegetable intake was positively associated with both high and low-risk adenomas, with approximately twice the higher risk in the 2nd quartile compared to the lowest quartile. For the high-risk adenomas this positive association was more obvious for the common allele (Tyr allele) of the EPHX1 codon 113 polymorphism. An association was also observed for the EPHX1 codon 113 polymorphism in the low-risk adenomas, although not as obvious.Although, the majority of the comparison groups are not significant, our results suggest an increased risk of colorectal adenomas in individuals for some of the higher ratios of total meat to total fruit, berry and vegetable intake. In addition the study supports the notion that the biotransformation enzymes GSTM1, GSTP1 and EPHX1 may modify the effect of dietary factors on the risk of developing colorectal carcinoma and adenoma.
| S-EPMC2228310 | biostudies-literature
Project description:BackgroundBoth genetic and dietary factors play significant roles in the etiology of colorectal cancer (CRC). To evaluate the relationship between certain food exposures and the risk of CRC, we carried out a large-scale association analysis in the UK Biobank.MethodsThe associations of 139 foods and nutrients' intake with CRC risk were assessed among 118,210 participants. A polygenic risk score (PRS) of CRC was created to explore any interaction between dietary factors and genetic susceptibility in CRC risk. The hazard ratio (HR) and 95% confidence interval (CI) of CRC risk linked to dietary variables and PRS were estimated using Cox regression models. Multiple comparisons were corrected using the error discovery rate (FDR).ResultsDuring a mean follow-up of 12.8 years, 1466 incidents of CRC were identified. In the UK Biobank, alcohol and white bread were associated with increased CRC risk, and their HRs were 1.08 (95% CI: 1.03-1.14; FDRP = 0.028) and 1.10 (95% CI: 1.05-1.16; FDRP = 0.003), whereas dietary fiber, calcium, magnesium, phosphorus, and manganese intakes were inversely associated. We found no evidence of any PRS-nutrient interaction relationship in relation to CRC risk.ConclusionsOur results show that higher intakes of alcohol and white bread are associated with increased CRC risk, whilst dietary fiber, calcium, magnesium, phosphorus, and manganese are inversely associated.
| S-EPMC10674290 | biostudies-literature
Project description:Familial colorectal cancer (CRC) is a major public health problem by virtue of its relatively high frequency. Some 15-20% of all CRCs are familial. Among these, familial adenomatous polyposis (FAP), caused by germline mutations in the APC gene, accounts for less than 1%. Hereditary non-polyposis colorectal cancer (HNPCC), also called Lynch syndrome, accounts for approximately 5-8% of all CRC patients. Among these, some 3% are mutation positive, that is, caused by germline mutations in the DNA mismatch repair genes that have so far been implicated (MLH1, MSH2, MSH6, PMS1, and PMS2). Most of the remaining patients belonging to HNPCC or HNPCC-like families are still molecularly unexplained. Among the remaining familial CRCs, a large proportion is probably caused by gene mutations and polymorphisms of low penetrance, of which the I1307K polymorphism in the APC gene is a prime example. Molecular genetic findings have enabled hereditary CRC to be divided into two groups: (1) tumours that show microsatellite instability (MSI), occur more frequently in the right colon, have diploid DNA, harbour characteristic mutations such as transforming growth factor beta type II receptor and BAX, and behave indolently, of which HNPCC is an example; and (2) tumours with chromosomal instability (CIN), which tend to be left sided, show aneuploid DNA, harbour characteristic mutations such as K-ras, APC, and p53, and behave aggressively, of which FAP is an example. This review focuses most heavily on the clinical features, pathology, molecular genetics, surveillance, and management including prophylactic surgery in HNPCC. Because of the difficulty in diagnosing HNPCC, a detailed differential diagnosis of the several hereditary CRC variants is provided. The extant genetic and phenotypic heterogeneity in CRC leads to the conclusion that it is no longer appropriate to discuss the genetics of CRC without defining the specific hereditary CRC syndrome of concern. Therefore, it is important to ascertain cancer of all anatomical sites, as well as non-cancer phenotypic stigmata (such as the perioral and mucosal pigmentations in Peutz-Jeghers syndrome), when taking a family cancer history.
| S-EPMC1734258 | biostudies-literature
Project description:Exposure to heterocyclic aromatic amines (HAAs), carcinogens produced when meat is cooked at high temperatures, is an emerging risk factor for colorectal cancer (CRC). In a cross-sectional study of 342 patients undergoing a screening colonoscopy, the role of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx) and 2-amino-3,4,8-trimethylimidazo[4,5-f]quinoxaline (DiMeIQx), the three most abundant HAAs found in cooked meats, and total mutagenic activity in cooked meats were examined in relation to colorectal adenoma risk. Given that genetic differences in the ability to biotransform HAAs and repair DNA are postulated to modify the HAA-CRC relationship, gene-diet interactions were also examined. Among the total study population, no relationships were observed between dietary HAAs or meat mutagenicity, and colorectal adenoma risk; however, in males, positive associations between dietary HAAs/meat mutagenicity exposures and adenoma risk were suggestive of a relationship. In a separate analysis, polymorphisms in CYP1B1 were found to be associated with colorectal adenoma risk. Additionally, gene-diet interactions were observed for dietary PhIP and polymorphisms in CYP1B1 and XPD, dietary DiMeIQx and XPD polymorphisms, and meat mutagenicity exposure and CYP1B1 polymorphisms. Overall, increased colorectal adenoma risk was observed with higher HAA/meat mutagenicity exposures among those with polymorphisms which confer greater activity to biotransform HAAs and/or lower ability to repair DNA. This research supports the link between dietary HAAs and genetic susceptibility in colorectal adenoma etiology. The vast majority of CRCs arise from colorectal adenomas; thus, the results of this study suggest that changes in meat preparation practices limiting the production of HAAs may be beneficial for CRC prevention.
| S-EPMC4166582 | biostudies-literature