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Chronic inflammation, colorectal cancer and gene polymorphisms.

ABSTRACT: Chronic inflammation is commonly present in gastrointestinal mucosal sites at increased risk for cancer, such as in inflammatory bowel disease (IBD) or chronic gastritis caused by Helicobacter pylori infection. Why some patients have more mucosal inflammation than others, and why certain individuals with chronic inflammation develop cancer, are problems that have not been solved. Unlike the case for the syndromic forms of familial colorectal cancer (CRC), the risks for IBD and other forms of chronic inflammation have not been linked to highly penetrant single gene mutations. Single nucleotide polymorphisms (SNP) are variations in DNA sequence that can be linked to any phenotype (cancer, chronic inflammation, etc.) in genome-wide association studies (GWAS). CRC has been linked to several highly penetrant single gene loci, as well as multiple SNP. The propensity to develop IBD has not been linked to single gene mutations in most instances, but has been linked to SNP in the NOD2 locus (which appear to create hypomorphic alleles for this bacterial response gene), the IL23R locus, the autophagy gene ATG16L1 and a wide range of other loci including the Toll-like receptors, JAK2 and STAT3, and perhaps 70 more. At present, the problem in predicting risk for chronic inflammation is that there are many genetic polymorphisms with relatively modest individual effects. Our challenge is to understand how the SNPs that are linked to variations in the inflammatory response interact with one another (i.e. to understand the 'epistasis' involved), and to integrate this with the variety of individual environmental exposures. This represents an opportunity for informatics science to help personalize our approach to chronic inflammatory diseases of the gut and identify those at greatest risk for cancer.

SUBMITTER: Boland CR

PROVIDER: S-EPMC2997443 | biostudies-literature | 2010

REPOSITORIES: biostudies-literature

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Chronic inflammation, colorectal cancer and gene polymorphisms.

Boland C Richard CR

Digestive diseases (Basel, Switzerland) 20101118 4-5

Chronic inflammation is commonly present in gastrointestinal mucosal sites at increased risk for cancer, such as in inflammatory bowel disease (IBD) or chronic gastritis caused by Helicobacter pylori infection. Why some patients have more mucosal inflammation than others, and why certain individuals with chronic inflammation develop cancer, are problems that have not been solved. Unlike the case for the syndromic forms of familial colorectal cancer (CRC), the risks for IBD and other forms of chr ...[more]

PMID: 21088407

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Project description:ObjectiveTo analyse the single-nucleotide polymorphisms (SNPs): ABCB1(1236C>T), ABCB1(2677G>T/A), ABCB1(3435C>T) and haplotypes in the ABCB1/MDR1 gene, which could contribute to genetic risk of colorectal cancer (CRC). Disease association between the ABCB1/MDR1 genotype, allele, haplotype frequencies and histological features, such as TNM classification, localization of primary carcinoma, grade of malignancy, histological type of tumour, lymphoid infiltration and vessel invasion were estimated. In this study, the potential role of SNPs of the ABCB1/MDR1 gene as a prognostic marker for CRC was analysed.Materials and methodsTumour specimens of 95 patients with CRC were studied. Using automated sequencing or PCR-RFLP method, DNA for three common SNPs of ABCB1/MDR1 was extracted and analysed. The results of genotyping and haplotype analysis with histopathological features, grading and clinical staging of neoplasms were correlated.ResultsA statistically significant higher frequency of T(1236) allele in T1/T2 (89.7%), M0 groups (81.6%) and I/II clinical staging (82.7%) in comparison with T3/T4 (68.2%), M1 groups (47.4%) and III/IV clinical staging (65.1%) was detected. Furthermore, multivariate analysis according to Cox's proportional hazard model indicated that the T(1236) allele is a good, independent prognostic factor and the presence of this allele decreases the risk of death in comparison with a group without this allele (HR = 0.26; p = 0.0424). In addition, a statistically significant higher frequency of C(3435) allele and significant differences in the C(3435) allele distribution in N1/N2 group (91.7% and 62.5%, respectively) than N0 group (71.2% and 44.9%, respectively) was found. Each of the eight possible haplotypes was noted in M0 or I/II group and only seven in M1 or III/IV group. Haplotype T(1236)-G(2677)-C(3435) only in less advanced CRC subjects (9.6% in I/II and 9.2% in M0 group) was detected. In addition, significant differences in haplotype distributions between M0 or I/II and M1 or III/IV group were found (p = 0.01 and p = 0.05, respectively).ConclusionsThese results suggest association between T(1236) allele and T(1236)-G(2677)-C(3435) haplotype and less advanced CRC, so these genetic markers may play a role as potentially good prognostic factors. Differences in haplotype distributions and degree of clinical staging may suggest that some other potential SNPs, especially in regulatory region of ABCB1/MDR1 gene, may influence P-glycoprotein function and CRC progression.

Dataset Information

Chronic inflammation, colorectal cancer and gene polymorphisms.

Publications

Chronic inflammation, colorectal cancer and gene polymorphisms.

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