Dataset Information

Inflammatory response gene polymorphisms and their relationship with colorectal cancer risk.

ABSTRACT:

Background

Patients with chronic inflammatory bowel disease (IBD) are at an increased risk of colorectal cancer (CRC) and it is estimated that one in six persons diagnosed with IBD will develop CRC. This fact suggests that genetic variations in inflammatory response genes may act as CRC disease risk modifiers.

Methods

In order to test this hypothesis we investigated a series of polymorphisms in 6 genes (NOD2, DLG5, OCTN1, OCTN2, IL4, TNFalpha) associated with the inflammatory response on a group of 607 consecutive newly diagnosed colorectal cancer patients and compared the results to controls (350 consecutive newborns and 607 age, sex and geographically matched controls).

Results

Of the six genes only one polymorphism in TNFalpha(-1031T/T) showed any tendency to be associated with disease risk (64.9% for controls and 71.4% for CRC) which we further characterized on a larger cohort of CRC patients and found a more profound relationship between the TNFalpha -1031T/T genotype and disease (64.5% for controls vs 74.7% for CRC cases above 70 yrs). Then, we investigated this result and identified a suggestive tendency, linking the TNFalpha -1031T/T genotype and a previously identified change in the CARD15/NOD2 gene (OR = 1.87; p = 0,02 for CRC cases above 60 yrs).

Conclusion

The association of polymorphisms in genes involved in the inflammatory response and CRC onset suggest that there are genetic changes capable of influencing disease risk in older persons.

SUBMITTER: Suchy J

PROVIDER: S-EPMC2386482 | biostudies-literature | 2008 Apr

REPOSITORIES: biostudies-literature

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Publications

Inflammatory response gene polymorphisms and their relationship with colorectal cancer risk.

Suchy Janina J Kłujszo-Grabowska Ewa E Kładny Józef J Cybulski Cezary C Wokołorczyk Dominika D Szymańska-Pasternak Jolanta J Kurzawski Grzegorz G Scott Rodney J RJ Lubiński Jan J

BMC cancer 20080423

<h4>Background</h4>Patients with chronic inflammatory bowel disease (IBD) are at an increased risk of colorectal cancer (CRC) and it is estimated that one in six persons diagnosed with IBD will develop CRC. This fact suggests that genetic variations in inflammatory response genes may act as CRC disease risk modifiers.<h4>Methods</h4>In order to test this hypothesis we investigated a series of polymorphisms in 6 genes (NOD2, DLG5, OCTN1, OCTN2, IL4, TNFalpha) associated with the inflammatory resp ...[more]

PMID: 18433468

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Project description:What is already known about this subject* Numerous clinical studies, including a few prospective ones, have reported conflicting results on the impact of gene polymorphisms related to fluorouracil (FU) and oxaliplatin pharmacodynamics.What this study adds* This prospective study is the first to report that clinical response to FOLFOX is significantly related to methylenetetrahydrofolate reductase (MTHFR) gene polymorphisms (677C-->T and 1298A-->C), with a response rate of 37, 53, 63 and 80% in patients harbouring no, one, two or three favourable MTHFR alleles, respectively. * Only polymorphisms of genes related to oxaliplatin pharmacodynamics (GSTpi 105Ile-->Val and XPD 751Ly-->Gln) influenced progression-free survival. * These results corroborate the observation that response was related to the cumulative FU dose, whereas progression-free survival was related to the cumulative oxaliplatin dose.AimsTo test prospectively the predictive value of germinal gene polymorphisms related to fluorouracil (FU) and oxaliplatin (Oxa) pharmacodynamics on toxicity and responsiveness of colorectal cancer (CRC) patients receiving FOLFOX therapy.MethodsAdvanced CRC patients (n= 117) receiving FOLFOX 7 therapy were enrolled. Gene polymorphisms relevant for FU [thymidylate synthase (TYMS, 28 bp repeats including the G-->C mutation + 6 bp deletion in 3'UTR), methylenetetrahydrofolate reductase (MTHFR, 677C-->T, 1298A-->C), dihydropyrimidine deshydrogenase (IVS14+1G-->A) and Oxa: glutathione S-transferase (GST) pi (105Ile-->Val, 114Ala-->Val), excision repair cross-complementing group 1 (ERCC1) (118AAT-->AAC), ERCC2 (XPD, 751Lys-->Gln) and XRCC1 (399Arg-->Gln)] were determined (blood mononuclear cells).ResultsNone of the genotypes was predictive of toxicity. Response rate (54.7% complete response + partial response) was related to FU pharmacogenetics, with both 677C-->T (P= 0.042) and 1298A-->C (P= 0.004) MTHFR genotypes linked to clinical response. Importantly, the score of favourable MTHFR alleles (677T and 1298C) was positively linked to response, with response rates of 37.1, 53.3, 62.5 and 80.0% in patients bearing no, one, two or three favourable alleles, respectively (P= 0.040). Polymorphisms of genes related to Oxa pharmacodynamics showed an influence on progression-free survival, with a better outcome in patients bearing GSTpi 105 Val/Val genotype or XPD 751Lys-containing genotype (P= 0.054).ConclusionsThese results show that response to FOLFOX therapy in CRC patients may be driven by MTHFR germinal polymorphisms.

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Dataset Information

Inflammatory response gene polymorphisms and their relationship with colorectal cancer risk.

Background

Methods

Results

Conclusion

Publications

Inflammatory response gene polymorphisms and their relationship with colorectal cancer risk.

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