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Coding variants in NOD-like receptors: An association study on risk and survival of colorectal cancer.

ABSTRACT: Nod-like receptors (NLRs) are important innate pattern recognition receptors and regulators of inflammation or play a role during development. We systematically analysed 41 non-synonymous single nucleotide polymorphisms (SNPs) in 21 NLR genes in a Czech discovery cohort of sporadic colorectal cancer (CRC) (1237 cases, 787 controls) for their association with CRC risk and survival. Five SNPs were found to be associated with CRC risk and eight with survival at 5% significance level. In a replication analysis using data of two large genome-wide association studies (GWASs) from Germany (DACHS: 1798 cases and 1810 controls) and Scotland (2210 cases and 9350 controls) the associations found in the Czech discovery set were not confirmed. However, expression analysis in human gut-related tissues and immune cells revealed that the NLRs associated with CRC risk or survival in the discovery set were expressed in primary human colon or rectum cells, CRC tissue and/or cell lines, providing preliminary evidence for a potential involvement of NLRs in general in CRC development and/or progression. Most interesting was the finding that the enigmatic development-related NLRP5 (also known as MATER) was not expressed in normal colon tissue but in colon cancer tissue and cell lines. Future studies may show whether regulatory variants instead of coding variants might affect the expression of NLRs and contribute to CRC risk and survival.

SUBMITTER: Huhn S

PROVIDER: S-EPMC6013205 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Coding variants in NOD-like receptors: An association study on risk and survival of colorectal cancer.

Huhn Stefanie S da Silva Filho Miguel I MI Sanmuganantham Tharmila T Pichulik Tica T Catalano Calogerina C Pardini Barbara B Naccarati Alessio A Polakova-Vymetálkova Veronika V Jiraskova Katerina K Vodickova Ludmila L Vodicka Pavel P Löffler Markus W MW Courth Lioba L Wehkamp Jan J Din Farhat V N FVN Timofeeva Maria M Farrington Susan M SM Jansen Lina L Hemminki Kari K Chang-Claude Jenny J Brenner Hermann H Hoffmeister Michael M Dunlop Malcolm G MG Weber Alexander N R ANR Försti Asta A

PloS one 20180621 6

Nod-like receptors (NLRs) are important innate pattern recognition receptors and regulators of inflammation or play a role during development. We systematically analysed 41 non-synonymous single nucleotide polymorphisms (SNPs) in 21 NLR genes in a Czech discovery cohort of sporadic colorectal cancer (CRC) (1237 cases, 787 controls) for their association with CRC risk and survival. Five SNPs were found to be associated with CRC risk and eight with survival at 5% significance level. In a replicati ...[more]

PMID: 29928061

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Project description:BACKGROUND:Single nucleotide polymorphisms (SNPs) in DNA repair genes have a potential clinical value in predicting treatment outcomes. In the current study, we examined the association of SNPs in the genes XRCC1-rs25487, ERCC1-rs11615, ERCC2-rs238406, and ERCC2-rs13181 with colorectal cancer (CRC) risk, relapse-free survival (RFS), overall survival (OS), and toxicity during chemotherapy. METHODS:SNPs were analysed in 590 CRC cases and 300 controls using TaqMan technology. The association of SNPs with CRC risk and toxicity during chemotherapy was analysed using Chi2 test. The Kaplan-Meier method and log-rank test was used to measure the effects of the SNPs on RFS and OS. RESULTS:The CC genotype of ERCC2-rs238406 and the ERCC2-rs13181 C allele were associated with a significantly increased risk of CRC. The ERCC1-rs11615 genotype T/T was associated with stomatitis in adjuvant chemotherapy (p?=?0.03). Also, more patients with the ERCC2-rs13181 C allele needed dose reduction compared to patients with the A/A genotype (p?=?0.02). In first line chemotherapy, more patients with the ERCC1-rs11615 C allele suffered from nausea compared to those with the T/T genotype (p?=?0.04) and eye reactions and thrombocytopenia were more common in patients with the ERCC2-rs13181 C allele compared to the A/A genotype (p?=?0.006 and p?=?0.004, respectively). ERCC2- rs238406 C/C was also associated with a higher frequency of thrombocytopenia (p?=?0.03). A shorter 5-year OS was detected in stage I & II CRC patients with the ERCC2- rs238406 C allele (p?=?0.02). However, there was no significant association between the SNPs and 5-year RFS. CONCLUSIONS:Both SNPs in ERCC2 were associated with risk of CRC as well as toxicity during first line treatment. In addition, ERCC2- rs238406 was linked to OS in early stage CRC. The ERCC1-rs11615 variant was associated with toxicity during adjuvant chemotherapy. The results add support to previous findings that SNPs in ERCC1 and ERCC2 have a prognostic and predictive value in clinical management of CRC.

Dataset Information

Coding variants in NOD-like receptors: An association study on risk and survival of colorectal cancer.

Publications

Coding variants in NOD-like receptors: An association study on risk and survival of colorectal cancer.

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