Single nucleotide polymorphisms in Wnt signaling and apoptotic pathway genes and susceptibility to colorectal cancer

B Frank; M Hoffmeister; N Klopp; T Illig; J Chang-Claude; H Brenner

doi:10.1055/s-0030-1266727

Das Gesundheitswesen, Inhaltsverzeichnis

Single nucleotide polymorphisms in Wnt signaling and apoptotic pathway genes and susceptibility to colorectal cancer

B Frank ¹, M Hoffmeister ¹, N Klopp ², T Illig ², J Chang-Claude ³, H Brenner ¹

¹Division of Clinical Epidemiology and Aging Research, German Cancer Research Center, Heidelberg, Germany
²Institute of Epidemiology, Research Centre for Environment and Health, Neuherberg, Germany
³Division of Cancer Epidemiology, German Cancer Research Center, Heidelberg, Germany

Abstract

Introduction: Constitutive activation of the canonical Wnt signaling pathway in consequence of mutations in APC, AXIN1 or CTNNB1 genes is regarded as initiating event in 90% of colorectal cancers (CRCs). Besides aberrant downstream target activation, numerous upstream Wnt signaling components were found deregulated in CRC. Additionally, Wnt signaling modulates apoptosis, encouraging CRC development and poor response to radiation. Therefore, we hypothesized that single nucleotide polymorphisms (SNPs) in Wnt signaling and apoptotic pathway genes affect CRC susceptibility. Material and Methods: This case-control study investigated associations between common, putative functional polymorphisms in DNFA5, HIF1A, NDRG1, PYGO1, SFRP2, SFRP4, WISP1 and WISP3 genes and CRC risk. SNPs were selected utilizing public databases (NCBI PubMed and GeneCards), searching epigenetically modulated or CRC-related genes with previous epidemiologic findings, indicating disease association. Selection was supported by programs detecting evolutionary conservation (WU-BLAST2) and functional prediction (PolyPhen, SIFT) of SNPs. Using genomic DNAs of 1795 cases and 1805 controls from the German population-based DACHS study, Sequenom's MassARRAY System (Sequenom, USA) was applied for genotyping. Unconditional logistic regression was employed to estimate odds ratios (ORs) and 95% confidence intervals (CIs). Results: Although we found no evidence for associations between selected SNPs and CRC risk, subsite analyses revealed a significant association of HIF1A c.*191T>C with rectal cancer risk (OR=1.25; 95% CI, 1.03–1.51; P=0.03), comparing minor allele carriers with major allele homozygotes. Furthermore, homozygosity for the minor allele of SFRP4 P320T was significantly associated with rectal cancer risk (OR=1.37; 95% CI, 1.06–1.79; P=0.02) and early-stage CRC (OR=1.33; 95% CI, 1.05–1.69; P=0.02). Conclusion: These findings support the hypothesis that SNPs involved in Wnt signaling and apoptosis contribute to CRC subsets, which may facilitate to assess individual susceptibility and to target potential measures of cancer prevention.