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Abstract

Deregulation of apoptosis is a frequent alteration in benign, pre-­‐cancerous lesions of the colon mucosa that has been extensively discussed as contributor to the development of colorectal cancer. Individual differences in the regulation of apoptosis are (epi-­‐)genetically determined and identification of SNPs within coding/ flanking regions of genes with apoptosis relevant function could provide a basis to assess the individual risk to develop these lesions. To identify a possible association between genetic polymorphisms and tumorigenesis we selected 865 genes with reported function within the apoptosis pathways or in related (e.g. stress related) pathways. Our screening was performed on a customized goldengate Illumina chip covering 1536 single nucleotide polymorphisms in a two stage approach. Stage I was performed on 272 patients harboring hyperplastic polyps and 512 controls. Stage II aimed to validate preliminary data by screening the candidate SNPs (p<0.01) on an independent cohort of patients and controls (n=76). After the meta-­‐analysis between stage1 and stage2 the false discovery rate (FDR) approach has been used to calculate the “q” of significativity in order to have a better compromise between Type1 and Type2 errors. Among the candidate polymorphisms 9 SNPs were significantly correlated with the occurrence of hyperplastic polyps. Out of these the variation rs4709583 (PARK2) presented the highest significativity level (q=0.003) and was therefore further analysed in-­‐vitro to identify its potential influence on splicing in the PARK2 gene.