Media type: E-Article Title: Genetic variants in apoptosis‐related genes associated with colorectal hyperplasia Contributor: Gerola, Stefano; Nittka, Stefanie; Kähler, Georg; Tao, Sha; Brenner, Hermann; Binelli, Giorgio; Eils, Roland; Brors, Benedikt; Neumaier, Michael imprint: Wiley, 2014 Published in: Genes, Chromosomes and Cancer Language: English DOI: 10.1002/gcc.22185 ISSN: 1045-2257; 1098-2264 Keywords: Cancer Research ; Genetics Origination: Footnote: Description: <jats:p>Deregulation of apoptosis is a frequent alteration in early benign lesions of the colon mucosa and is thought to be a major contributor to tumor progression and cancer. Single nucleotide polymorphisms (SNPs) within apoptosis‐related genes could affect apoptotic responses and their identification might provide a basis to assess individual risk for development of early lesions. To investigate a possible association between genetic polymorphisms and the occurrence of hyperplastic polyps (HP), we developed a custom DNA chip assay for 1,536 SNPs in the coding and flanking regions of 826 genes with known functional roles in apoptosis or apoptosis‐associated (e.g., stress‐related) pathways. During a first round of screening, genotypes were determined for 272 endoscopy patients harboring hyperplastic colorectal polyps and for 512 sex and aged‐matched controls. A set of 14 candidate SNPs associated with HP (<jats:italic>P</jats:italic> < 0.01) was then evaluated in an independent cohort of patients (<jats:italic>n</jats:italic> = 38) and controls (<jats:italic>n</jats:italic> = 38). Following meta‐analysis of Stages I and II, a false discovery rate approach was applied. Among the 14 candidate SNPs, eight showed significant association (combined <jats:italic>P</jats:italic> < 0.01) with the occurrence of HP. The SNPs rs4709583 (<jats:italic>PARK2</jats:italic>) and rs10476823 (<jats:italic>HDAC3</jats:italic>) were analyzed for potential functional effects on RNA splicing and RNA half‐life. Despite its location near a splice site, alternative splicing was not detected for rs4709583 (<jats:italic>PARK3</jats:italic>). By contrast, cDNA analysis revealed use of a cryptic polyadenylation signal in the 3′UTR of <jats:italic>HDAC3</jats:italic> mRNA and a longer mRNA half‐life in a cell line heterozygous for rs10476823. © 2014 Wiley Periodicals, Inc.</jats:p>