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 (P < 0.01) was then evaluated in an independent cohort of patients (n = 38) and controls (n = 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 P < 0.01) with the occurrence of HP. The SNPs rs4709583 (PARK2) and rs10476823 (HDAC3) 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 (PARK3). By contrast, cDNA analysis revealed use of a cryptic polyadenylation signal in the 3'UTR of HDAC3 mRNA and a longer mRNA half-life in a cell line heterozygous for rs10476823.
%0 Journal Article
%1 Gerola2014
%A Gerola, Stefano
%A Nittka, Stefanie
%A Kähler, Georg
%A Tao, Sha
%A Brenner, Hermann
%A Binelli, Giorgio
%A Eils, Roland
%A Brors, Benedikt
%A Neumaier, Michael
%D 2014
%J Genes Chromosomes Cancer
%K ABI myown
%N 9
%P 769--778
%R 10.1002/gcc.22185
%T Genetic variants in apoptosis-related genes associated with colorectal hyperplasia.
%U http://dx.doi.org/10.1002/gcc.22185
%V 53
%X 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 (P < 0.01) was then evaluated in an independent cohort of patients (n = 38) and controls (n = 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 P < 0.01) with the occurrence of HP. The SNPs rs4709583 (PARK2) and rs10476823 (HDAC3) 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 (PARK3). By contrast, cDNA analysis revealed use of a cryptic polyadenylation signal in the 3'UTR of HDAC3 mRNA and a longer mRNA half-life in a cell line heterozygous for rs10476823.
@article{Gerola2014,
__markedentry = {[bbrors:6]},
abstract = {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 (P < 0.01) was then evaluated in an independent cohort of patients (n = 38) and controls (n = 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 P < 0.01) with the occurrence of HP. The SNPs rs4709583 (PARK2) and rs10476823 (HDAC3) 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 (PARK3). By contrast, cDNA analysis revealed use of a cryptic polyadenylation signal in the 3'UTR of HDAC3 mRNA and a longer mRNA half-life in a cell line heterozygous for rs10476823.},
added-at = {2015-04-09T12:36:21.000+0200},
author = {Gerola, Stefano and Nittka, Stefanie and K{\"{a}}hler, Georg and Tao, Sha and Brenner, Hermann and Binelli, Giorgio and Eils, Roland and Brors, Benedikt and Neumaier, Michael},
biburl = {https://www.bibsonomy.org/bibtex/285bf208ded0ddb4d63c91e3e1413f7b8/bbrors},
doi = {10.1002/gcc.22185},
institution = {Institute for Clinical Chemistry, Universitätsmedizin Mannheim, Medical Faculty Mannheim, University of Heidelberg, Mannheim, 68167, Germany.},
interhash = {5492077b390d0cf03bcc67c7a4ccbd00},
intrahash = {85bf208ded0ddb4d63c91e3e1413f7b8},
journal = {Genes Chromosomes Cancer},
keywords = {ABI myown},
language = {eng},
medline-pst = {ppublish},
month = sep,
number = 9,
owner = {bbrors},
pages = {769--778},
pmid = {24861865},
timestamp = {2015-05-26T11:32:34.000+0200},
title = {Genetic variants in apoptosis-related genes associated with colorectal hyperplasia.},
url = {http://dx.doi.org/10.1002/gcc.22185},
volume = 53,
year = 2014
}