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.

Genetic Variants in Apoptosis Related Genes Associated with Colorectal Hyperplasia.

BINELLI, GIORGIO PIETRO MARIO;
2014-01-01

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.
2014
Aged; Apoptosis; Case-Control Studies; Cohort Studies; Colonic Polyps; Female; Genetic Association Studies; Genetic Markers; Genotype; Histone Deacetylases; Humans; Hyperplasia; Intestinal Polyps; Male; Metabolic Networks and Pathways; Middle Aged; Oligonucleotide Array Sequence Analysis; Polymorphism, Single Nucleotide; Rectum
Gerola, S.; Nittka, S.; Kahler, G.; Tao, S.; Brenner, H.; Binelli, GIORGIO PIETRO MARIO; Eils, R.; Brors, B.; Neumaier, M.
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11383/1942120
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