Abstract
BackgroundProstate cancer (PCa) and colorectal cancer (CRC) are the most commonly diagnosed cancers and cancer-related causes of death in Poland. To date, numerous single nucleotide polymorphisms (SNPs) associated with susceptibility to both cancer types have been identified, but their effect on disease risk may differ among populations.MethodsTo identify new SNPs associated with PCa and CRC in the Polish population, a genome-wide association study (GWAS) was performed using DNA sample pools on Affymetrix Genome-Wide Human SNP 6.0 arrays. A total of 135 PCa patients and 270 healthy men (PCa sub-study) and 525 patients with adenoma (AD), 630 patients with CRC and 690 controls (AD/CRC sub-study) were included in the analysis. Allele frequency distributions were compared with t-tests and χ2-tests. Only those significantly associated SNPs with a proxy SNP (p<0.001; distance of 100 kb; r2>0.7) were selected. GWAS marker selection was conducted using PLINK. The study was replicated using extended cohorts of patients and controls. The association with previously reported PCa and CRC susceptibility variants was also examined. Individual patients were genotyped using TaqMan SNP Genotyping Assays.ResultsThe GWAS selected six and 24 new candidate SNPs associated with PCa and CRC susceptibility, respectively. In the replication study, 17 of these associations were confirmed as significant in additive model of inheritance. Seven of them remained significant after correction for multiple hypothesis testing. Additionally, 17 previously reported risk variants have been identified, five of which remained significant after correction.ConclusionPooled-DNA GWAS enabled the identification of new susceptibility loci for CRC in the Polish population. Previously reported CRC and PCa predisposition variants were also identified, validating the global nature of their associations. Further independent replication studies are required to confirm significance of the newly uncovered candidate susceptibility loci.
Highlights
Cancers are highly heterogeneous, polygenic disorders that arise in a multi-step process involving the selection of successive cellular clones and result from genetic as well as specific environmental factors
We describe a pooled DNA sample-based genome-wide association studies (GWAS) as a cost-effective alternative to identify genetic variants of moderate effect associated with colorectal cancer (CRC) and Prostate cancer (PCa) in the Polish population
A reason why so many of PCa patient pools had to be rejected from further consideration is not clear
Summary
Polygenic disorders that arise in a multi-step process involving the selection of successive cellular clones and result from genetic as well as specific environmental factors. In the former case, both high-penetrance mutations and low-penetrance polymorphisms may determine a patient’s defense and adaptive mechanisms against exposure to carcinogenic factors, determining susceptibility to this disease. The association between allele frequency and susceptibility to disease can be studied by focusing on individually selected variants or, instead, on the position of over a million DNA variants, using single nucleotide polymorphism (SNP) microarray technology. Numerous single nucleotide polymorphisms (SNPs) associated with susceptibility to both cancer types have been identified, but their effect on disease risk may differ among populations
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