Polymorphisms in DNA-Repair Genes in a Cohort of Prostate Cancer Patients from Different Areas in Spain: Heterogeneity between Populations as a Confounding Factor in Association Studies

Abstract

BackgroundDifferences in the distribution of genotypes between individuals of the same ethnicity are an important confounder factor commonly undervalued in typical association studies conducted in radiogenomics.ObjectiveTo evaluate the genotypic distribution of SNPs in a wide set of Spanish prostate cancer patients for determine the homogeneity of the population and to disclose potential bias.Design, Setting, and ParticipantsA total of 601 prostate cancer patients from Andalusia, Basque Country, Canary and Catalonia were genotyped for 10 SNPs located in 6 different genes associated to DNA repair: XRCC1 (rs25487, rs25489, rs1799782), ERCC2 (rs13181), ERCC1 (rs11615), LIG4 (rs1805388, rs1805386), ATM (rs17503908, rs1800057) and P53 (rs1042522). The SNP genotyping was made in a Biotrove OpenArray® NT Cycler.Outcome Measurements and Statistical AnalysisComparisons of genotypic and allelic frequencies among populations, as well as haplotype analyses were determined using the web-based environment SNPator. Principal component analysis was made using the SnpMatrix and XSnpMatrix classes and methods implemented as an R package. Non-supervised hierarchical cluster of SNP was made using MultiExperiment Viewer.Results and LimitationsWe observed that genotype distribution of 4 out 10 SNPs was statistically different among the studied populations, showing the greatest differences between Andalusia and Catalonia. These observations were confirmed in cluster analysis, principal component analysis and in the differential distribution of haplotypes among the populations. Because tumor characteristics have not been taken into account, it is possible that some polymorphisms may influence tumor characteristics in the same way that it may pose a risk factor for other disease characteristics.ConclusionDifferences in distribution of genotypes within different populations of the same ethnicity could be an important confounding factor responsible for the lack of validation of SNPs associated with radiation-induced toxicity, especially when extensive meta-analysis with subjects from different countries are carried out.

Intraethnic variation in steroid-5-alpha-reductase polymorphisms in prostate cancer patients: a potential factor implicated in 5-alpha-reductase inhibitor treatment

“…We have recently reported differences in the distribution of genotypes within different populations of the same ethnicity (Henriquez- Hernandez et al 2013a), highlighting the importance of ethnic-specific differences in drug responsiveness (Yasuda et al 2008;Ma and Lu 2011). In the present paper, we observed that genotype distribution of 12 of 22 SNPs were statistically different among the studied populations.…”

“…Geographical distribution of patients was as follows (Henriquez-Hernandez et al 2013a): 91 (15.14%) from Andalusia, 51 (8.48%) from Basque Country, 238 (39.60%) from Canary and 221 (36.77%) from Catalonia. All patients were of Spanish origin and all of them received written informed consent before sample collection.…”

“…The quality value of the data points was determined by a threshold above 0.95. Genotyping analysis was done for each population separately and it was done automatically without any manual assignment of genotypes as previously reported (Henriquez-Hernandez et al 2013a). All the genotyped samples met the quality criteria and all samples were genotyped with the same batch of material and at the same time.…”

“…These genetic variations in key genes belonging to the androgen pathway seem to be important for the prostate response to androgens (Lindstrom et al 2006). We have recently reported that differences in the distribution of genotypes within different populations of the same ethnicity could be an important confounding factor in association studies (Henriquez-Hernandez et al 2013a).…”

Genetic variations in genes involved in testosterone metabolism are associated with prostate cancer progression: A Spanish multicenter study

“…The patients were recruited from 4 different regions of Spain, as has been previously published [15]. As genotypic and allelic frequencies vary among subjects from these regions, and Andalusian patients showed the greatest differences [15,16], we excluded these subset of patients from further analyses to avoid bias. Patients who were initially operated were also excluded to form a homogenous group of patients with PCa.…”