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.
BACKGROUND
Differences 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.


OBJECTIVE
To 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.


METHODS
A 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.


METHODS
Comparisons 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.


CONCLUSIONS
We 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.


CONCLUSIONS
Differences 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.
Radiation Oncology Department, Hospital Universitario de Gran Canaria Dr. Negrín, Las Palmas, Spain. lhenriquez@dcc.ulpgc.es
Luis Alberto
LA
Henríquez-Hernández
Almudena
A
Valenciano
Palmira
P
Foro-Arnalot
María Jesús
MJ
Alvarez-Cubero
José Manuel
JM
Cozar
José Francisco
JF
Suárez-Novo
Manel
M
Castells-Esteve
Adriana
A
Ayala-Gil
Pablo
P
Fernández-Gonzalo
Montse
M
Ferrer
Ferrán
F
Guedea
Gemma
G
Sancho-Pardo
Jordi
J
Craven-Bartle
María José
MJ
Ortiz-Gordillo
Patricia
P
Cabrera-Roldán
Estefanía
E
Herrera-Ramos
Pedro C
PC
Lara
D000483:Alleles; D016000:Cluster Analysis; D015331:Cohort Studies; D015986:Confounding Factors, Epidemiologic; D004260:DNA Repair / Q000235:genetics*; D005787:Gene Frequency / Q000235:genetics; D056726:Genetic Association Studies; D018740:Genetic Heterogeneity; D020022:Genetic Predisposition to Disease; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D008297:Male; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D025341:Principal Component Analysis; D011471:Prostatic Neoplasms / Q000453:epidemiology* / Q000235:genetics*; D013030:Spain / Q000453:epidemiology