Polymorphic variation in the androgen receptor gene: association with risk of testicular germ cell cancer and metastatic disease.
Increasing incidence of testicular germ cell cancer (TGCC) is most probably related to environment and lifestyle. However, an underlying genetic predisposition may play a role and since sex steroids are assumed to be important for the rise and progression of TGCC, a study of androgen receptor (AR) gene polymorphisms in relation to the risk, histological type and progression of TGCC was undertaken. In 367 TGCC cases and 214 controls, AR CAG and GGN repeat lengths were determined and 11 haplotype-tagging single nucleotide polymorphisms (SNPs) were genotyped. By binary logistic regression, odds ratios (ORs) and 95% confidence intervals (95% CI) were calculated for the risk of TGCC, non-seminoma versus seminoma and metastatic versus localised (stage I) disease. For the non-coding SNP, rs12014709, the minor genotype (G) was found in 10% of the cases and in 5.1% of the controls, conferring an OR of 2.07 (95% CI: 1.03-4.15) for having TGCC. Furthermore, short GGN (<23) was associated with an increased risk of metastatic disease (OR: 2.15; 95% CI: 1.04-4.45). The AR polymorphisms found by us might be involved in gene-environment interaction by increasing the susceptibility to the effect of endocrine disruptors. From a biological point of view, our findings strengthen the hypothesis of the importance of androgen action in the aetiology and pathogenesis of testicular malignancy. Future studies should focus on the impact of sex hormones on foetal germ cell development and the interaction between environmental factors and androgen receptor variants in relation to the risk of testicular malignancy.
Västermark
Åke
Å
Department of Clinical Sciences, Molecular Genetic Reproductive Medicine, Lund University, Lund, Sweden.
Giwercman
Yvonne Lundberg
YL
Hagströmer
Oskar
O
Rajpert De-Meyts
Ewa
E
Eberhard
Jakob
J
Ståhl
Olof
O
Cedermark
Gabriella Cohn
GC
Rastkhani
Hamideh
H
Daugaard
Gedske
G
Arver
Stefan
S
Giwercman
Aleksander
A
D000328:Adult; D016022:Case-Control Studies; D003718:Denmark; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005838:Genotype; D006801:Humans; D008297:Male; D009373:Neoplasms, Germ Cell and Embryonal / Q000235:genetics* / Q000556:secondary; D016017:Odds Ratio; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011944:Receptors, Androgen / Q000235:genetics*; D012307:Risk Factors; D013548:Sweden; D013736:Testicular Neoplasms / Q000235:genetics*
D011944:Receptors, Androgen