title: Profiling genetic variation along the androgen biosynthesis and metabolism pathways implicates several single nucleotide polymorphisms and their combinations as prostate cancer risk factors.
abstract: Several candidate genes along androgen pathway have been suggested to affect prostate cancer risk but no single gene seems to be overwhelmingly important for a large fraction of the patients. In this study, we first screened for variants in candidate genes and then chose to explore the association between 18 variants and prostate cancer risk by genotyping DNA samples from unselected (n = 847) and familial (n = 121) prostate cancer patients and population controls (n = 923). We identified a novel single nucleotide polymorphism (SNP) in the CYP19A1 gene, T201M, with a mild significant association with prostate cancer [odds ratio (OR), 2.04; 95% confidence interval (95% CI), 1.03-4.03; P = 0.04]. Stratified analysis revealed that this risk was most apparent in patients with organ-confined (T(1)-T(2)) and low-grade (WHO grade 1) tumors (OR, 5.42; 95% CI, 2.33-12.6; P < 0.0001). In contrast, CYP17A1 -34T>C alteration was associated with moderate to poorly differentiated (WHO grade 2-3) organ-confined disease (OR, 1.42; 95% CI, 1.09-1.83; P = 0.007). We also tested a multigenic model of prostate cancer risk by calculating the joint effect of CYP19A1 T201M with five other common SNPs. Individuals carrying both the CYP19A1 and KLK3 -252A>G variant alleles had a significantly increased risk for prostate cancer (OR, 2.87; 95% CI, 1.10-7.49; P = 0.03). In conclusion, our results suggest that several SNPs along the androgen pathway, especially in CYP19A1 and CYP17A1, may influence prostate cancer development and progression. These genes may have different contributions to distinct clinical subsets as well as combinatorial effects in others illustrating that profiling and joint analysis of several genes along each pathway may be needed to understand genetic contributions to prostate cancer etiology.
authors.affiliation: Laboratory of Cancer Genetics, Institute of Medical Technology, University of Tampere and Tampere University Hospital, Tampere FIN-33014, Finland.
authors.forename: Nina
authors.initials: N
authors.lastname: Mononen
authors.forename: Eija H
authors.initials: EH
authors.lastname: Seppälä
authors.forename: Priya
authors.initials: P
authors.lastname: Duggal
authors.forename: Ville
authors.initials: V
authors.lastname: Autio
authors.forename: Tarja
authors.initials: T
authors.lastname: Ikonen
authors.forename: Pekka
authors.initials: P
authors.lastname: Ellonen
authors.forename: Juha
authors.initials: J
authors.lastname: Saharinen
authors.forename: Janna
authors.initials: J
authors.lastname: Saarela
authors.forename: Mauno
authors.initials: M
authors.lastname: Vihinen
authors.forename: Teuvo L J
authors.initials: TL
authors.lastname: Tammela
authors.forename: Olli
authors.initials: O
authors.lastname: Kallioniemi
authors.forename: Joan E
authors.initials: JE
authors.lastname: Bailey-Wilson
authors.forename: Johanna
authors.initials: J
authors.lastname: Schleutker
mesh_terms: D000368:Aged; D000728:Androgens / Q000096:biosynthesis*; D001141:Aromatase / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D008875:Middle Aged; D016017:Odds Ratio; D020641:Polymorphism, Single Nucleotide; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000503:physiopathology; D012307:Risk Factors; D013254:Steroid 17-alpha-Hydroxylase / Q000235:genetics*
chemical_list: D000728:Androgens; D001141:Aromatase; D013254:Steroid 17-alpha-Hydroxylase