title: Regulatory BCL2 promoter polymorphism (-938C>A) is associated with adverse outcome in patients with prostate carcinoma.
abstract: Molecular markers predictive of prostate cancer prognosis are urgently needed. Overexpression of the antiapoptotic protein, Bcl-2, has repeatedly been shown to be associated with adverse outcome in this malignancy. We hypothesized that a regulatory BCL2 -938C>A promoter polymorphism, which significantly affects promoter activity and Bcl-2 expression in different malignancies, may influence survival. Reporter assays and electrophoretic mobility shift assays reveled that the -938C>A BCL2 promoter polymorphism significantly affects promoter activity and transcription factor binding in prostate cancer cells. Significantly higher BCL2 mRNA expression was observed in primary prostate carcinomas derived from patients with the AA, compared to CC, genotype. Survival analysis showed that the -938AA genotype was an independent, unfavorable prognostic factor for relapse-free survival in a primary cohort of 142 patients and in an independent replication cohort of 148 patients, with hazard ratios (HR) of 4.4 (95% CI, 1.3-15.1; p = 0.018) and 4.6 (95% CI, 1.5-14.2; p = 0.009). Furthermore, the -938AA genotype was independently associated with worse overall survival in the replication series, with a HR of 10.9 (95% CI, 1.2-99.3; p = 0.034). We conclude that the BCL2 -938C>A polymorphism is an independent predictor of relapse-free and overall survival in patients with prostate cancer. The BCL2 -938C>A polymorphism should be evaluated prospectively and may also have promise in assisting optimal patient choice for treatment with BCL2-targeted drugs already in evaluation for prostate cancer treatment.
authors.affiliation: Institute of Pharmacogenetics, University Hospital Essen, Hufelandstr. 55, 45122 Essen, Germany.
authors.forename: Hagen S
authors.initials: HS
authors.lastname: Bachmann
authors.forename: Lukas C
authors.initials: LC
authors.lastname: Heukamp
authors.forename: Klaus J
authors.initials: KJ
authors.lastname: Schmitz
authors.forename: Caroline F
authors.initials: CF
authors.lastname: Hilburn
authors.forename: Philip
authors.initials: P
authors.lastname: Kahl
authors.forename: Reinhard
authors.initials: R
authors.lastname: Buettner
authors.forename: Holger
authors.initials: H
authors.lastname: Nückel
authors.forename: Andreas
authors.initials: A
authors.lastname: Eisenhardt
authors.forename: Herbert
authors.initials: H
authors.lastname: Rübben
authors.forename: Kurt Werner
authors.initials: KW
authors.lastname: Schmid
authors.forename: Winfried
authors.initials: W
authors.lastname: Siffert
authors.forename: Angelika
authors.initials: A
authors.lastname: Eggert
authors.forename: Alexander
authors.initials: A
authors.lastname: Schramm
authors.forename: Johannes H
authors.initials: JH
authors.lastname: Schulte
mesh_terms: D000368:Aged; D045744:Cell Line, Tumor; D018572:Disease-Free Survival; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D011379:Prognosis; D011401:Promoter Regions, Genetic; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000401:mortality; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics* / Q000378:metabolism
chemical_list: D019253:Proto-Oncogene Proteins c-bcl-2