Adiponectin Receptor 2 Expression Predicts Lethal Prostate Cancer.
Jennifer R Stark, Stephen P Finn, Jing Ma, Jennifer A Sinnott, Fredrick Schumacher, Rosina Lis, Kathryn L Penney, Julie L Kasperzyk, Howard D Sesso, Meir J Stampfer, Edward L Giovannucci, Massimo Loda, Lorelei A Mucci. Brigham and Women's Hospital, Boston, MA; University of Dublin, Trinity College, Dublin, Ireland; Harvard School of Public Health, Boston, MA; UCLA Keck School of Medicine, Los Angeles, CA; Dana-Farber Cancer Institute, Boston, MA
Background: We previously showed that adiponectin, an adipokine, is inversely associated with adiposity and prostate cancer (PCa) risk and progression. Polymorphisms in ADIPOQ, the gene encoding adiponectin, are associated with PCa risk and plasma adiponectin levels. Little is known about the role of adiponectin or its receptors locally in the prostate. We assessed adiponectin receptor 2 (ADIPOR2) tumor expression, as well as genetic variation in ADIPOQ and in adiponectin receptor genes ADIPOR1 and ADIPOR2 with respect to PCa survival.
Design: Using TMAs from 753 archival prostatectomy specimens from men in the Physicians' Health Study (PHS) and Health Professionals Follow-up Study, we semi-quantitatively scored tumor expression of ADIPOR2 protein by immunohistochemistry. Among 1286 cases from PHS we evaluated 29 common SNPs in ADIPOQ, ADIPOR1 and ADIPOR2. We related genotype and ADIPOR2 expression with development of lethal PCa during 25 years of follow-up using Cox proportional hazards models. Using ANOVA, we also evaluated each genotype in relation to tumor expression of ADIPOR2 for a subset of 180 cases.
Results: Men with greater waist circumference had increased tumor expression of ADIPOR2. ADIPOR2 expression was positively associated with Gleason score (p=0.05) and Ki67 expression (p=0.001). Controlling for age at diagnosis, Gleason, Ki67 expression and BMI, hazard ratios (HR) for lethal PCa comparing cases in the 3rd and 4th quartiles of ADIPOR2 expression to those in the lowest quartile were 5.5 (95% CI. 1.7 -18.9) and 3.8 (95% CI: 1.1-13.3), respectively. Two of 29 polymorphisms evaluated, one in ADIPOR1 (rs16850799) and one in ADIPOR2 (rs1044471), were significantly associated with time to lethal PCa. For ADIPOR2 rs1044471, HRs compared to wildtype homozygotes were 0.6 (95% CI: 0.4, 0.9) for heterozygotes and 0.8 (95% CI: 0.6, 1.2) for rare homozygotes (likelihood ratio p=0.03). Variant carriers of ADIPOR2 rs1044471 had significantly lower ADIPOR2 expression (p-trend=0.02).
Conclusions: ADIPOR2 predicts lethal PCa independently of other prognostic markers. Variant allele status in ADIPOR2 rs1044471 predicted ADIPOR2 expression levels and lethal PCa in the anticipated direction. Our work suggests a role of germ-line variation in adiponectin and its receptors, circulating adiponectin levels, and local prostatic expression of ADIPOR2 in aggressive PCa.
Category: Genitourinary (including renal tumors)
Tuesday, March 1, 2011 2:30 PM
Platform Session: Section A, Tuesday Afternoon