耿俊閎1,2,3,4, 張哲維2,3,4, Anna Plym1,6,8, Mark Pomerantz5, Kathryn L. Penney6,7, Junaid Nabi1, Christopher Sweeney5, Lorelei A. Mucci6,7, Adam S. Kibel1
高雄市市立小港醫院 泌尿部2 ；高雄醫學大學附設醫院 泌尿部3
Inherited variants of adiponectin and its receptors are associated with the time to castration-resistant prostate cancer
Jiun-Hung Geng1,2,3,4, Che-Wei Chang2,3,4, Anna Plym1,6,8, Mark Pomerantz5, Kathryn L. Penney6,7, Junaid Nabi1, Christopher Sweeney5, Lorelei A. Mucci6,7, Adam S. Kibel1
1 Division of Urological Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA, 2 Department of Urology, Kaohsiung Municipal Hsiao-Kang Hospital, Kaohsiung, Taiwan, 3 Department of Urology, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan, 4 Kaohsiung Medical University, Kaohsiung, Taiwan, 5 Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, 6 Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, 7 Channing Division of Network Medicine, Harvard Medical School and Brigham & Women's Hospital, Boston, Massachusetts, 8 Department of Medical Epidemiology and Biostatistics, Karolinska Institute, Stockholm, Sweden
Purpose: Metabolic syndrome traits play an important role in the progression of prostate cancer. Adiponectin and its receptors, key metabolic syndrome cellular mediators, contribute to tumor invasiveness. However, the association between genetic variants of adiponectin and its receptors with clinical outcomes in prostate cancer (PCa) patients receiving androgen deprivation therapy (ADT) has not been determined.
Materials and Methods: We used a tagging single nucleotide polymorphisms (SNPs) approach to select 11 genetic variants for the investigation of the genetic variability in adiponectin, adiponectin receptor 1 (ADIPOR1) and adiponectin receptor 2 (ADIPOR2) to study in 416 metastatic hormone sensitive PCa patients receiving first line ADT from 1996 to 2013. Multivariable Cox proportional hazards regression adjusting for known prognostic factors estimated the association of these genetic variants with time to CRPC, defined as the duration between initiating ADT and PCWG3 definition of CRPC. To access the functional roles of the associated SNPs, we used the Genotype-Tissue Expression (GTEx) database to examine the correlations between SNPs and gene expression levels in human prostate tissues. To further validate our findings, the association between ADIPOR2 expression and overall survival in PCa patients was analyzed by using data from The Cancer Genome Atlas (TCGA).
Results: Two of 5 SNPs within ADIPOR2 rs11061974 and rs11061973 were significantly associated with time to CRPC after adjusted for age at ADT initiation, prostate specific antigen (PSA) at ADT initiation, biopsy Gleason score at diagnosis, M stage at ADT initiation, PSA nadir, time to PSA nadir and treatment modality (P value=0.006 and 0.013 respectively). A gene-dosage effect on ADT response was found when two genetic loci of interest were analyzed in combination, with the hazards ratio increasing as the number of risk alleles increased (p for trend = 0.0004). Supporting the role of these genes in PCa progression, the GTEx database revealed a significant trend toward increased ADIPOR2 mRNA expression in the prostate tissues of rs11061974 risk allele. In addition, analysis of TCGA expression demonstrated a correlation with worse patient overall survival.
Conclusion: Genetic variation within ADIPOR2 has a potential value to improve outcome prediction in prostate cancer patients receiving ADT.