轉移性攝護腺癌接受荷爾蒙治療反應之全基因組關聯分析
耿俊閎1,2,3,4、李明儒2,3,4、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高雄市立小港醫院 泌尿部；3高雄醫學大學附設醫院 泌尿部；4高雄醫學大學；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 Institutet, Stockholm, Sweden
Genome-wide association study (GWAS) of response to androgen deprivation therapy (ADT) in metastatic prostate cancer (PCa).
Jiun-Hung Geng1,2,3,4、Ming-Ru Lee,2,3,4、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 Institutet, Stockholm, Sweden
Purpose: Inherited genetic factors are among the variables influencing prostate cancer (PCa) outcome and response to treatment. We conducted a genome-wide association study (GWAS) to identify germline genetic polymorphisms associated with time to castration resistance prostate cancer (CRPC) from starting androgen deprivation therapy (ADT).
Materials and Methods: DNA isolated from blood from 1,048 subjects with metastatic hormone-sensitive PCa were genotyped for approximately one million single nucleotide polymorphisms (SNPs) with minor allele frequency ≥ 0.05 (1,037 samples with call rate > 85%). The 416 patients treated with ADT alone for metastatic disease were included in this study. An additional 80 million SNPs per sample were imputed using data from the 1000 Genomes Project. Time to CRPC was defined as the duration between initiating ADT and PCWG3 definition of CRPC.
Results: Median time to CRPC from start of ADT was 18.4 months. We identified ten novel susceptibility loci reaching a genome-wide threshold of P < 5.0x10−8. The SNPs most highly associated with time to CRPC were polymorphisms residing in intronic regions of the genes VAV2 (p-value, 1.5x10-9) and EYA2 (p-value, 1.5x10-8).
Conclusion: Our preliminary data identified ten loci near VAV2 and EYA2, on 9q34.2 and 20q13.12 respectively, are associated with duration of ADT response in metastatic PCa patients. Reproducibility needs to be assessed in an independent cohort. Proven associations with ADT response will provide novel insights into ADT resistance as well as potential clinical biomarkers.