Targeted Next-Generation Sequencing Reveals Heterogenous Genomic Features in Viscerally Metastatic Prostate Cancer

No AccessJournal of UrologyAdult Urology1 Aug 2021Targeted Next-Generation Sequencing Reveals Heterogenous Genomic Features in Viscerally Metastatic Prostate CancerThis article is commented on by the following:Editorial Comment Yiming Gong, Liancheng Fan, Xiaochen Fei, Yinjie Zhu, Xinxing Du, Yuman He, Jiahua Pan, Baijun Dong, and Wei Xue Yiming GongYiming Gong Department of Urology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China Equal study contribution. Financial and/or other relationship with National Natural Science Foundation of China. More articles by this author , Liancheng FanLiancheng Fan Department of Urology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China Equal study contribution. Financial and/or other relationship with National Natural Science Foundation of China. More articles by this author , Xiaochen FeiXiaochen Fei Department of Urology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China Equal study contribution. Financial and/or other relationship with National Institutes of Health (NIH). More articles by this author , Yinjie ZhuYinjie Zhu Department of Urology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China Financial and/or other relationship with National Natural Science Foundation of China. More articles by this author , Xinxing DuXinxing Du Department of Urology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China Financial and/or other relationship with National Natural Science Foundation of China. More articles by this author , Yuman HeYuman He State Key Laboratory of Oncogenes and Related Genes, Renji-Med-X Stem Cell Research Center, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China Financial and/or other relationship with National Institutes of Health (NIH). More articles by this author , Jiahua PanJiahua Pan Department of Urology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China Financial and/or other relationship with National Natural Science Foundation of China. More articles by this author , Baijun DongBaijun Dong §Correspondence: School of Medicine, Shanghai Jiao Tong University, Ren Ji Hospital, 160 Pujian Rd., Shanghai200127, China telephone: 86-21-68383917; FAX: 86-21-68383916; E-mail Address: [email protected] Department of Urology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China Financial and/or other relationship with National Natural Science Foundation of China. More articles by this author , and Wei XueWei Xue § E-mail Address: [email protected] Department of Urology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China Financial and/or other relationship with National Institutes of Health (NIH). More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000001731AboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract Purpose: We sought to explore the genomic features of bone-only metastasis, hepatic metastasis and pulmonary metastasis without liver involvement in prostate cancer using targeted next-generation sequencing. Materials and Methods: A hybridization capture-based next-generation sequencing was performed to detected genomic alterations in 50 genes, including androgen receptor, DNA damage response and other clinical relevant drivers. Results: We successfully sequenced circulating tumor DNA from 109 blood samples and 29 metastatic tissue samples from 129 patients with metastatic castration-resistant prostate cancer (metastatic castration-resistant prostate cancer). We observed distinct genomic profiles of metastatic castration-resistant prostate cancer across various metastatic sites. High prevalence of PTEN alteration was found in viscerally metastatic prostate cancer compared with bone-only metastatic prostate cancer (PTEN, 9.09% vs 2.08%, p=0.105). When comparing viscerally metastatic prostate cancer according to the metastatic sites, AR alteration rarely occurs in hepatically metastatic prostate cancer, which stood in great contrast to the high alteration frequency in hepatically metastatic prostate cancer (0.0% vs 42.1%, p=0.01). For overall DNA damage response alteration, the highest frequency was found in hepatically metastatic prostate cancer (63.2%). Conclusions: Through genomic profiling of prostate cancer across various metastatic sites, we identified an extremely low frequency of AR alterations in pulmonarily metastatic prostate cancer without liver involvement, high prevalence of DNA damage response pathway deficiency in hepatically metastatic prostate cancer and high PTEN alteration rates in viscerally metastatic prostate cancer. We discovered the genomic diversity among bone-only metastatic prostate cancer, hepatically metastatic prostate cancer and pulmonarily metastatic prostate cancer without liver involvement. Our findings shed new light on the heterogenous prognosis in visceral metastases and hint at potential therapeutic targets in both hepatically metastatic prostate cancer and pulmonarily metastatic prostate cancer without liver involvement. References 1. : Metastatic prostate cancer. N Engl J Med 2018; 378: 645. Google Scholar 2. : Distribution of metastatic sites in patients with prostate cancer: a population-based analysis. Prostate 2014; 74: 210. Google Scholar 3. : Visceral disease in castration-resistant prostate cancer. Eur Urol 2014; 65: 270. Google Scholar 4. : The prognostic importance of metastatic site in men with metastatic castration-resistant prostate cancer. Eur Urol 2014; 65: 3. Google Scholar 5. : Enzalutamide in castration-resistant prostate cancer patients with visceral disease in the liver and/or lung: outcomes from the randomized controlled phase 3 AFFIRM trial. Cancer 2017; 123: 253. Google Scholar 6. : Impact of the site of metastases on survival in patients with metastatic prostate cancer. Eur Urol 2015; 68: 325. Google Scholar 7. : Meta-analysis evaluating the impact of site of metastasis on overall survival in men with castration-resistant prostate cancer. J Clin Oncol 2016; 34: 1652. Google Scholar 8. : Effect of visceral disease site on outcomes in patients with metastatic castration-resistant prostate cancer treated with enzalutamide in the PREVAIL trial. Clin Genitourin Cancer 2017; 15: 610. Google Scholar 9. : Enzalutamide in metastatic prostate cancer before chemotherapy. N Engl J Med 2014; 371: 424. Google Scholar 10. : Integrative clinical genomics of advanced prostate cancer. Cell 2015; 161: 1215. Google Scholar 11. : Genomics of lethal prostate cancer at diagnosis and castration resistance. J Clin Invest 2020; 130: 1743. Google Scholar 12. : The genomic landscape of metastatic castration-resistant prostate cancers reveals multiple distinct genotypes with potential clinical impact. Nat Commun 2019; 10: 5251. Google Scholar 13. : The mutational landscape of lethal castration-resistant prostate cancer. Nature 2012; 487: 239. Google Scholar 14. : Novel biomarker signature that may predict aggressive disease in African American men with prostate cancer. J Clin Oncol 2015; 33: 2789. Google Scholar 15. : Association of prostate cancer risk with genetic polymorphisms in vitamin D receptor and androgen receptor. J Natl Cancer Inst 1997; 89: 166. Google Scholar 16. : PROREPAIR-B: a prospective cohort study of the impact of germline DNA repair mutations on the outcomes of patients with metastatic castration-resistant prostate cancer. J Clin Oncol 2019; 37: 490. Google Scholar 17. : Genomic drivers of poor prognosis and enzalutamide resistance in metastatic castration-resistant prostate cancer. Eur Urol 2019; 76: 562. Google Scholar 18. : Abiraterone acetate for metastatic prostate cancer in patients with suboptimal biochemical response to hormone induction. JAMA Oncol 2017; 3: e170231. Google Scholar 19. : Olaparib for metastatic castration-resistant prostate cancer. N Engl J Med 2020; 382: 2091. Google Scholar 20. : DNA-repair defects and olaparib in metastatic prostate cancer. N Engl J Med 2015; 373: 1697. Google Scholar 21. : Pan-cancer analysis of CDK12 alterations identifies a subset of prostate cancers with distinct genomic and clinical characteristics. Eur Urol 2020; 78: 671. Google Scholar 22. : Concordance of circulating tumor DNA and matched metastatic tissue biopsy in prostate cancer. J Natl Cancer Inst 2017; 109: djx118. Google Scholar 23. : Androgen receptor burden and poor response to abiraterone or enzalutamide in TP53 wild-type metastatic castration-resistant prostate cancer. JAMA Oncol 2019; 5: 1060. Google Scholar 24. : Genomic alterations in cell-free DNA and enzalutamide resistance in castration-resistant prostate cancer. JAMA Oncol 2016; 2: 1598. Google Scholar 25. : DNA damage repair deficiency in prostate cancer. Trends Cancer 2020; 6: 974. Google Scholar 26. : Platinum-based chemotherapy in metastatic prostate cancer with DNA repair gene alterations. JCO Precis Oncol 2020; 4: 355. Google Scholar 27. : Clinical features and therapeutic outcomes in men with advanced prostate cancer and DNA mismatch repair gene mutations. Eur Urol 2019; 75: 378. Google Scholar 28. : Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade. Science 2017; 357: 409. Google Scholar 29. : Clinical implications of PTEN loss in prostate cancer. Nat Rev Urol 2018; 15: 222. Google Scholar 30. : Targeting the PI3K/AKT pathway for the treatment of prostate cancer. Clin Cancer Res 2009; 15: 4799. Google Scholar Support: This study was supported by funds to Department of Urology, Ren Ji hospital from the National Natural Science Foundation of China (81772742, 81672850), Youth Program of National Natural Science Foundation of China (82002710), Shanghai Municipal Education Commission-Gaofeng Clinical Medicine Grant Support (20191906); Shanghai Sailing Program (20YF1425300). © 2021 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetailsRelated articlesJournal of UrologyMay 10, 2021, 12:00:00 AMEditorial Comment Volume 206Issue 2August 2021Page: 279-288Supplementary Materials Advertisement Copyright & Permissions© 2021 by American Urological Association Education and Research, Inc.Keywordsreceptorsprostatic neoplasmsandrogenAcknowledgmentsWe thank Fangqin Wang, Chunhe Yang and Yining Yang, who gave strong support to the present study.MetricsAuthor Information Yiming Gong Department of Urology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China Equal study contribution. Financial and/or other relationship with National Natural Science Foundation of China. More articles by this author Liancheng Fan Department of Urology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China Equal study contribution. Financial and/or other relationship with National Natural Science Foundation of China. More articles by this author Xiaochen Fei Department of Urology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China Equal study contribution. Financial and/or other relationship with National Institutes of Health (NIH). More articles by this author Yinjie Zhu Department of Urology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China Financial and/or other relationship with National Natural Science Foundation of China. More articles by this author Xinxing Du Department of Urology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China Financial and/or other relationship with National Natural Science Foundation of China. More articles by this author Yuman He State Key Laboratory of Oncogenes and Related Genes, Renji-Med-X Stem Cell Research Center, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China Financial and/or other relationship with National Institutes of Health (NIH). More articles by this author Jiahua Pan Department of Urology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China Financial and/or other relationship with National Natural Science Foundation of China. More articles by this author Baijun Dong Department of Urology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China §Correspondence: School of Medicine, Shanghai Jiao Tong University, Ren Ji Hospital, 160 Pujian Rd., Shanghai200127, China telephone: 86-21-68383917; FAX: 86-21-68383916; E-mail Address: [email protected] Financial and/or other relationship with National Natural Science Foundation of China. More articles by this author Wei Xue Department of Urology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China § E-mail Address: [email protected] Financial and/or other relationship with National Institutes of Health (NIH). More articles by this author Expand All Support: This study was supported by funds to Department of Urology, Ren Ji hospital from the National Natural Science Foundation of China (81772742, 81672850), Youth Program of National Natural Science Foundation of China (82002710), Shanghai Municipal Education Commission-Gaofeng Clinical Medicine Grant Support (20191906); Shanghai Sailing Program (20YF1425300). Advertisement Loading ...