Associations of Luminal and Basal Subtyping of Prostate Cancer With Prognosis and Response to Androgen Deprivation Therapy.
Shuang G. Zhao,S. Laura Chang,Nicholas Erho,Menggang Yu,Jonathan Lehrer,Mohammed Alshalalfa,Corey Speers,Matthew R. Cooperberg,Won Kim,Charles J. Ryan,Robert B. Den,Stephen J. Freedland,Edwin M. Posadas,Howard M. Sandler,Eric A. Klein,Peter C. Black,Roland Seiler,Scott A. Tomlins,Arul M. Chinnaiyan,Robert B. Jenkins,Elai Davicioni,Ashley E. Ross,Edward M. Schaeffer,Paul L. Nguyen,Peter R. Carroll,R. Jeffrey Karnes,Daniel E. Spratt,Felix Y. Feng,Felix Y. Feng +28 more
TLDR
Luminal- and basal-like prostate cancers demonstrate divergent clinical behavior, and patients with luminal B tumors respond better to postoperative ADT than do patients with non–luminal B tumor tumors, contributing novel insight into prostate cancer biology.Abstract:
Importance There is a clear need for a molecular subtyping approach in prostate cancer to identify clinically distinct subgroups that benefit from specific therapies. Objectives To identify prostate cancer subtypes based on luminal and basal lineage and to determine associations with clinical outcomes and response to treatment. Design, Setting, and Participants The PAM50 classifier was used to subtype 1567 retrospectively collected (median follow-up, 10 years) and 2215 prospectively collected prostate cancer samples into luminal- and basal-like subtypes. Main Outcomes and Measures Metastasis, biochemical recurrence, overall survival, prostate cancer–specific survival, associations with biological pathways, and clinicopathologic variables were the main outcomes. Results Among the 3782 samples, the PAM50 classifier consistently segregated prostate cancer into 3 subtypes in both the retrospective and prospective cohorts: luminal A (retrospective, 538 [34.3%]; prospective, 737 [33.3%]), luminal B (retrospective, 447 [28.5%]; prospective, 723 [32.6%]), and basal (retrospective, 582 [37.1%]; prospective, 755 [34.1%]). Known luminal lineage markers, such as NKX3.1 and KRT18 , were enriched in luminal-like cancers, and the basal lineage CD49f signature was enriched in basal-like cancers, demonstrating the connection between these subtypes and established prostate cancer biology. In the retrospective cohort, luminal B prostate cancers exhibited the poorest clinical prognoses on both univariable and multivariable analyses accounting for standard clinicopathologic prognostic factors (10-year biochemical recurrence-free survival [bRFS], 29%; distant metastasis-free survival [DMFS], 53%; prostate cancer-specific survival [PCSS], 78%; overall survival [OS], 69%), followed by basal prostate cancers (10-year bRFS, 39%; DMFS, 73%; PCSS, 86%; OS, 80%) and luminal A prostate cancers (10-year bRFS, 41%; DMFS, 73%; PCSS, 89%; OS, 82%). Although both luminal-like subtypes were associated with increased androgen receptor expression and signaling, only luminal B prostate cancers were significantly associated with postoperative response to androgen deprivation therapy (ADT) in a subset analysis in our retrospective cohorts (n = 315) matching patients based on clinicopathologic variables (luminal B 10-year metastasis: treated, 33% vs untreated, 55%; nonluminal B 10-year metastasis: treated, 37% vs untreated, 21%; P = .006 for interaction). Conclusions and Relevance Luminal- and basal-like prostate cancers demonstrate divergent clinical behavior, and patients with luminal B tumors respond better to postoperative ADT than do patients with non–luminal B tumors. These findings contribute novel insight into prostate cancer biology, providing a potential clinical tool to personalize ADT treatment for prostate cancer by predicting which men may benefit from ADT after surgery.read more
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Journal ArticleDOI
Widespread and Functional RNA Circularization in Localized Prostate Cancer
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TL;DR: Ultra-deep total RNA-seq on 144 tumors with rich clinical annotation revealed a linear transcriptomic subtype associated with the aggressive intraductal carcinoma sub-histology and a fusion profile that differentiates localized from metastatic disease.
Journal ArticleDOI
Recent Advances in Prostate Cancer Treatment and Drug Discovery.
TL;DR: The identification of improved, personalized treatments will be much supported by the major progress recently made in the molecular characterization of early- and late-stage prostate cancer using “omics” technologies, and should greatly help in the choice of novel targeted therapies best tailored to the needs of patients.
Journal ArticleDOI
The DNA methylation landscape of advanced prostate cancer
Shuang G. Zhao,Shuang G. Zhao,William S. Chen,William S. Chen,Haolong Li,Adam Foye,Meng Zhang,Martin Sjöström,Rahul Aggarwal,Denise Playdle,Arnold Liao,Joshi J. Alumkal,Rajdeep Das,Jonathan Chou,Junjie Tony Hua,Travis J. Barnard,Adina M. Bailey,Eric D. Chow,Marc D. Perry,Ha X. Dang,Rendong Yang,Ruhollah Moussavi-Baygi,Li Zhang,Mohammed Alshalalfa,S. Laura Chang,Kathleen E. Houlahan,Kathleen E. Houlahan,Kathleen E. Houlahan,Yu Jia Shiah,Tomasz M. Beer,George Thomas,Kim N. Chi,Martin E. Gleave,Amina Zoubeidi,Robert E. Reiter,Matthew Rettig,Matthew Rettig,Owen N. Witte,M. Yvonne Kim,Lawrence Fong,Daniel E. Spratt,Todd M. Morgan,Rohit Bose,Franklin W. Huang,Hui Li,Lisa N. Chesner,Tanushree R. Shenoy,Hani Goodarzi,Irfan A. Asangani,Shahneen Sandhu,Joshua M. Lang,Nupam P. Mahajan,Primo N. Lara,Christopher P. Evans,Phillip G. Febbo,Serafim Batzoglou,Karen E. Knudsen,Housheng Hansen He,Housheng Hansen He,Jiaoti Huang,Wilbert Zwart,Joseph F. Costello,Jianhua Luo,Scott A. Tomlins,Alexander W. Wyatt,Scott M. Dehm,Alan Ashworth,Luke A. Gilbert,Paul C. Boutros,Paul C. Boutros,Kyle Kai-How Farh,Arul M. Chinnaiyan,Christopher G. Maher,Eric J. Small,David A. Quigley,Felix Y. Feng +75 more
TL;DR: This study identifies genomic regions that are differentially methylated during disease progression and a novel epigenomic subtype and shows that differential methylation during progression preferentially occurs at somatic mutational hotspots and putative regulatory regions.
Journal ArticleDOI
Single-cell analysis reveals transcriptomic remodellings in distinct cell types that contribute to human prostate cancer progression
Sujun Chen,Guanghui Zhu,Yue Yang,Fubo Wang,Yu-Tian Xiao,Na Zhang,Xiaojie Bian,Yasheng Zhu,Yongwei Yu,Fei Liu,Ke-Qin Dong,Javier Mariscal,Yin Liu,Fraser Soares,Helen Loo Yau,Helen Loo Yau,Bo Zhang,Weidong Chen,Chao Wang,Dai Chen,Qinghua Guo,Zhengfang Yi,Mingyao Liu,Michael Fraser,Daniel D. De Carvalho,Daniel D. De Carvalho,Paul C. Boutros,Dolores Di Vizio,Zhou Jiang,Theodorus H. van der Kwast,Alejandro Berlin,Alejandro Berlin,Song Wu,Jianhua Wang,Housheng Hansen He,Housheng Hansen He,Shancheng Ren +36 more
TL;DR: In this paper, the authors have profiled the transcriptomes of 36,424 single cells from 13 prostate tumours and identified the epithelial cells underlying disease aggressiveness. But the transcriptomic heterogeneity of prostate cancer is poorly understood.
Journal ArticleDOI
The Immune Landscape of Prostate Cancer and Nomination of PD-L2 as a Potential Therapeutic Target
Shuang G. Zhao,Jonathan Lehrer,S. Laura Chang,Rajdeep Das,Nicholas Erho,Yang Liu,Martin Sjöström,Robert B. Den,Stephen J. Freedland,Eric A. Klein,R. Jeffrey Karnes,Edward M. Schaeffer,Melody J. Xu,Corey Speers,Paul L. Nguyen,Ashley E. Ross,June M. Chan,Matthew R. Cooperberg,Peter R. Carroll,Elai Davicioni,Lawrence Fong,Daniel E. Spratt,Felix Y. Feng +22 more
TL;DR: The largest study of its kind to date, these results illustrate the complex relationship between the tumor-immune interaction, prognosis, and response to radiotherapy, and nominate PD-L2 as a potential novel therapeutic target in prostate cancer, potentially in combination with radiotherapy.
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