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203. A Novel Role for DNA-PK in Metabolism by Regulating Glycolysis in Castration Resistant Prostate Cancer

Author

Dylgjeri, Emanuela, Kothari, Vishal, Shafi, Ayesha A, Semenova, Galina, Gallagher, Peter T, Guan, Yi Fang, Pang, Angel, Goodwin, Jonathan F, Irani, Swati, McCann, Jennifer J, Mandigo, Amy C, Chand, Saswati, McNair, Christopher M, Vasilevskaya, Irina, Schiewer, Matthew J, Lallas, Costas D, McCue, Peter A, Gomella, Leonard G, Seifert, Erin L, Carroll, Jason S, Butler, Lisa M, Holst, Jeff, Kelly, William K, Knudsen, Karen E, Carroll, Jason [0000-0003-3643-0080], and Apollo - University of Cambridge Repository

Subjects
Male, Proteomics, Prostatic Neoplasms, Castration-Resistant, Pyruvate Kinase, Humans, DNA, DNA-Activated Protein Kinase, Glycolysis
Abstract

PURPOSE: DNA-dependent kinase catalytic subunit (DNA-PKcs, herein referred as DNA-PK) is a multifunctional kinase of high cancer relevance. DNA-PK is deregulated in multiple tumor types, including prostate cancer (PCa), and is associated with poor outcomes. DNA-PK was previously nominated as a therapeutic target and DNA-PK inhibitors are currently undergoing clinical investigation. While DNA-PK is well studied in DNA repair and transcriptional regulation, much remains to be understood about the way by which DNA-PK drives aggressive disease phenotypes. EXPERIMENTAL DESIGN: Here, unbiased proteomic and metabolomic approaches in clinically relevant tumor models uncovered a novel role of DNA-PK in metabolic regulation of cancer progression. DNA-PK regulation of metabolism was interrogated using pharmacological and genetic perturbation using in vitro cell models, in vivo xenografts, and ex vivo in patient-derived explants (PDE). RESULTS: Key findings reveal: i) the first-in-field DNA-PK protein-protein interactome; ii) numerous DNA-PK novel partners involved in glycolysis, iii) DNA-PK interacts with, phosphorylates (in vitro) and increases the enzymatic activity of glycolytic enzymes ALDOA and PKM2, iv) DNA-PK drives synthesis of glucose-derived pyruvate and lactate, v) DNA-PK regulates glycolysis in vitro, in vivo and ex vivo, and vi) combination of DNA-PK inhibitor with glycolytic inhibitor 2-deoxyglucose leads to additive anti-proliferative effects in aggressive disease. CONCLUSIONS: Findings herein unveil novel DNA-PK partners, substrates, and function in PCa. The role of DNA-PK impacts glycolysis through direct interaction with glycolytic enzymes and modulation of enzymatic activity. These events support energy production that may contribute to generation and/or maintenance of DNA-PK-mediated aggressive disease phenotypes.

Published
2022
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206. Patient-Level DNA Damage and Repair Pathway Profiles and Prognosis After Prostatectomy for High-Risk Prostate Cancer

Author

Evans, Joseph R., Zhao, Shuang G., Chang, S. Laura, Tomlins, Scott A., Erho, Nicholas, Sboner, Andrea, Schiewer, Matthew J., Spratt, Daniel E., Kothari, Vishal, Klein, Eric A., Den, Robert B., Dicker, Adam P., Karnes, R. Jeffrey, Yu, Xiaochun, Nguyen, Paul L., Rubin, Mark A., de Bono, Johann, Knudsen, Karen E., Davicioni, Elai, and Feng, Felix Y.

Published
2016
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208. A Novel Role for DNA-PK in Metabolism by Regulating Glycolysis in Castration-Resistant Prostate Cancer

Author

Dylgjeri, Emanuela, primary, Kothari, Vishal, additional, Shafi, Ayesha A., additional, Semenova, Galina, additional, Gallagher, Peter T., additional, Guan, Yi F., additional, Pang, Angel, additional, Goodwin, Jonathan F., additional, Irani, Swati, additional, McCann, Jennifer J., additional, Mandigo, Amy C., additional, Chand, Saswati, additional, McNair, Christopher M., additional, Vasilevskaya, Irina, additional, Schiewer, Matthew J., additional, Lallas, Costas D., additional, McCue, Peter A., additional, Gomella, Leonard G., additional, Seifert, Erin L., additional, Carroll, Jason S., additional, Butler, Lisa M., additional, Holst, Jeff, additional, Kelly, William K., additional, and Knudsen, Karen E., additional

Published
2022
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212. Mutant p53 elicits context-dependent pro-tumorigenic phenotypes

Author

McCann, Jennifer J., primary, Vasilevskaya, Irina A., additional, McNair, Christopher, additional, Gallagher, Peter, additional, Neupane, Neermala Poudel, additional, de Leeuw, Renée, additional, Shafi, Ayesha A., additional, Dylgjeri, Emanuela, additional, Mandigo, Amy C., additional, Schiewer, Matthew J., additional, and Knudsen, Karen E., additional

Published
2021
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213. Novel Oncogenic Transcription Factor Cooperation in RB-Deficient Cancer

Author

Mandigo, Amy C., primary, Shafi, Ayesha A., additional, McCann, Jennifer J., additional, Yuan, Wei, additional, Laufer, Talya S., additional, Bogdan, Denisa, additional, Gallagher, Lewis, additional, Dylgjeri, Emanuela, additional, Semenova, Galina, additional, Vasilevskaya, Irina A., additional, Schiewer, Matthew J., additional, McNair, Chris M., additional, de Bono, Johann S., additional, and Knudsen, Karen E., additional

Published
2021
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214. Convergence of oncogenic and hormone receptor pathways promotes metastatic phenotypes

Author

Augello, Michael A., Burd, Craig J., Birbe, Ruth, McNair, Christopher, Ertel, Adam, Magee, Michael S., Frigo, Daniel E., Wilder-Romans, Kari, Shilkrut, Mark, Han, Sumin, Jernigan, Danielle L., Dean, Jeffry L., Fatatis, Alessandro, McDonnell, Donald P., Visakorpi, Tapio, Feng, Felix Y., and Knudsen, Karen E.

Subjects
Research, Transcription (Genetics) -- Research, Tumors -- Research, Cancer metastasis -- Research, Metastasis -- Research, Genetic transcription -- Research
Abstract

Cyclin D1b is a splice variant of the cell cycle regulator cyclin D1 and is known to harbor divergent and highly oncogenic functions in human cancer. While cyclin D1b is [...]

Published
2013
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217. The retinoblastoma tumor suppressor controls androgen signaling and human prostate cancer progression

Author

Sharma, Ankur, Yeow, Wen-Shuz, Ertel, Adam, Coleman, Ilsa, Clegg, Nigel, Thangavel, Chellappagounder, Morrissey, Colm, Zhang, Xiaotun, Comstock, Clay E.S., Witkiewicz, Agnieszka K., Gomella, Leonard, Knudsen, Erik S., Nelson, Peter S., and Knudsen, Karen E.

Subjects
Identification and classification, Care and treatment, Development and progression, Genetic aspects, Properties, Retinoblastoma -- Development and progression -- Care and treatment, Tumor suppressor genes -- Identification and classification, Prostate cancer -- Development and progression -- Care and treatment, Cellular signal transduction -- Genetic aspects, Androgens -- Properties
Abstract

Introduction Retinoblastoma (RB; encoded by RB1), a tumor suppressor protein, is a critical negative regulator of tumor development. RB prevents tumorigenesis by suppressing cell cycle progression (1). However, the role [...], Retinoblastoma (RB; encoded by RB1) is a tumor suppressor that is frequently disrupted in tumorigenesis and acts in multiple cell types to suppress cell cycle progression. The role of RB in tumor progression, however, is poorly defined. Here, we have identified a critical role for RB in protecting against tumor progression through regulation of targets distinct from cell cycle control. In analyses of human prostate cancer samples, RB loss was infrequently observed in primary disease and was predominantly associated with transition to the incurable, castration-resistant state. Further analyses revealed that loss of the RB1 locus may be a major mechanism of RB disruption and that loss of RB function was associated with poor clinical outcome. Modeling of RB dysfunction in vitro and in vivo revealed that RB controlled nuclear receptor networks critical for tumor progression and that it did so via E2F transcription factor 1-mediated regulation of androgen receptor (AR) expression and output. Through this pathway, RB depletion induced unchecked AR activity that underpinned therapeutic bypass and tumor progression. In agreement with these findings, disruption of the RB/E2F/nuclear receptor axis was frequently observed in the transition to therapy resistance in human disease. Together, these data reveal what we believe to be a new paradigm for RB function in controlling prostate tumor progression and lethal tumor phenotypes.

Published
2010
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219. Differential expression of αVβ3 and αVβ6 integrins in prostate cancer progression

Author

Quaglia, Fabio, Krishn, Shiv Ram, Wang, Yanqing, Goodrich, David W., McCue, Peter, Kossenkov, Andrew V., Mandigo, Amy C., Knudsen, Karen E., Weinreb, Paul H., Corey, Eva, Kelly, William K., and Languino, Lucia R.

Subjects
Male, Integrins, Retinoblastoma Protein, Lung and Intrathoracic Tumors, Metastasis, Mice, Basic Cancer Research, Medicine and Health Sciences, Prostate Cancer, Genetically Modified Organisms, Prostate Diseases, Prostate, Animal Models, Extracellular Matrix, Gene Expression Regulation, Neoplastic, Oncology, Experimental Organism Systems, Disease Progression, Engineering and Technology, Medicine, Cellular Structures and Organelles, Anatomy, Genetic Engineering, Research Article, Biotechnology, Urology, Science, Synaptophysin, Mice, Nude, Mouse Models, Bioengineering, Mice, Transgenic, Adenocarcinoma, Research and Analysis Methods, Model Organisms, Exocrine Glands, Antigens, Neoplasm, Cell Line, Tumor, Cell Adhesion, Animals, Humans, Genetically Modified Animals, Biology and Life Sciences, Cancers and Neoplasms, Prostatic Neoplasms, Cell Biology, Integrin alphaVbeta3, Genitourinary Tract Tumors, Disease Models, Animal, Animal Studies, Prostate Gland, Tumor Suppressor Protein p53, Neoplasm Transplantation
Abstract

Neuroendocrine prostate cancer (NEPrCa) arises de novo or after accumulation of genomic alterations in pre-existing adenocarcinoma tumors in response to androgen deprivation therapies. We have provided evidence that small extracellular vesicles released by PrCa cells and containing the αVβ3 integrin promote neuroendocrine differentiation of PrCa in vivo and in vitro. Here, we examined αVβ3 integrin expression in three murine models carrying a deletion of PTEN (SKO), PTEN and RB1 (DKO), or PTEN, RB1 and TRP53 (TKO) genes in the prostatic epithelium; of these three models, the DKO and TKO tumors develop NEPrCa with a gene signature comparable to those of human NEPrCa. Immunostaining analysis of SKO, DKO and TKO tumors shows that αVβ3 integrin expression is increased in DKO and TKO primary tumors and metastatic lesions, but absent in SKO primary tumors. On the other hand, SKO tumors show higher levels of a different αV integrin, αVβ6, as compared to DKO and TKO tumors. These results are confirmed by RNA-sequencing analysis. Moreover, TRAMP mice, which carry NEPrCa and adenocarcinoma of the prostate, also have increased levels of αVβ3 in their NEPrCa primary tumors. In contrast, the αVβ6 integrin is only detectable in the adenocarcinoma areas. Finally, analysis of 42 LuCaP patient-derived xenografts and primary adenocarcinoma samples shows a positive correlation between αVβ3, but not αVβ6, and the neuronal marker synaptophysin; it also demonstrates that αVβ3 is absent in prostatic adenocarcinomas. In summary, we demonstrate that αVβ3 integrin is upregulated in NEPrCa primary and metastatic lesions; in contrast, the αVβ6 integrin is confined to adenocarcinoma of the prostate. Our findings suggest that the αVβ3 integrin, but not αVβ6, may promote a shift in lineage plasticity towards a NE phenotype and might serve as an informative biomarker for the early detection of NE differentiation in prostate cancer.

Published
2021

221. Novel strategy for disease risk prediction incorporating predicted gene expression and DNA methylation data: a multi‐phased study of prostate cancer

Author

Wu, Chong, primary, Zhu, Jingjing, additional, King, Austin, additional, Tong, Xiaoran, additional, Lu, Qing, additional, Park, Jong Y., additional, Wang, Liang, additional, Gao, Guimin, additional, Deng, Hong‐Wen, additional, Yang, Yaohua, additional, Knudsen, Karen E., additional, Rebbeck, Timothy R., additional, Long, Jirong, additional, Zheng, Wei, additional, Pan, Wei, additional, Conti, David V., additional, Haiman, Christopher A, additional, and Wu, Lang, additional

Published
2021
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223. Abstract 2362: Long non-coding RNA NORAD interaction with miR-346 impacts DNA damage response and anti-tumor immunity in prostate cancer

Author

Fletcher, Claire, primary, Deng, Lin, additional, Orafidiya, Folake, additional, Yuan, Wei, additional, Figueiredo, Ines, additional, Gurel, Bora, additional, Leach, Damien, additional, Issa, Fadi, additional, Neeb, Antje, additional, Bogdan, Denisa, additional, Dobbs, Felix, additional, Philippou, Yiannis, additional, Murphy, Emma A., additional, Zhao, Shuang G., additional, Hester, Joanna, additional, Bryant, Richard J., additional, Reed, Simon H., additional, Knudsen, Karen E., additional, Mills, Ian G., additional, de Bono, Johann, additional, and Bevan, Charlotte L., additional

Published
2021
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224. The Quandary of DNA-Based Treatment Assessment in De Novo Metastatic Prostate Cancer in the Era of Precision Oncology.

Author

Nakken, Sigve, Lilleby, Wolfgang, Switlyk, Marta D., Knudsen, Karen E, Lilleby, Oscar, Zhao, Sen, Kaveh, Fatemeh, Ekstrøm, Per O., Urbanucci, Alfonso, Hovig, Eivind, Nakken, Sigve, Lilleby, Wolfgang, Switlyk, Marta D., Knudsen, Karen E, Lilleby, Oscar, Zhao, Sen, Kaveh, Fatemeh, Ekstrøm, Per O., Urbanucci, Alfonso, and Hovig, Eivind

Abstract

Guidelines for genetic testing have been established for multiple tumor types, frequently indicating the most confident molecularly targeted treatment options. However, considering the often-complex presentation of individual cancer patients, in addition to the combinatorial complexity and inherent uncertainties of molecular findings, deriving optimal treatment strategies frequently becomes very challenging. Here, we report a comprehensive analysis of a 68-year-old male with metastatic prostate cancer, encompassing pathology and MRI findings, transcriptomic results, and key genomics findings from whole-exome sequencing, both somatic aberrations and germline variants. We identify multiple somatic aberrations that are known to be enriched in prostate cancer, including a deletion of PTEN and a fusion transcript involving BRCA2. The gene expression patterns in the tumor biopsy were also strikingly similar to prostate tumor samples from TCGA. Furthermore, we detected multiple lines of evidence for homologous recombination repair deficiency (HRD), including a dominant contribution by mutational signature SBS3, which is specifically attributed to HRD. On the basis of the genomic and transcriptomic findings, and in light of the clinical case presentation, we discussed the personalized treatment options that exist for this patient and the various challenges that one faces in the process of translating high-throughput sequencing data towards treatment regimens.

Published
2021

225. The circadian cryptochrome, CRY1, is a pro-tumorigenic factor that rhythmically modulates DNA repair.

Author

Shafi, Ayesha A, McNair, Chris M, McCann, Jennifer J, Alshalalfa, Mohammed, Shostak, Anton, Severson, Tesa M, Zhu, Yanyun, Bergman, Andre, Gordon, Nicolas, Mandigo, Amy C, Chand, Saswati N, Gallagher, Peter, Dylgjeri, Emanuela, Laufer, Talya S, Vasilevskaya, Irina A, Schiewer, Matthew J, Brunner, Michael, Feng, Felix Y, Zwart, Wilbert, Knudsen, Karen E, Shafi, Ayesha A, McNair, Chris M, McCann, Jennifer J, Alshalalfa, Mohammed, Shostak, Anton, Severson, Tesa M, Zhu, Yanyun, Bergman, Andre, Gordon, Nicolas, Mandigo, Amy C, Chand, Saswati N, Gallagher, Peter, Dylgjeri, Emanuela, Laufer, Talya S, Vasilevskaya, Irina A, Schiewer, Matthew J, Brunner, Michael, Feng, Felix Y, Zwart, Wilbert, and Knudsen, Karen E

Abstract

Mechanisms regulating DNA repair processes remain incompletely defined. Here, the circadian factor CRY1, an evolutionally conserved transcriptional coregulator, is identified as a tumor specific regulator of DNA repair. Key findings demonstrate that CRY1 expression is androgen-responsive and associates with poor outcome in prostate cancer. Functional studies and first-in-field mapping of the CRY1 cistrome and transcriptome reveal that CRY1 regulates DNA repair and the G2/M transition. DNA damage stabilizes CRY1 in cancer (in vitro, in vivo, and human tumors ex vivo), which proves critical for efficient DNA repair. Further mechanistic investigation shows that stabilized CRY1 temporally regulates expression of genes required for homologous recombination. Collectively, these findings reveal that CRY1 is hormone-induced in tumors, is further stabilized by genomic insult, and promotes DNA repair and cell survival through temporal transcriptional regulation. These studies identify the circadian factor CRY1 as pro-tumorigenic and nominate CRY1 as a new therapeutic target.

Published
2021

226. Unique bisphenol a transcriptome in prostate cancer: novel effects on ERβ expression that correspond to androgen receptor mutation status

Author

Hess-Wilson, Janet K., Webb, Siobhan L., Daly, Hannah K., Leung, Yuet-Kin, Boldison, Joanne, Comstock, Clay E.S., Sartor, Maureen A., Ho, Shuk-Mei, and Knudsen, Karen E.

Subjects
Research, Risk factors, Health aspects, Bisphenol-A -- Health aspects -- Research, Endocrine disruptors -- Research -- Health aspects, Prostate cancer -- Risk factors -- Research
Abstract

Accruing evidence indicates that exposure to environmental compounds that affect the function of the endocrine system may adversely impact human health. These substances deemed 'endocrine disrupting compounds,' or EDCs, are [...], BACKGROUND: Prostatic adenocarcinomas are dependent on androgen receptor (AR) activity for growth and progression, and therapy for disseminated disease depends on ablation of AR activity. Recurrent tumors ultimately arise wherein AR has been re-activated. One mechanism of AR restoration is via somatic mutation, wherein cells containing mutant receptors become susceptible to activation by alternative ligands, including bisphenol A (BPA). In tumors with specific AR mutations, BPA promotes therapeutic bypass, suggesting significant negative impact to the clinical management of prostate cancer. OBJECTIVE: Our goal was to determine the mechanism of BPA action in cancer cells carrying BPAresponsive AR mutants. METHODS: The molecular signature of BPA activity in prostate cancer cells harboring mutant AR was delineated via genetic microarray analysis. Specificity of BPA action was assessed by comparison with the molecular signature elicited by dihydrotestosterone (DHT). RESULTS: BPA and DHT elicited distinct transcriptional signatures in prostate cancer cells expressing the BPA-responsive mutant AR-T877A. BPA dramatically attenuated estrogen receptor beta (ERβ) expression; this finding was specific to prostate tumor cells in which BPA induces cellular proliferation. CONCLUSIONS: BPA induces a distinct gene expression signature in prostate cancer cells expressing somatic AR mutation, and a major molecular consequence of BPA action is down-regulation of ERβ. Since ERβ functions to antagonize AR function and AR-dependent proliferation, these findings reveal a novel mechanism by which BPA likely regulates cellular proliferation. Future investigation directed at dissecting the importance of ERβ in the proliferative response to BPA will establish the contribution of this event to adverse effects associated with human exposure. KEY WORDS: androgen receptor, endocrine disruptor, microarray, prostatic adenocarcinoma, xenoestrogen. Environ Health Perspect 115:1646-1653 (2007). doi:10.1289/ehp.10283 available via http://dx.doi.org/ [Online 23 August 2007]

Published
2007

227. The retinoblastoma tumor suppressor modifies the therapeutic response of breast cancer

Author

Bosco, Emily E., Wang, Ying, Xu, Huan, Zilfou, Jack T., Knudsen, Karen E., Aronow, Bruce J., Lowe, Scott W., and Knudsen, Erik S.

Subjects
Care and treatment, Research, Health aspects, Retinoblastoma -- Research -- Health aspects -- Care and treatment, Tumor suppressor genes -- Research -- Health aspects, Breast cancer -- Research -- Care and treatment
Abstract

The retinoblastoma tumor suppressor (RB) protein is functionally inactivated in the majority of human cancers and is aberrant in one-third of all breast cancers. RB regulates [G.sub.1]/S-phase cell-cycle progression and [...]

Published
2007

230. The SAGA complex regulates early steps in transcription via its deubiquitylase module subunit USP22

Author

Stanek, Timothy J, primary, Gennaro, Victoria J, additional, Tracewell, Mason A, additional, Di Marcantonio, Daniela, additional, Pauley, Kristen L, additional, Butt, Sabrina, additional, McNair, Christopher, additional, Wang, Feng, additional, Kossenkov, Andrew V, additional, Knudsen, Karen E, additional, Butt, Tauseef, additional, Sykes, Stephen M, additional, and McMahon, Steven B, additional

Published
2021
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232. RB/E2F1 as a Master Regulator of Cancer Cell Metabolism in Advanced Disease

Author

Mandigo, Amy C., primary, Yuan, Wei, additional, Xu, Kexin, additional, Gallagher, Peter, additional, Pang, Angel, additional, Guan, Yi Fang, additional, Shafi, Ayesha A., additional, Thangavel, Chellappagounder, additional, Sheehan, Beshara, additional, Bogdan, Denisa, additional, Paschalis, Alec, additional, McCann, Jennifer J., additional, Laufer, Talya S., additional, Gordon, Nicolas, additional, Vasilevskaya, Irina A., additional, Dylgjeri, Emanuela, additional, Chand, Saswati N., additional, Schiewer, Matthew J., additional, Domingo-Domenech, Josep, additional, Den, Robert B., additional, Holst, Jeff, additional, McCue, Peter A., additional, de Bono, Johann S., additional, McNair, Christopher, additional, and Knudsen, Karen E., additional

Published
2021
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237. A Randomized Phase II Study of Androgen Deprivation Therapy with or without Palbociclib in RB-positive Metastatic Hormone-Sensitive Prostate Cancer

Author

Palmbos, Phillip L., primary, Daignault-Newton, Stephanie, additional, Tomlins, Scott A., additional, Agarwal, Neeraj, additional, Twardowski, Przemyslaw, additional, Morgans, Alicia K., additional, Kelly, Wm. Kevin, additional, Arora, Vivek K., additional, Antonarakis, Emmanuel S., additional, Siddiqui, Javed, additional, Jacobson, Jon A., additional, Davenport, Matthew S., additional, Robinson, Dan R., additional, Chinnaiyan, Arul M., additional, Knudsen, Karen E., additional, and Hussain, Maha, additional

Published
2021
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239. Prostate cancer

Author

Rebello, Richard J., primary, Oing, Christoph, additional, Knudsen, Karen E., additional, Loeb, Stacy, additional, Johnson, David C., additional, Reiter, Robert E., additional, Gillessen, Silke, additional, Van der Kwast, Theodorus, additional, and Bristow, Robert G., additional

Published
2021
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240. The circadian cryptochrome, CRY1, is a pro-tumorigenic factor that rhythmically modulates DNA repair

Author

Shafi, Ayesha A., primary, McNair, Chris M., additional, McCann, Jennifer J., additional, Alshalalfa, Mohammed, additional, Shostak, Anton, additional, Severson, Tesa M., additional, Zhu, Yanyun, additional, Bergman, Andre, additional, Gordon, Nicolas, additional, Mandigo, Amy C., additional, Chand, Saswati N., additional, Gallagher, Peter, additional, Dylgjeri, Emanuela, additional, Laufer, Talya S., additional, Vasilevskaya, Irina A., additional, Schiewer, Matthew J., additional, Brunner, Michael, additional, Feng, Felix Y., additional, Zwart, Wilbert, additional, and Knudsen, Karen E., additional

Published
2021
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245. Implementation of Germline Testing for Prostate Cancer: Philadelphia Prostate Cancer Consensus Conference 2019

Author

Giri, Veda N., primary, Knudsen, Karen E., additional, Kelly, William K., additional, Cheng, Heather H., additional, Cooney, Kathleen A., additional, Cookson, Michael S., additional, Dahut, William, additional, Weissman, Scott, additional, Soule, Howard R., additional, Petrylak, Daniel P., additional, Dicker, Adam P., additional, AlDubayan, Saud H., additional, Toland, Amanda E., additional, Pritchard, Colin C., additional, Pettaway, Curtis A., additional, Daly, Mary B., additional, Mohler, James L., additional, Parsons, J. Kellogg, additional, Carroll, Peter R., additional, Pilarski, Robert, additional, Blanco, Amie, additional, Woodson, Ashley, additional, Rahm, Alanna, additional, Taplin, Mary-Ellen, additional, Polascik, Thomas J., additional, Helfand, Brian T., additional, Hyatt, Colette, additional, Morgans, Alicia K., additional, Feng, Felix, additional, Mullane, Michael, additional, Powers, Jacqueline, additional, Concepcion, Raoul, additional, Lin, Daniel W., additional, Wender, Richard, additional, Mark, James Ryan, additional, Costello, Anthony, additional, Burnett, Arthur L., additional, Sartor, Oliver, additional, Isaacs, William B., additional, Xu, Jianfeng, additional, Weitzel, Jeffrey, additional, Andriole, Gerald L., additional, Beltran, Himisha, additional, Briganti, Alberto, additional, Byrne, Lindsey, additional, Calvaresi, Anne, additional, Chandrasekar, Thenappan, additional, Chen, David Y. T., additional, Den, Robert B., additional, Dobi, Albert, additional, Crawford, E. David, additional, Eastham, James, additional, Eggener, Scott, additional, Freedman, Matthew L., additional, Garnick, Marc, additional, Gomella, Patrick T., additional, Handley, Nathan, additional, Hurwitz, Mark D., additional, Izes, Joseph, additional, Karnes, R. Jeffrey, additional, Lallas, Costas, additional, Languino, Lucia, additional, Loeb, Stacy, additional, Lopez, Ana Maria, additional, Loughlin, Kevin R., additional, Lu-Yao, Grace, additional, Malkowicz, S. Bruce, additional, Mann, Mark, additional, Mille, Patrick, additional, Miner, Martin M., additional, Morgan, Todd, additional, Moreno, Jose, additional, Mucci, Lorelei, additional, Myers, Ronald E., additional, Nielsen, Sarah M., additional, O’Neil, Brock, additional, Pinover, Wayne, additional, Pinto, Peter, additional, Poage, Wendy, additional, Raj, Ganesh V., additional, Rebbeck, Timothy R., additional, Ryan, Charles, additional, Sandler, Howard, additional, Schiewer, Matthew, additional, Scott, E. Michael D., additional, Szymaniak, Brittany, additional, Tester, William, additional, Trabulsi, Edouard J., additional, Vapiwala, Neha, additional, Yu, Evan Y., additional, Zeigler-Johnson, Charnita, additional, and Gomella, Leonard G., additional

Published
2020
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246. The DNA methylation landscape of advanced prostate cancer

Author

Zhao, Shuang G., primary, Chen, William S., additional, Li, Haolong, additional, Foye, Adam, additional, Zhang, Meng, additional, Sjöström, Martin, additional, Aggarwal, Rahul, additional, Playdle, Denise, additional, Liao, Arnold, additional, Alumkal, Joshi J., additional, Das, Rajdeep, additional, Chou, Jonathan, additional, Hua, Junjie T., additional, Barnard, Travis J., additional, Bailey, Adina M., additional, Chow, Eric D., additional, Perry, Marc D., additional, Dang, Ha X., additional, Yang, Rendong, additional, Moussavi-Baygi, Ruhollah, additional, Zhang, Li, additional, Alshalalfa, Mohammed, additional, Laura Chang, S., additional, Houlahan, Kathleen E., additional, Shiah, Yu-Jia, additional, Beer, Tomasz M., additional, Thomas, George, additional, Chi, Kim N., additional, Gleave, Martin, additional, Zoubeidi, Amina, additional, Reiter, Robert E., additional, Rettig, Matthew B., additional, Witte, Owen, additional, Yvonne Kim, M., additional, Fong, Lawrence, additional, Spratt, Daniel E., additional, Morgan, Todd M., additional, Bose, Rohit, additional, Huang, Franklin W., additional, Li, Hui, additional, Chesner, Lisa, additional, Shenoy, Tanushree, additional, Goodarzi, Hani, additional, Asangani, Irfan A., additional, Sandhu, Shahneen, additional, Lang, Joshua M., additional, Mahajan, Nupam P., additional, Lara, Primo N., additional, Evans, Christopher P., additional, Febbo, Phillip, additional, Batzoglou, Serafim, additional, Knudsen, Karen E., additional, He, Housheng H., additional, Huang, Jiaoti, additional, Zwart, Wilbert, additional, Costello, Joseph F., additional, Luo, Jianhua, additional, Tomlins, Scott A., additional, Wyatt, Alexander W., additional, Dehm, Scott M., additional, Ashworth, Alan, additional, Gilbert, Luke A., additional, Boutros, Paul C., additional, Farh, Kyle, additional, Chinnaiyan, Arul M., additional, Maher, Christopher A., additional, Small, Eric J., additional, Quigley, David A., additional, and Feng, Felix Y., additional

Published
2020
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247. Clinical outcomes and markers of treatment response in a randomized phase II study of androgen deprivation therapy with or without palbociclib in RB-intact metastatic hormone-sensitive prostate cancer (mHSPC).

Author

Palmbos, Phillip Lee, primary, Tomlins, Scott A., additional, Daignault, Stephanie, additional, Agarwal, Neeraj, additional, Twardowski, Przemyslaw, additional, Morgans, Alicia K., additional, Kelly, William Kevin, additional, Arora, Vivek, additional, Antonarakis, Emmanuel S., additional, Siddiqui, Javed, additional, Robinson, Dan, additional, Knudsen, Karen E., additional, Chinnaiyan, Arul, additional, and Hussain, Maha H. A., additional

Published
2020
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250. Novel RB1-Loss Transcriptomic Signature Is Associated with Poor Clinical Outcomes across Cancer Types

Author

Chen, William S, Alshalalfa, Mohammed, Zhao, Shuang G, Liu, Yang, Mahal, Brandon A, Quigley, David A, Wei, Ting, Davicioni, Elai, Rebbeck, Timothy R, Kantoff, Philip W, Maher, Christopher A, Knudsen, Karen E, Small, Eric J, Nguyen, Paul L, and Feng, Felix Y

Subjects
Male, Tumor, Human Genome, Oncology and Carcinogenesis, Prognosis, Rare Diseases, Good Health and Well Being, Clinical Research, Neoplasms, Disease Progression, Genetics, Humans, Oncology & Carcinogenesis, Transcriptome, Biomarkers, Cancer
Abstract

PurposeRb-pathway disruption is of great clinical interest, as it has been shown to predict outcomes in multiple cancers. We sought to develop a transcriptomic signature for detecting biallelic RB1 loss (RBS) that could be used to assess the clinical implications of RB1 loss on a pan-cancer scale.Experimental designWe utilized data from the Cancer Cell Line Encyclopedia (N = 995) to develop the first pan-cancer transcriptomic signature for predicting biallelic RB1 loss (RBS). Model accuracy was validated using The Cancer Genome Atlas (TCGA) Pan-Cancer dataset (N = 11,007). RBS was then used to assess the clinical relevance of biallelic RB1 loss in TCGA Pan-Cancer and in an additional metastatic castration-resistant prostate cancer (mCRPC) cohort.ResultsRBS outperformed the leading existing signature for detecting RB1 biallelic loss across all cancer types in TCGA Pan-Cancer (AUC, 0.89 vs. 0.66). High RBS (RB1 biallelic loss) was associated with promoter hypermethylation (P = 0.008) and gene body hypomethylation (P = 0.002), suggesting RBS could detect epigenetic gene silencing. TCGA Pan-Cancer clinical analyses revealed that high RBS was associated with short progression-free (P < 0.00001), overall (P = 0.0004), and disease-specific (P < 0.00001) survival. On multivariable analyses, high RBS was predictive of shorter progression-free survival in TCGA Pan-Cancer (P = 0.03) and of shorter overall survival in mCRPC (P = 0.004) independently of the number of DNA alterations in RB1.ConclusionsOur study provides the first validated tool to assess RB1 biallelic loss across cancer types based on gene expression. RBS can be useful for analyzing datasets with or without DNA-sequencing results to investigate the emerging prognostic and treatment implications of Rb-pathway disruption.See related commentary by Choudhury and Beltran, p. 4199.

Published
2019

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