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Integrative Clinical Genomics of Advanced Prostate Cancer
Open accessAbstract
Toward development of a precision medicine framework for metastatic, castration-resistant prostate cancer (mCRPC), we established a multi-institutional clinical sequencing infrastructure to conduct prospective whole-exome and transcriptome sequencing of bone or soft tissue tumor biopsies from a cohort of 150 mCRPC affected individuals. Aberrations of AR, ETS genes, TP53, and PTEN were frequent (40%-60% of cases), with TP53 and AR alterations enriched in mCRPC compared to primary prostate cancer. We identified new genomic alterations in PIK3CA/B, R-spondin, BRAF/RAF1, APC, β-catenin, and ZBTB16/PLZF. Moreover, aberrations of BRCA2, BRCA1, and ATM were observed at substantially higher frequencies (19.3% overall) compared to those in primary prostate cancers. 89% of affected individuals harbored a clinically actionable aberration, including 62.7% with aberrations in AR, 65% in other cancer-related genes, and 8% with actionable pathogenic germline alterations. This cohort study provides clinically actionable information that could impact treatment decisions for these affected individuals.
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“The androgen receptor (AR) is a critical driver of prostate cancer (PCa).”
From Genome-scale CRISPR screens identify PTGES3 as a direct modulator of androgen receptor function in advanced prostate cancer (2025) · cites this paper as [1]
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“The consortium utilized two sequencing and analysis centers, one centralized digital pathology review center, and one centralized data visualization portal (Cerami et al., 2012; Gao et al., 2013; Robinson et al., 2011; Thorvaldsdóttir et al., 2013).”
Self-citationRobinson, J. T., Thorvaldsdóttir, H., Winckler, W., Guttman, M., Lander, E. S., Getz, G., & Mesirov, J. P. (2011) · Nature Biotechnology · doi:10.1038/nbt.1754 · Cited by 15,390 · cited 3×
“Somatic mutation analysis was performed as described previously (Cibulskis et al., 2013; Van Allen et al., 2014c) and reviewed with Integrated Genomics Viewer (IGV) (Robinson et al., 2011).”
Integrative Analysis of Complex Cancer Genomics and Clinical Profiles Using the cBioPortal
Gao, J., Aksoy, B. A., Dogrusoz, U., Dresdner, G., Gross, B., Sumer, S. O., Sun, Y., Jacobsen, A., Sinha, R., Larsson, E., et al. (2013) · Science Signaling · doi:10.1126/scisignal.2004088 · Cited by 15,160
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“…analysis reveals that the majority of affected individuals with metastatic castration-resistant prostate cancer harbor clinically actionable molecular alterations, highlighting the need for genetic counseling to inform precision medicine in affected individuals with advanced prostate cancer.”
Mutational heterogeneity in cancer and the search for new cancer-associated genes
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Self-citationSensitive detection of somatic point mutations in impure and heterogeneous cancer samples
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Self-citationIncreased Survival with Enzalutamide in Prostate Cancer after Chemotherapy
Scher, H. I., Fizazi, K., Saad, F., Taplin, M.-E., Sternberg, C. N., Miller, K., de Wit, R., Mulders, P., Chi, K. N., Shore, N. D., et al. (2012) · New England Journal of Medicine · doi:10.1056/nejmoa1207506 · Cited by 4,586 · cited 1×
“…on the PI3K pathway, PIK3CB-specific inhibitors may have utility in affected individuals with mutation, amplification, and/or fusion of this gene (Schwartz et al., 2015); multiple affected individuals who achieved durable (>1 year) responses to PIK3CB-specificin inhibition harbored activating…”
Self-citationAbiraterone and Increased Survival in Metastatic Prostate Cancer
de Bono, J. S., Logothetis, C. J., Molina, A., Fizazi, K., North, S., Chu, L., Chi, K. N., Jones, R. J., Goodman, O. B., Saad, F., et al. (2011) · New England Journal of Medicine · doi:10.1056/nejmoa1014618 · Cited by 4,407
Self-citationRecurrent Fusion of TMPRSS2 and ETS Transcription Factor Genes in Prostate Cancer
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“Among chimeric fusion transcripts identified, recurrent ETS fusions (Tomlins et al., 2005) were observed in 84 cases (56%), of which the majority were fused to ERG and others to FLI1, ETV4, and ETV5 (Figure 3B).”
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Metadata
- Authors
- Robinson, D., Van Allen, E. M., Wu, Y.-M., Schultz, N., Lonigro, R. J., Mosquera, J.-M., Montgomery, B., Taplin, M.-E., Pritchard, C. C., Attard, G., Beltran, H., Abida, W., Bradley, R. K., Vinson, J., Cao, X., Vats, P., Kunju, L. P., Hussain, M., Feng, F. Y., Tomlins, S. A., Cooney, K. A., Smith, D. C., Brennan, C., Siddiqui, J., Mehra, R., Chen, Y., Rathkopf, D. E., Morris, M. J., Solomon, S. B., Durack, J. C., Reuter, V. E., Gopalan, A., Gao, J., Loda, M., Lis, R. T., Bowden, M., Balk, S. P., Gaviola, G., Sougnez, C., Gupta, M., Yu, E. Y., Mostaghel, E. A., Cheng, H. H., Mulcahy, H., True, L. D., Plymate, S. R., Dvinge, H., Ferraldeschi, R., Flohr, P., Miranda, S., Zafeiriou, Z., Tunariu, N., Mateo, J., Perez-Lopez, R., Demichelis, F., Robinson, B. D., Schiffman, M., Nanus, D. M., Tagawa, S. T., Sigaras, A., Eng, K. W., Elemento, O., Sboner, A., Heath, E. I., Scher, H. I., Pienta, K. J., Kantoff, P., de Bono, J. S., Rubin, M. A., Nelson, P. S., Garraway, L. A., Sawyers, C. L., & Chinnaiyan, A. M.
- Affiliations
- University of Michigan (US)
- Memorial Sloan Kettering Cancer Center (US)
- NewYork–Presbyterian Hospital (US)
- University of Washington (US)
- Dana-Farber Cancer Institute (US)
- Royal Marsden NHS Foundation Trust (GB)
- Howard Hughes Medical Institute (US)
- Broad Institute (US)
- Brigham and Women's Hospital (US)
- Beth Israel Deaconess Medical Center (US)
- University of Washington Medical Center (US)
- University of Trento (IT)
- Cornell University (US)
- Wayne State University (US)
- Johns Hopkins University (US)
- Corresponding author
- Sawyers, Charles L.
- Chinnaiyan, Arul M.
- ORCID
- Robinson, Dan
- Schultz, Nikolaus
- Mosquera, Juan-Miguel
- Montgomery, Bruce
- Taplin, Mary-Ellen
- Pritchard, Colin C.
- Attard, Gerhardt
- Beltran, Himisha
- Abida, Wassim
- Bradley, Robert K.
- Vinson, Jake
- Cao, Xuhong
- Vats, Pankaj
- Kunju, Lakshmi P.
- Hussain, Maha
- Feng, Felix Y.
- Tomlins, Scott A.
- Cooney, Kathleen A.
- Smith, David C.
- Brennan, Christine
- Siddiqui, Javed
- Mehra, Rohit
- Chen, Yu
- Rathkopf, Dana E.
- Morris, Michael J.
- Solomon, Stephen B.
- Durack, Jeremy C.
- Gopalan, Anuradha
- Gao, Jianjiong
- Loda, Massimo
- Lis, Rosina T.
- Bowden, Michaela
- Gupta, Manaswi
- Yu, Evan Y.
- Mostaghel, Elahe A.
- Cheng, Heather H.
- Mulcahy, Hyojeong
- True, Lawrence D.
- Plymate, Stephen R.
- Dvinge, Heidi
- Flohr, Penny
- Miranda, Susana
- Zafeiriou, Zafeiris
- Tunariu, Nina
- Demichelis, Francesca
- Robinson, Brian D.
- Schiffman, Marc
- Nanus, David M.
- Tagawa, Scott T.
- Sigaras, Alexandros
- Eng, Kenneth W.
- Elemento, Olivier
- Sboner, Andrea
- Heath, Elisabeth I.
- Scher, Howard I.
- Pienta, Kenneth J.
- Kantoff, Philip
- Rubin, Mark A.
- Nelson, Peter S.
- Garraway, Levi A.
- Sawyers, Charles L.
- Chinnaiyan, Arul M.
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2015-05
- Volume
- 161
- Issue
- 5
- Pages
- 1215-1228
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC4484602
- OpenAlex
- W1578291413
- Cited by
- 3,645
- References
- 64
- Citations by year
- 2026: 178 · 2025: 258 · 2024: 320 · 2023: 363 · 2022: 360 · 2021: 392 · 2020: 378 · 2019: 346 · 2018: 358 · 2017: 355 · 2016: 263 · 2015: 63
- FWCI
- 273.95
- Type
- journal article
- Language
- en
- Update notices
- erratum (2015-07-16)
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Iris (University of Trento) (submittedVersion)
- Funders
- Howard Hughes Medical Institute
- Cancer Research UK (13239)
- National Institute for Health and Care Research (CL-2008-22-001)
- Prostate Cancer UK (CEO13_2-002, PG12-49)
- National Institutes of Health (DP2OD002750)
- Medical Research Council (MR/M003272/1)
- National Human Genome Research Institute (UM1HG006508)
- National Cancer Institute (P50 CA 90381, R01CA136578, L30 CA111031, K08CA188615, R21CA128352, U01CA111275, P50CA090381, R01CA131945, UO1CA111275, L30 CA103810, R01CA116337, R01CA129435, P50CA069568, K08CA115927, R01CA092629, R01CA155169, R01CA193910, R01CA085912, P30CA008748, P01CA163227, P50CA097186, P50CA186786, P50CA092629, P30CA006516, R01CA193837)
- National Institute of General Medical Sciences (T32GM007266, R01GM107427)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Prostate Cancer Treatment and Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chromatin Remodeling and Cancer
- Keywords
- metastatic castration-resistant prostate cancer, exome sequencing, transcriptome sequencing, actionable genomic alterations, androgen receptor alterations, ETS gene fusions, TP53, PTEN, R-spondin, APC, β-catenin, BRCA2, BRCA1, ATM, germline pathogenic variants, precision medicine
- MeSH terms
- Humans, Male, Mutation, Neoplasm Metastasis, Cohort Studies, Gene Expression Profiling, Prostatic Neoplasms, Castration-Resistant
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