@article{23abc52026734eac9cfa3951a9ab9549,
title = "Genomic Hallmarks and Structural Variation in Metastatic Prostate Cancer",
abstract = "While mutations affecting protein-coding regions have been examined across many cancers, structural variants at the genome-wide level are still poorly defined. Through integrative deep whole-genome and -transcriptome analysis of 101 castration-resistant prostate cancer metastases (109X tumor/38X normal coverage), we identified structural variants altering critical regulators of tumorigenesis and progression not detectable by exome approaches. Notably, we observed amplification of an intergenic enhancer region 624 kb upstream of the androgen receptor (AR) in 81% of patients, correlating with increased AR expression. Tandem duplication hotspots also occur near MYC, in lncRNAs associated with post-translational MYC regulation. Classes of structural variations were linked to distinct DNA repair deficiencies, suggesting their etiology, including associations of CDK12 mutation with tandem duplications, TP53 inactivation with inverted rearrangements and chromothripsis, and BRCA2 inactivation with deletions. Together, these observations provide a comprehensive view of how structural variations affect critical regulators in metastatic prostate cancer. Integrative whole-genome and -transcriptome sequencing provides a comprehensive view of structural variations that affect major regulators in prostate cancer and would escape detection by exome-based approaches.",
keywords = "BRCA2, androgen receptor, castration resistant prostate cancer, chromothripsis, gene fusion, genomics, metastases, structural variation, tandem duplication, whole-genome sequencing",
author = "Quigley, {David A.} and Dang, {Ha X.} and Zhao, {Shuang G.} and Paul Lloyd and Rahul Aggarwal and Alumkal, {Joshi J.} and Adam Foye and Vishal Kothari and Perry, {Marc D.} and Bailey, {Adina M.} and Denise Playdle and Barnard, {Travis J.} and Li Zhang and Jin Zhang and Youngren, {Jack F.} and Cieslik, {Marcin P.} and Abhijit Parolia and Beer, {Tomasz M.} and George Thomas and Chi, {Kim N.} and Martin Gleave and Lack, {Nathan A.} and Amina Zoubeidi and Reiter, {Robert E.} and Rettig, {Matthew B.} and Owen Witte and Ryan, {Charles J.} and Lawrence Fong and Won Kim and Terence Friedlander and Jonathan Chou and Haolong Li and Rajdeep Das and Hui Li and Ruhollah Moussavi-Baygi and Hani Goodarzi and Gilbert, {Luke A.} and Lara, {Primo N.} and Evans, {Christopher P.} and Goldstein, {Theodore C.} and Stuart, {Joshua M.} and Tomlins, {Scott A.} and Spratt, {Daniel E.} and Cheetham, {R. Keira} and Cheng, {Donavan T.} and Kyle Farh and Gehring, {Julian S.} and J{\"o}rg Hakenberg and Arnold Liao and Febbo, {Philip G.} and John Shon and Brad Sickler and Serafim Batzoglou and Knudsen, {Karen E.} and He, {Housheng H.} and Jiaoti Huang and Wyatt, {Alexander W.} and Dehm, {Scott M.} and Alan Ashworth and Chinnaiyan, {Arul M.} and Maher, {Christopher A.} and Small, {Eric J.} and Feng, {Felix Y.}",
note = "Funding Information: We thank the patients who selflessly contributed samples to this study and without whom this research would not have been possible. This research was primarily supported by a Stand Up To Cancer-Prostate Cancer Foundation Prostate Cancer Dream Team Award ( SU2C-AACR-DT0812 to E.J.S.) and by the Movember Foundation. Stand Up To Cancer is a division of the Entertainment Industry Foundation. This research grant was administered by the American Association for Cancer Research, the scientific partner of SU2C. This project was also supported by the following awards: Goldberg-Benioff Research Fund for Prostate Cancer Translational Biology (to F.Y.F.), Stand Up To Cancer-Prostate Cancer Foundation Prostate Cancer Dream Team Award ( SU2C-AACR-DT0712 to A.M.C.), several Prostate Cancer Foundation Challenge grants (to C.A.M., F.Y.F., S.M.D., and L.F.), V Foundation Scholar Grant (to F.Y.F.), BRCA Foundation Young Investigator Award (to D.A.Q.), Department of Defense (DOD) ( W81XWH-16-1-0747 to F.Y.F., W81XWH-15-1-0562 to A.M.C., PC160429 to M.P.C., and W81XWH-17-1-0192 to Hui Li), Early Detection Research Network ( U01 CA214170 to A.M.C.), Prostate SPORE ( P50 CA186786 and P50 CA097186 to A.M.C.), NIH ( R01CA174777 to S.M.D.) and NCI T32 training grant ( CA108462 to J.C.). D.A.Q., S.G.Z., R.A., M.P.C., W.K., and V.K. are supported by Prostate Cancer Foundation Young Investigator Awards. Funding Information: A.M.C. is on the scientific advisory board of Tempus. F.Y.F. is co-founder of PFS Genomics. R.K.C., D.T.C., K.F., J.S.G., J. Hakenberg, A.L., J.S., S.B., and P.F. are employees of Illumina, Inc. and hold stock in the company. The University of Michigan has been issued a patent on ETS gene fusions in prostate cancer on which A.M.C. and S.A.T. are co-inventors. The diagnostic field of use has been licensed to Hologic/Gen-Probe, Inc., which has sublicensed rights to Roche/Ventana Medical Systems. S.A.T. has an unrelated sponsored research agreement with Astellas. S.A.T. has served as a consultant for and received honoraria from Almac Diagnostics, Janssen, and Astellas/Medivation. S.A.T. is a co-founder of, consultant for, and Laboratory Director of Strata Oncology. K.C. receives consultant, honoraria, and research funding from Janssen and Astellas. Publisher Copyright: {\textcopyright} 2018 Elsevier Inc.",
year = "2018",
month = jul,
day = "26",
doi = "10.1016/j.cell.2018.06.039",
language = "English (US)",
volume = "174",
pages = "758--769.e9",
journal = "Cell",
issn = "0092-8674",
publisher = "Cell Press",
number = "3",
}