title: Comprehensive Pan-Genomic Characterization of Adrenocortical Carcinoma.
abstract: We describe a comprehensive genomic characterization of adrenocortical carcinoma (ACC). Using this dataset, we expand the catalogue of known ACC driver genes to include PRKAR1A, RPL22, TERF2, CCNE1, and NF1. Genome wide DNA copy-number analysis revealed frequent occurrence of massive DNA loss followed by whole-genome doubling (WGD), which was associated with aggressive clinical course, suggesting WGD is a hallmark of disease progression. Corroborating this hypothesis were increased TERT expression, decreased telomere length, and activation of cell-cycle programs. Integrated subtype analysis identified three ACC subtypes with distinct clinical outcome and molecular alterations which could be captured by a 68-CpG probe DNA-methylation signature, proposing a strategy for clinical stratification of patients based on molecular markers.
authors.affiliation: Departments of Genomic Medicine, Bioinformatics, and Computational Biology, Endocrine Neoplasia and Hormonal Disorders, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Siyuan
authors.initials: S
authors.lastname: Zheng
authors.affiliation: The Eli and Edythe L. Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, MA 02142, USA; Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Cherniack
authors.affiliation: Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Ninad
authors.initials: N
authors.lastname: Dewal
authors.affiliation: Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Moffitt
authors.affiliation: The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, Baltimore, MD 21287, USA.
authors.forename: Ludmila
authors.initials: L
authors.lastname: Danilova
authors.affiliation: The Eli and Edythe L. Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, MA 02142, USA; Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Bradley A
authors.initials: BA
authors.lastname: Murray
authors.affiliation: Unidade de Suprarrenal, Laboratório de Hormônios e Genética Molecular LIM42, Serviço de Endocrinologia e Metabologia, Hospital das Clínicas, Faculdade de Medicina da Universidade de São Paulo, São Paulo 05403-900, Brazil; Departments of Cell & Developmental Biology, Pathology, Molecular & Integrative Physiology, Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA; University of Michigan Comprehensive Cancer Center, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Antonio M
authors.initials: AM
authors.lastname: Lerario
authors.affiliation: Departments of Cell & Developmental Biology, Pathology, Molecular & Integrative Physiology, Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA; University of Michigan Comprehensive Cancer Center, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Tobias
authors.initials: T
authors.lastname: Else
authors.affiliation: Institute for Systems Biology, Seattle, WA 98109, USA.
authors.forename: Theo A
authors.initials: TA
authors.lastname: Knijnenburg
authors.affiliation: Department of Computational Biology, University of Lausanne, Rue du Bugnon 27, 1005 Lausanne, Switzerland; Computational Biology Center, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Ciriello
authors.affiliation: Translational Genomics Research Institute, Phoenix, AZ 85004, USA.
authors.forename: Seungchan
authors.initials: S
authors.lastname: Kim
authors.affiliation: Inserm U1016, CNRS UMR 8104, Institut Cochin, 75014 Paris, France; Faculté de Médecine Paris Descartes, Université Paris Descartes, Sorbonne Paris Cité, 75006 Paris, France; Department of Endocrinology, Referral Center for Rare Adrenal Diseases, Assistance Publique Hôpitaux de Paris, Hôpital Cochin, 75014 Paris, France; European Network for the Study of Adrenal Tumors, 75014 Paris, France.
authors.forename: Guillaume
authors.initials: G
authors.lastname: Assie
authors.affiliation: University of California Santa Cruz Genomics Institute, University California Santa Cruz, Santa Cruz, CA 95064, USA.
authors.forename: Olena
authors.initials: O
authors.lastname: Morozova
authors.affiliation: Departments of Genomic Medicine, Bioinformatics, and Computational Biology, Endocrine Neoplasia and Hormonal Disorders, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Rehan
authors.initials: R
authors.lastname: Akbani
authors.affiliation: The Eli and Edythe L. Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, MA 02142, USA; Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Juliann
authors.initials: J
authors.lastname: Shih
authors.affiliation: Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
authors.forename: Katherine A
authors.initials: KA
authors.lastname: Hoadley
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA; Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA.
authors.forename: Toni K
authors.initials: TK
authors.lastname: Choueiri
authors.affiliation: European Network for the Study of Adrenal Tumors, 75014 Paris, France; Department of Visceral, Thoracic and Vascular Surgery, University Hospital Giessen and Marburg, Campus Marburg, General Surgery, Endocrine Center, 34501 Marburg, Germany.
authors.forename: Jens
authors.initials: J
authors.lastname: Waldmann
authors.affiliation: Department of Laboratory Medicine and Pathobiology, University Health Network, Toronto, ON M5G 2C4, Canada.
authors.forename: Ozgur
authors.initials: O
authors.lastname: Mete
authors.affiliation: Canada's Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, BC V5Z 4S6, Canada.
authors.forename: A Gordon
authors.initials: AG
authors.lastname: Robertson
authors.affiliation: Department of Computer Science, Brown University, Providence, RI 02906, USA.
authors.forename: Hsin-Ta
authors.initials: HT
authors.lastname: Wu
authors.affiliation: Department of Computer Science, Brown University, Providence, RI 02906, USA.
authors.forename: Benjamin J
authors.initials: BJ
authors.lastname: Raphael
authors.affiliation: Departments of Cell & Developmental Biology, Pathology, Molecular & Integrative Physiology, Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Lina
authors.initials: L
authors.lastname: Shao
authors.affiliation: The Eli and Edythe L. Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, MA 02142, USA; Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA; Department of Pathology, Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Matthew
authors.initials: M
authors.lastname: Meyerson
authors.affiliation: Translational Genomics Research Institute, Phoenix, AZ 85004, USA.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Demeure
authors.affiliation: European Network for the Study of Adrenal Tumors, 75014 Paris, France; Endocrine Research Unit, Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, 80336 Munich, Germany.
authors.forename: Felix
authors.initials: F
authors.lastname: Beuschlein
authors.affiliation: Cancer Diagnosis and Pathology Group and Cancer Genetics Laboratory, Kolling Institute of Medical Research, University of Sydney, Sydney, NSW 2006, Australia; Department of Anatomical Pathology, Royal North Shore Hospital, St Leonards, NSW 2065, Australia.
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Gill
authors.affiliation: Cancer Diagnosis and Pathology Group and Cancer Genetics Laboratory, Kolling Institute of Medical Research, University of Sydney, Sydney, NSW 2006, Australia; Endocrine Surgical Unit, Royal North Shore Hospital, St Leonards, NSW 2065, Australia.
authors.forename: Stan B
authors.initials: SB
authors.lastname: Sidhu
authors.affiliation: Unidade de Suprarrenal, Laboratório de Hormônios e Genética Molecular LIM42, Serviço de Endocrinologia e Metabologia, Hospital das Clínicas, Faculdade de Medicina da Universidade de São Paulo, São Paulo 05403-900, Brazil; Instituto do Câncer do Estado de São Paulo (ICESP), Faculdade de Medicina da Universidade de São Paulo, São Paulo 05403-900, Brazil.
authors.forename: Madson Q
authors.initials: MQ
authors.lastname: Almeida
authors.affiliation: Unidade de Suprarrenal, Laboratório de Hormônios e Genética Molecular LIM42, Serviço de Endocrinologia e Metabologia, Hospital das Clínicas, Faculdade de Medicina da Universidade de São Paulo, São Paulo 05403-900, Brazil; Instituto do Câncer do Estado de São Paulo (ICESP), Faculdade de Medicina da Universidade de São Paulo, São Paulo 05403-900, Brazil.
authors.forename: Maria C B V
authors.initials: MCBV
authors.lastname: Fragoso
authors.affiliation: The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, Baltimore, MD 21287, USA.
authors.forename: Leslie M
authors.initials: LM
authors.lastname: Cope
authors.affiliation: Endocrine Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Electron
authors.initials: E
authors.lastname: Kebebew
authors.affiliation: Departments of Genomic Medicine, Bioinformatics, and Computational Biology, Endocrine Neoplasia and Hormonal Disorders, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Mouhammed A
authors.initials: MA
authors.lastname: Habra
authors.affiliation: Translational Genomics Research Institute, Phoenix, AZ 85004, USA.
authors.forename: Timothy G
authors.initials: TG
authors.lastname: Whitsett
authors.affiliation: Translational Genomics Research Institute, Phoenix, AZ 85004, USA; NantOmics, LLC, The Biodesign Institute, Arizona State University, Tempe, AZ 85287-5001, USA.
authors.forename: Kimberly J
authors.initials: KJ
authors.lastname: Bussey
authors.affiliation: Departments of Cell & Developmental Biology, Pathology, Molecular & Integrative Physiology, Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA; University of Michigan Comprehensive Cancer Center, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: William E
authors.initials: WE
authors.lastname: Rainey
authors.affiliation: Department of Laboratory Medicine and Pathobiology, University Health Network, Toronto, ON M5G 2C4, Canada.
authors.forename: Sylvia L
authors.initials: SL
authors.lastname: Asa
authors.affiliation: Inserm U1016, CNRS UMR 8104, Institut Cochin, 75014 Paris, France; Faculté de Médecine Paris Descartes, Université Paris Descartes, Sorbonne Paris Cité, 75006 Paris, France; Department of Endocrinology, Referral Center for Rare Adrenal Diseases, Assistance Publique Hôpitaux de Paris, Hôpital Cochin, 75014 Paris, France; European Network for the Study of Adrenal Tumors, 75014 Paris, France.
authors.forename: Jérôme
authors.initials: J
authors.lastname: Bertherat
authors.affiliation: European Network for the Study of Adrenal Tumors, 75014 Paris, France; Endocrine and Diabetes Unit, Department of Internal Medicine I, University Hospital Würzburg, 97080 Würzburg, Germany; Comprehensive Cancer Center Mainfranken, University of Würzburg, 97080 Würzburg, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Fassnacht
authors.affiliation: Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: David A
authors.initials: DA
authors.lastname: Wheeler
authors.affiliation: Departments of Cell & Developmental Biology, Pathology, Molecular & Integrative Physiology, Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA; University of Michigan Comprehensive Cancer Center, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Gary D
authors.initials: GD
authors.lastname: Hammer
authors.affiliation: Departments of Cell & Developmental Biology, Pathology, Molecular & Integrative Physiology, Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA; University of Michigan Comprehensive Cancer Center, University of Michigan, Ann Arbor, MI 48109, USA. Electronic address: giordano@med.umich.edu.
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Giordano
authors.affiliation: Departments of Genomic Medicine, Bioinformatics, and Computational Biology, Endocrine Neoplasia and Hormonal Disorders, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. Electronic address: rverhaak@mdanderson.org.
authors.forename: Roel G W
authors.initials: RGW
authors.lastname: Verhaak
mesh_terms: D000293:Adolescent; D000306:Adrenal Cortex Neoplasms / Q000235:genetics* / Q000473:pathology / Q000628:therapy; D018268:Adrenocortical Carcinoma / Q000235:genetics* / Q000473:pathology / Q000628:therapy; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002648:Child; D019175:DNA Methylation; D018572:Disease-Free Survival; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods; D015972:Gene Expression Regulation, Neoplastic; D020022:Genetic Predisposition to Disease / Q000235:genetics; D015894:Genome, Human / Q000235:genetics*; D023281:Genomics / Q000379:methods*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D017063:Outcome Assessment, Health Care; D011379:Prognosis; D055815:Young Adult