Comprehensive Pan-Genomic Characterization of Adrenocortical Carcinoma

Siyuan Zheng; Andrew D Cherniack; Ninad Dewal; Richard A Moffitt; Ludmila Danilova; Bradley A Murray; Antonio M Lerario; Tobias Else; Theo A Knijnenburg; Giovanni Ciriello; Seungchan Kim; Guillaume Assie; Olena Morozova; Rehan Akbani; Juliann Shih; Katherine A Hoadley; Toni K Choueiri; Jens Waldmann; Ozgur Mete; A Gordon Robertson; Hsin-Ta Wu; Benjamin J Raphael; Lina Shao; Matthew Meyerson; Michael J Demeure; Felix Beuschlein; Anthony J Gill; Stan B Sidhu; Madson Q Almeida; Maria C B V Fragoso; Leslie M Cope; Electron Kebebew; Mouhammed A Habra; Timothy G Whitsett; Kimberly J Bussey; William E Rainey; Sylvia L Asa; Jérôme Bertherat; Martin Fassnacht; David A Wheeler; Cancer Genome Atlas Research Network; Gary D Hammer; Thomas J Giordano; Roel G W Verhaak

doi:10.1016/j.ccell.2016.04.002

Comprehensive Pan-Genomic Characterization of Adrenocortical Carcinoma

Cancer Cell. 2016 May 9;29(5):723-736. doi: 10.1016/j.ccell.2016.04.002.

Authors

Siyuan Zheng¹, Andrew D Cherniack², Ninad Dewal³, Richard A Moffitt⁴, Ludmila Danilova⁵, Bradley A Murray², Antonio M Lerario⁶, Tobias Else⁷, Theo A Knijnenburg⁸, Giovanni Ciriello⁹, Seungchan Kim¹⁰, Guillaume Assie¹¹, Olena Morozova¹², Rehan Akbani¹, Juliann Shih², Katherine A Hoadley⁴, Toni K Choueiri¹³, Jens Waldmann¹⁴, Ozgur Mete¹⁵, A Gordon Robertson¹⁶, Hsin-Ta Wu¹⁷, Benjamin J Raphael¹⁷, Lina Shao¹⁸, Matthew Meyerson¹⁹, Michael J Demeure¹⁰, Felix Beuschlein²⁰, Anthony J Gill²¹, Stan B Sidhu²², Madson Q Almeida²³, Maria C B V Fragoso²³, Leslie M Cope⁵, Electron Kebebew²⁴, Mouhammed A Habra¹, Timothy G Whitsett¹⁰, Kimberly J Bussey²⁵, William E Rainey⁷, Sylvia L Asa¹⁵, Jérôme Bertherat¹¹, Martin Fassnacht²⁶, David A Wheeler³; Cancer Genome Atlas Research Network; Gary D Hammer⁷, Thomas J Giordano²⁷, Roel G W Verhaak²⁸

Collaborators

Cancer Genome Atlas Research Network:
Siyuan Zheng, Roel G W Verhaak, Thomas J Giordano, Gary D Hammer, Andrew D Cherniack, Ninad Dewal, Richard A Moffitt, Ludmila Danilova, Bradley A Murray, Antonio M Lerario, Tobias Else, Theo A Knijnenburg, Giovanni Ciriello, Seungchan Kim, Guillaume Assié, Olena Morozova, Rehan Akbani, Juliann Shih, Katherine A Hoadley, Toni K Choueiri, Jens Waldmann, Ozgur Mete, A Gordon Robertson, Hsin-Tu Wu, Benjamin J Raphael, Matthew Meyerson, Michael J Demeure, Felix Beuschlein, Anthony J Gill, Stan B Sidhu, Madson Almeida, Maria Candida Barisson Fragoso, Leslie M Cope, Electron Kebebew, Mouhammed Amir Habra, Timothy G Whitsett, Kimberly J Bussey, William E Rainey, Sylvia L Asa, Jérôme Bertherat, Martin Fassnacht, David A Wheeler, Christopher Benz, Adrian Ally, Miruna Balasundaram, Reanne Bowlby, Denise Brooks, Yaron S N Butterfield, Rebecca Carlsen, Noreen Dhalla, Ranabir Guin, Robert A Holt, Steven J M Jones, Katayoon Kasaian, Darlene Lee, Haiyan I Li, Lynette Lim, Yussanne Ma, Marco A Marra, Michael Mayo, Richard A Moore, Andrew J Mungall, Karen Mungall, Sara Sadeghi, Jacqueline E Schein, Payal Sipahimalani, Angela Tam, Nina Thiessen, Peter J Park, Matthias Kroiss, Jianjiong Gao, Chris Sander, Nikolaus Schultz, Corbin D Jones, Raju Kucherlapati, Piotr A Mieczkowski, Joel S Parker, Charles M Perou, Donghui Tan, Umadevi Veluvolu, Matthew D Wilkerson, D Neil Hayes, Marc Ladanyi, Marcus Quinkler, J Todd Auman, Ana Claudia Latronico, Berenice B Mendonca, Mathilde Sibony, Zack Sanborn, Michelle Bellair, Christian Buhay, Kyle Covington, Mahmoud Dahdouli, Huyen Dinh, Harsha Doddapaneni, Brittany Downs, Jennifer Drummond, Richard Gibbs, Walker Hale, Yi Han, Alicia Hawes, Jianhong Hu, Nipun Kakkar, Divya Kalra, Ziad Khan, Christine Kovar, Sandy Lee, Lora Lewis, Margaret Morgan, Donna Morton, Donna Muzny, Jireh Santibanez, Liu Xi, Bertrand Dousset, Lionel Groussin, Rossella Libé, Lynda Chin, Sheila Reynolds, Ilya Shmulevich, Sudha Chudamani, Jia Liu, Laxmi Lolla, Ye Wu, Jen Jen Yeh, Saianand Balu, Tom Bodenheimer, Alan P Hoyle, Stuart R Jefferys, Shaowu Meng, Lisle E Mose, Yan Shi, Janae V Simons, Matthew G Soloway, Junyuan Wu, Wei Zhang, Kenna R Mills Shaw, John A Demchok, Ina Felau, Margi Sheth, Roy Tarnuzzer, Zhining Wang, Liming Yang, Jean C Zenklusen, Jiashan Julia Zhang, Tanja Davidsen, Catherine Crawford, Carolyn M Hutter, Heidi J Sofia, Jeffrey Roach, Wiam Bshara, Carmelo Gaudioso, Carl Morrison, Patsy Soon, Shelley Alonso, Julien Baboud, Todd Pihl, Rohini Raman, Qiang Sun, Yunhu Wan, Rashi Naresh, Harindra Arachchi, Rameen Beroukhim, Scott L Carter, Juok Cho, Scott Frazer, Stacey B Gabriel, Gad Getz, David I Heiman, Jaegil Kim, Michael S Lawrence, Pei Lin, Michael S Noble, Gordon Saksena, Steven E Schumacher, Carrie Sougnez, Doug Voet, Hailei Zhang, Jay Bowen, Sara Coppens, Julie M Gastier-Foster, Mark Gerken, Carmen Helsel, Kristen M Leraas, Tara M Lichtenberg, Nilsa C Ramirez, Lisa Wise, Erik Zmuda, Stephen Baylin, James G Herman, Janine LoBello, Aprill Watanabe, David Haussler, Amie Radenbaugh, Arjun Rao, Jingchun Zhu, Detlef K Bartsch, Silviu Sbiera, Bruno Allolio, Timo Deutschbein, Cristina Ronchi, Victoria M Raymond, Michelle Vinco, Lina Shao, Linda Amble, Moiz S Bootwalla, Phillip H Lai, David J Van Den Berg, Daniel J Weisenberger, Bruce Robinson, Zhenlin Ju, Hoon Kim, Shiyun Ling, Wenbin Liu, Yiling Lu, Gordon B Mills, Kanishka Sircar, Qianghu Wang, Kosuke Yoshihara, Peter W Laird, Yu Fan, Wenyi Wang, Eve Shinbrot, Martin Reincke, John N Weinstein, Sam Meier, Timothy Defreitas

Affiliations

¹ 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.
² 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.
³ Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA.
⁴ Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
⁵ The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, Baltimore, MD 21287, USA.
⁶ 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.
⁷ 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.
⁸ Institute for Systems Biology, Seattle, WA 98109, USA.
⁹ 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.
¹⁰ Translational Genomics Research Institute, Phoenix, AZ 85004, USA.
¹¹ 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.
¹² University of California Santa Cruz Genomics Institute, University California Santa Cruz, Santa Cruz, CA 95064, USA.
¹³ 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.
¹⁴ 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.
¹⁵ Department of Laboratory Medicine and Pathobiology, University Health Network, Toronto, ON M5G 2C4, Canada.
¹⁶ Canada's Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, BC V5Z 4S6, Canada.
¹⁷ Department of Computer Science, Brown University, Providence, RI 02906, USA.
¹⁸ Departments of Cell & Developmental Biology, Pathology, Molecular & Integrative Physiology, Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA.
¹⁹ 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.
²⁰ 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.
²¹ 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.
²² 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.
²³ 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.
²⁴ Endocrine Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
²⁵ Translational Genomics Research Institute, Phoenix, AZ 85004, USA; NantOmics, LLC, The Biodesign Institute, Arizona State University, Tempe, AZ 85287-5001, USA.
²⁶ 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.
²⁷ 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.
²⁸ 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.

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.

Publication types

Multicenter Study
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Adolescent
Adrenal Cortex Neoplasms / genetics*
Adrenal Cortex Neoplasms / pathology
Adrenal Cortex Neoplasms / therapy
Adrenocortical Carcinoma / genetics*
Adrenocortical Carcinoma / pathology
Adrenocortical Carcinoma / therapy
Adult
Aged
Aged, 80 and over
Child
DNA Methylation
Disease-Free Survival
Female
Gene Expression Profiling / methods
Gene Expression Regulation, Neoplastic
Genetic Predisposition to Disease / genetics
Genome, Human / genetics*
Genomics / methods*
Humans
Male
Middle Aged
Mutation
Outcome Assessment, Health Care
Prognosis
Young Adult

Abstract

Publication types

MeSH terms

Grants and funding