Cell Reports (Jun 2018)
Integrated Molecular Characterization of Testicular Germ Cell Tumors
- Hui Shen,
- Juliann Shih,
- Daniel P. Hollern,
- Linghua Wang,
- Reanne Bowlby,
- Satish K. Tickoo,
- Vésteinn Thorsson,
- Andrew J. Mungall,
- Yulia Newton,
- Apurva M. Hegde,
- Joshua Armenia,
- Francisco Sánchez-Vega,
- John Pluta,
- Louise C. Pyle,
- Rohit Mehra,
- Victor E. Reuter,
- Guilherme Godoy,
- Jeffrey Jones,
- Carl S. Shelley,
- Darren R. Feldman,
- Daniel O. Vidal,
- Davor Lessel,
- Tomislav Kulis,
- Flavio M. Cárcano,
- Kristen M. Leraas,
- Tara M. Lichtenberg,
- Denise Brooks,
- Andrew D. Cherniack,
- Juok Cho,
- David I. Heiman,
- Katayoon Kasaian,
- Minwei Liu,
- Michael S. Noble,
- Liu Xi,
- Hailei Zhang,
- Wanding Zhou,
- Jean C. ZenKlusen,
- Carolyn M. Hutter,
- Ina Felau,
- Jiashan Zhang,
- Nikolaus Schultz,
- Gad Getz,
- Matthew Meyerson,
- Joshua M. Stuart,
- Rehan Akbani,
- David A. Wheeler,
- Peter W. Laird,
- Katherine L. Nathanson,
- Victoria K. Cortessis,
- Katherine A. Hoadley,
- Linghua Wang,
- Liu Xi,
- David Wheeler,
- Daniel Hughes,
- Kyle Covington,
- Joy C. Jayaseelan,
- Viktoriya Korchina,
- Lora Lewis,
- Jianhong Hu,
- HarshaVardhan Doddapaneni,
- Donna Muzny,
- Richard Gibbs,
- Katherine A. Hoadley,
- Daniel Hollern,
- Benjamin G. Vincent,
- Shengjie Chai,
- Christof C. Smith,
- J. Todd Auman,
- Yan Shi,
- Shaowu Meng,
- Tara Skelly,
- Donghui Tan,
- Umadevi Veluvolu,
- Piotr A. Mieczkowski,
- Corbin D. Jones,
- Matthew D. Wilkerson,
- Saianand Balu,
- Tom Bodenheimer,
- Alan P. Hoyle,
- Stuart R. Jefferys,
- Lisle E. Mose,
- Janae V. Simons,
- Matthew G. Soloway,
- Jeffrey Roach,
- Joel S. Parker,
- D. Neil Hayes,
- Charles M. Perou,
- Juliann Shih,
- Andrew D. Cherniack,
- Matthew Meyerson,
- Gordon Saksena,
- Carrie Cibulskis,
- Steven E. Schumacher,
- Rameen Beroukhim,
- Stacey B. Gabriel,
- Reanne Bowlby,
- Andrew J. Mungall,
- Denise Brooks,
- Katayoon Kasaian,
- Adrian Ally,
- Miruna Balasundaram,
- Rebecca Carlsen,
- Dorothy Cheung,
- Eric Chuah,
- Noreen Dhalla,
- Robert A. Holt,
- Steven J.M. Jones,
- Yussanne Ma,
- Michael Mayo,
- Richard A. Moore,
- A. Gordon Robertson,
- Jacqueline E. Schein,
- Payal Sipahimalani,
- Angela Tam,
- Nina Thiessen,
- Tina Wong,
- Marco A. Marra,
- Hui Shen,
- Wanding Zhou,
- Peter W. Laird,
- Daniel J. Weisenberger,
- David J. Van Den Berg,
- Phillip H. Lai,
- Mario Berrios,
- Andrea Holbrook,
- Moiz S. Bootwalla,
- Dennis T. Maglinte,
- Joshua Armenia,
- Francisco Sánchez-Vega,
- Nikolaus Schultz,
- Debyani Chakravarty,
- Jianjiong Gao,
- Zachary Heins,
- Ritika Kundra,
- Angelica Ochoa,
- Minwei Liu,
- Chris Sander,
- Marc Ladanyi,
- Vesteinn Thorsson,
- Amie J. Radenbaugh,
- Yulia Newton,
- Joshua M. Stuart,
- Juok Cho,
- David I. Heiman,
- Michael S. Noble,
- Hailei Zhang,
- Gad Getz,
- Nils Gehlenborg,
- Gordon Saksena,
- Doug Voet,
- Pei Lin,
- Scott Frazer,
- Jaegil Kim,
- Michael S. Lawrence,
- Sam Meier,
- Timothy Defreitas,
- Lynda Chin,
- Apurva M. Hegde,
- Rehan Akbani,
- John N. Weinstein,
- Wenbin Liu,
- Gordon B. Mills,
- Yiling Lu,
- Louise C. Pyle,
- John Pluta,
- Katherine L. Nathanson,
- Satish K. Tickoo,
- Victor E. Reuter,
- Rohit Mehra,
- Leendert Looijenga,
- Alan H. Bryce,
- Flavio M. Cárcano,
- André L. Carvalho,
- Victoria K. Cortessis,
- Darren Feldman,
- Guilherme Godoy,
- Michael Ittmann,
- Jeffrey Jones,
- Tomislav Kulis,
- Seth Lerner,
- Davor Lessel,
- Katherine L. Nathanson,
- Carl S. Shelley,
- Daniel O. Vidal,
- Kristen M. Leraas,
- Tara M. Lichtenberg,
- Jay Bowen,
- Julie M. Gastier-Foster,
- Mark Gerken,
- Carmen Helsel,
- Nilsa C. Ramirez,
- Lisa Wise,
- Erik Zmuda,
- Sandra Cottingham,
- David Chesla,
- Charles Saller,
- Katherine Tarvin,
- Luiz Fernando Lopes,
- Cristovam Scapulatempo-Neto,
- Natália D.A. Aredes,
- Wolter Oosterhuis,
- Ad Gillis,
- Hans Stoop,
- Wil Eijkenboom,
- George Sandusky,
- Sue Ellen Martin,
- Manju Aron,
- Siamak Daneshmand,
- Hooman Djaladat,
- David Quinn,
- Tanya Dorff,
- Jochen K. Lennerz,
- Leigh B. Thorne,
- Marija Gamulin,
- Zeljko Kastelan,
- Tvrtko Hudolin,
- Christian Kubisch,
- Lori Boice,
- Mei Huang,
- Amy H. Perou,
- W. Kimryn Rathmell,
- Todd Pihl,
- Yunhu Wan,
- Qiang Sun,
- Rashi Naresh,
- Sudha Chudamani,
- Jia Liu,
- Laxmi Lolla,
- Ye Wu,
- Martin L. Ferguson,
- Jean C. Zenklusen,
- Ina Felau,
- Jiashan (Julia) Zhang,
- Margi Sheth,
- John A. Demchok,
- Liming Yang,
- Zhining Wang,
- Roy Tarnuzzer,
- Carolyn M. Hutter,
- Heidi J. Sofia,
- Tanja M. Davidsen
Affiliations
- Hui Shen
- Van Andel Research Institute, Grand Rapids, MI 49503, USA
- Juliann Shih
- 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, Boston, MA 02215, USA; Tufts University School of Medicine, 136 Harrison Avenue, Boston, MA 02111, USA
- Daniel P. Hollern
- Department of Genetics, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
- Linghua Wang
- Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA; Department of Genomic Medicine, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA
- Reanne Bowlby
- Canada’s Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, BC V5Z 4S6, Canada
- Satish K. Tickoo
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
- Vésteinn Thorsson
- Institute for Systems Biology, Seattle, WA 98109, USA
- Andrew J. Mungall
- Canada’s Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, BC V5Z 4S6, Canada
- Yulia Newton
- Department of Biomolecular Engineering and Center for Biomolecular Science and Engineering, University of California, Santa Cruz, Santa Cruz, CA 95064, USA
- Apurva M. Hegde
- Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
- Joshua Armenia
- Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA
- Francisco Sánchez-Vega
- Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA
- John Pluta
- Division of Translational Medicine and Human Genetics, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19105, USA
- Louise C. Pyle
- Division of Translational Medicine and Human Genetics, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19105, USA; Division of Genetics and Metabolism, Department of Pediatrics, Children’s Hospital of Philadelphia, Philadelphia, PA 19104, USA
- Rohit Mehra
- University of Michigan Hospital and Health Systems, 2G332 UH, 1500 East Medical Center Drive, Ann Arbor, MI 48109, USA
- Victor E. Reuter
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
- Guilherme Godoy
- Scott Department of Urology, Baylor College of Medicine, Houston, TX 77030, USA
- Jeffrey Jones
- Scott Department of Urology, Baylor College of Medicine, Houston, TX 77030, USA
- Carl S. Shelley
- University of Wisconsin School of Medicine and Public Health, Madison, WI 53726, USA
- Darren R. Feldman
- Genitourinary Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
- Daniel O. Vidal
- Molecular Oncology Research Center, Barretos Cancer Hospital, Rua Antenor Duarte Villela, 1331, Barretos, Sao Paolo-SP, 14784-400, Brazil
- Davor Lessel
- Institute of Human Genetics, University of Ulm, 89081 Ulm, Germany; Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany
- Tomislav Kulis
- Department of Urology, University Hospital Center Zagreb, University of Zagreb School of Medicine, 10000 Zagreb, Croatia
- Flavio M. Cárcano
- Department of Clinical Oncology, Barretos Cancer Hospital, Rua Antenor Duarte Villela, 1331, Barretos, Sao Paolo-SP, 14784-400, Brazil
- Kristen M. Leraas
- The Research Institute at Nationwide Children’s Hospital, Columbus, OH 43205, USA
- Tara M. Lichtenberg
- The Research Institute at Nationwide Children’s Hospital, Columbus, OH 43205, USA
- Denise Brooks
- Canada’s Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, BC V5Z 4S6, Canada
- Andrew D. Cherniack
- 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, Boston, MA 02215, USA
- Juok Cho
- The Eli and Edythe L. Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, MA 02142, USA
- David I. Heiman
- The Eli and Edythe L. Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, MA 02142, USA
- Katayoon Kasaian
- Canada’s Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, BC V5Z 4S6, Canada
- Minwei Liu
- Computational Biology Center, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
- Michael S. Noble
- The Eli and Edythe L. Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, MA 02142, USA
- Liu Xi
- Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA
- Hailei Zhang
- The Eli and Edythe L. Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, MA 02142, USA
- Wanding Zhou
- Van Andel Research Institute, Grand Rapids, MI 49503, USA
- Jean C. ZenKlusen
- National Cancer Institute, NIH, Bethesda, MD 20892, USA
- Carolyn M. Hutter
- National Human Genome Research Institute, NIH, Bethesda, MD 20892, USA
- Ina Felau
- National Cancer Institute, NIH, Bethesda, MD 20892, USA
- Jiashan Zhang
- National Cancer Institute, NIH, Bethesda, MD 20892, USA
- Nikolaus Schultz
- Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA
- Gad Getz
- The Eli and Edythe L. Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, MA 02142, USA; Massachusetts General Hospital Cancer Center and Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA
- Matthew Meyerson
- 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, Boston, MA 02215, USA
- Joshua M. Stuart
- Department of Biomolecular Engineering and Center for Biomolecular Science and Engineering, University of California, Santa Cruz, Santa Cruz, CA 95064, USA
- Rehan Akbani
- Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
- David A. Wheeler
- Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA
- Peter W. Laird
- Van Andel Research Institute, Grand Rapids, MI 49503, USA
- Katherine L. Nathanson
- Division of Translational Medicine and Human Genetics, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19105, USA; Abramson Cancer Center, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA
- Victoria K. Cortessis
- Departments of Preventive Medicine and Obstetrics and Gynecology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA; Corresponding author
- Katherine A. Hoadley
- Department of Genetics, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Corresponding author
- Linghua Wang
- Liu Xi
- David Wheeler
- Daniel Hughes
- Kyle Covington
- Joy C. Jayaseelan
- Viktoriya Korchina
- Lora Lewis
- Jianhong Hu
- HarshaVardhan Doddapaneni
- Donna Muzny
- Richard Gibbs
- Katherine A. Hoadley
- Daniel Hollern
- Benjamin G. Vincent
- Shengjie Chai
- Christof C. Smith
- J. Todd Auman
- Yan Shi
- Shaowu Meng
- Tara Skelly
- Donghui Tan
- Umadevi Veluvolu
- Piotr A. Mieczkowski
- Corbin D. Jones
- Matthew D. Wilkerson
- Saianand Balu
- Tom Bodenheimer
- Alan P. Hoyle
- Stuart R. Jefferys
- Lisle E. Mose
- Janae V. Simons
- Matthew G. Soloway
- Jeffrey Roach
- Joel S. Parker
- D. Neil Hayes
- Charles M. Perou
- Juliann Shih
- Andrew D. Cherniack
- Matthew Meyerson
- Gordon Saksena
- Carrie Cibulskis
- Steven E. Schumacher
- Rameen Beroukhim
- Stacey B. Gabriel
- Reanne Bowlby
- Andrew J. Mungall
- Denise Brooks
- Katayoon Kasaian
- Adrian Ally
- Miruna Balasundaram
- Rebecca Carlsen
- Dorothy Cheung
- Eric Chuah
- Noreen Dhalla
- Robert A. Holt
- Steven J.M. Jones
- Yussanne Ma
- Michael Mayo
- Richard A. Moore
- A. Gordon Robertson
- Jacqueline E. Schein
- Payal Sipahimalani
- Angela Tam
- Nina Thiessen
- Tina Wong
- Marco A. Marra
- Hui Shen
- Wanding Zhou
- Peter W. Laird
- Daniel J. Weisenberger
- David J. Van Den Berg
- Phillip H. Lai
- Mario Berrios
- Andrea Holbrook
- Moiz S. Bootwalla
- Dennis T. Maglinte
- Joshua Armenia
- Francisco Sánchez-Vega
- Nikolaus Schultz
- Debyani Chakravarty
- Jianjiong Gao
- Zachary Heins
- Ritika Kundra
- Angelica Ochoa
- Minwei Liu
- Chris Sander
- Marc Ladanyi
- Vesteinn Thorsson
- Amie J. Radenbaugh
- Yulia Newton
- Joshua M. Stuart
- Juok Cho
- David I. Heiman
- Michael S. Noble
- Hailei Zhang
- Gad Getz
- Nils Gehlenborg
- Gordon Saksena
- Doug Voet
- Pei Lin
- Scott Frazer
- Jaegil Kim
- Michael S. Lawrence
- Sam Meier
- Timothy Defreitas
- Lynda Chin
- Apurva M. Hegde
- Rehan Akbani
- John N. Weinstein
- Wenbin Liu
- Gordon B. Mills
- Yiling Lu
- Louise C. Pyle
- John Pluta
- Katherine L. Nathanson
- Satish K. Tickoo
- Victor E. Reuter
- Rohit Mehra
- Leendert Looijenga
- Alan H. Bryce
- Flavio M. Cárcano
- André L. Carvalho
- Victoria K. Cortessis
- Darren Feldman
- Guilherme Godoy
- Michael Ittmann
- Jeffrey Jones
- Tomislav Kulis
- Seth Lerner
- Davor Lessel
- Katherine L. Nathanson
- Carl S. Shelley
- Daniel O. Vidal
- Kristen M. Leraas
- Tara M. Lichtenberg
- Jay Bowen
- Julie M. Gastier-Foster
- Mark Gerken
- Carmen Helsel
- Nilsa C. Ramirez
- Lisa Wise
- Erik Zmuda
- Sandra Cottingham
- David Chesla
- Charles Saller
- Katherine Tarvin
- Luiz Fernando Lopes
- Cristovam Scapulatempo-Neto
- Natália D.A. Aredes
- Wolter Oosterhuis
- Ad Gillis
- Hans Stoop
- Wil Eijkenboom
- George Sandusky
- Sue Ellen Martin
- Manju Aron
- Siamak Daneshmand
- Hooman Djaladat
- David Quinn
- Tanya Dorff
- Jochen K. Lennerz
- Leigh B. Thorne
- Marija Gamulin
- Zeljko Kastelan
- Tvrtko Hudolin
- Christian Kubisch
- Lori Boice
- Mei Huang
- Amy H. Perou
- W. Kimryn Rathmell
- Todd Pihl
- Yunhu Wan
- Qiang Sun
- Rashi Naresh
- Sudha Chudamani
- Jia Liu
- Laxmi Lolla
- Ye Wu
- Martin L. Ferguson
- Jean C. Zenklusen
- Ina Felau
- Jiashan (Julia) Zhang
- Margi Sheth
- John A. Demchok
- Liming Yang
- Zhining Wang
- Roy Tarnuzzer
- Carolyn M. Hutter
- Heidi J. Sofia
- Tanja M. Davidsen
- Journal volume & issue
-
Vol. 23,
no. 11
pp. 3392 – 3406
Abstract
Summary: We studied 137 primary testicular germ cell tumors (TGCTs) using high-dimensional assays of genomic, epigenomic, transcriptomic, and proteomic features. These tumors exhibited high aneuploidy and a paucity of somatic mutations. Somatic mutation of only three genes achieved significance—KIT, KRAS, and NRAS—exclusively in samples with seminoma components. Integrated analyses identified distinct molecular patterns that characterized the major recognized histologic subtypes of TGCT: seminoma, embryonal carcinoma, yolk sac tumor, and teratoma. Striking differences in global DNA methylation and microRNA expression between histology subtypes highlight a likely role of epigenomic processes in determining histologic fates in TGCTs. We also identified a subset of pure seminomas defined by KIT mutations, increased immune infiltration, globally demethylated DNA, and decreased KRAS copy number. We report potential biomarkers for risk stratification, such as miRNA specifically expressed in teratoma, and others with molecular diagnostic potential, such as CpH (CpA/CpC/CpT) methylation identifying embryonal carcinomas. : Shen et al. identify molecular characteristics that classify testicular germ cell tumor types, including a separate subset of seminomas defined by KIT mutations. This provides a set of candidate biomarkers for risk stratification and potential therapeutic targeting. Keywords: The Cancer Genome Atlas, testicular germ cell tumors, seminoma, nonseminoma, DNA methylation, exome sequencing, KIT, copy number, miR-375
