Integrated Molecular Characterization of Testicular Germ Cell Tumors
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,...
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| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2018-06-01
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| Series: | Cell Reports |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S221112471830785X |
| _version_ | 1829117407733481472 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Hui Shen |
| collection | DOAJ |
| description | 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 |
| first_indexed | 2024-12-13T01:16:35Z |
| format | Article |
| id | doaj.art-c533a0bc874e45efaf5d8d5173568742 |
| institution | Directory Open Access Journal |
| issn | 2211-1247 |
| language | English |
| last_indexed | 2024-12-13T01:16:35Z |
| publishDate | 2018-06-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports |
| spelling | doaj.art-c533a0bc874e45efaf5d8d51735687422022-12-22T00:04:20ZengElsevierCell Reports2211-12472018-06-01231133923406Integrated Molecular Characterization of Testicular Germ Cell TumorsHui Shen0Juliann Shih1Daniel P. Hollern2Linghua Wang3Reanne Bowlby4Satish K. Tickoo5Vésteinn Thorsson6Andrew J. Mungall7Yulia Newton8Apurva M. Hegde9Joshua Armenia10Francisco Sánchez-Vega11John Pluta12Louise C. Pyle13Rohit Mehra14Victor E. Reuter15Guilherme Godoy16Jeffrey Jones17Carl S. Shelley18Darren R. Feldman19Daniel O. Vidal20Davor Lessel21Tomislav Kulis22Flavio M. Cárcano23Kristen M. Leraas24Tara M. Lichtenberg25Denise Brooks26Andrew D. Cherniack27Juok Cho28David I. Heiman29Katayoon Kasaian30Minwei Liu31Michael S. Noble32Liu Xi33Hailei Zhang34Wanding Zhou35Jean C. ZenKlusen36Carolyn M. Hutter37Ina Felau38Jiashan Zhang39Nikolaus Schultz40Gad Getz41Matthew Meyerson42Joshua M. Stuart43Rehan Akbani44David A. Wheeler45Peter W. Laird46Katherine L. Nathanson47Victoria K. Cortessis48Katherine A. Hoadley49Linghua WangLiu XiDavid WheelerDaniel HughesKyle CovingtonJoy C. JayaseelanViktoriya KorchinaLora LewisJianhong HuHarshaVardhan DoddapaneniDonna MuznyRichard GibbsKatherine A. HoadleyDaniel HollernBenjamin G. VincentShengjie ChaiChristof C. SmithJ. Todd AumanYan ShiShaowu MengTara SkellyDonghui TanUmadevi VeluvoluPiotr A. MieczkowskiCorbin D. JonesMatthew D. WilkersonSaianand BaluTom BodenheimerAlan P. HoyleStuart R. JefferysLisle E. MoseJanae V. SimonsMatthew G. SolowayJeffrey RoachJoel S. ParkerD. Neil HayesCharles M. PerouJuliann ShihAndrew D. CherniackMatthew MeyersonGordon SaksenaCarrie CibulskisSteven E. SchumacherRameen BeroukhimStacey B. GabrielReanne BowlbyAndrew J. MungallDenise BrooksKatayoon KasaianAdrian AllyMiruna BalasundaramRebecca CarlsenDorothy CheungEric ChuahNoreen DhallaRobert A. HoltSteven J.M. JonesYussanne MaMichael MayoRichard A. MooreA. Gordon RobertsonJacqueline E. ScheinPayal SipahimalaniAngela TamNina ThiessenTina WongMarco A. MarraHui ShenWanding ZhouPeter W. LairdDaniel J. WeisenbergerDavid J. Van Den BergPhillip H. LaiMario BerriosAndrea HolbrookMoiz S. BootwallaDennis T. MaglinteJoshua ArmeniaFrancisco Sánchez-VegaNikolaus SchultzDebyani ChakravartyJianjiong GaoZachary HeinsRitika KundraAngelica OchoaMinwei LiuChris SanderMarc LadanyiVesteinn ThorssonAmie J. RadenbaughYulia NewtonJoshua M. StuartJuok ChoDavid I. HeimanMichael S. NobleHailei ZhangGad GetzNils GehlenborgGordon SaksenaDoug VoetPei LinScott FrazerJaegil KimMichael S. LawrenceSam MeierTimothy DefreitasLynda ChinApurva M. HegdeRehan AkbaniJohn N. WeinsteinWenbin LiuGordon B. MillsYiling LuLouise C. PyleJohn PlutaKatherine L. NathansonSatish K. TickooVictor E. ReuterRohit MehraLeendert LooijengaAlan H. BryceFlavio M. CárcanoAndré L. CarvalhoVictoria K. CortessisDarren FeldmanGuilherme GodoyMichael IttmannJeffrey JonesTomislav KulisSeth LernerDavor LesselKatherine L. NathansonCarl S. ShelleyDaniel O. VidalKristen M. LeraasTara M. LichtenbergJay BowenJulie M. Gastier-FosterMark GerkenCarmen HelselNilsa C. RamirezLisa WiseErik ZmudaSandra CottinghamDavid CheslaCharles SallerKatherine TarvinLuiz Fernando LopesCristovam Scapulatempo-NetoNatália D.A. AredesWolter OosterhuisAd GillisHans StoopWil EijkenboomGeorge SanduskySue Ellen MartinManju AronSiamak DaneshmandHooman DjaladatDavid QuinnTanya DorffJochen K. LennerzLeigh B. ThorneMarija GamulinZeljko KastelanTvrtko HudolinChristian KubischLori BoiceMei HuangAmy H. PerouW. Kimryn RathmellTodd PihlYunhu WanQiang SunRashi NareshSudha ChudamaniJia LiuLaxmi LollaYe WuMartin L. FergusonJean C. ZenklusenIna FelauJiashan (Julia) ZhangMargi ShethJohn A. DemchokLiming YangZhining WangRoy TarnuzzerCarolyn M. HutterHeidi J. SofiaTanja M. DavidsenVan Andel Research Institute, Grand Rapids, MI 49503, USAThe 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, USADepartment of Genetics, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USAHuman 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, USACanada’s Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, BC V5Z 4S6, CanadaDepartment of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USAInstitute for Systems Biology, Seattle, WA 98109, USACanada’s Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, BC V5Z 4S6, CanadaDepartment of Biomolecular Engineering and Center for Biomolecular Science and Engineering, University of California, Santa Cruz, Santa Cruz, CA 95064, USADepartment of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USACenter for Molecular Oncology, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USACenter for Molecular Oncology, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USADivision of Translational Medicine and Human Genetics, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19105, USADivision 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, USAUniversity of Michigan Hospital and Health Systems, 2G332 UH, 1500 East Medical Center Drive, Ann Arbor, MI 48109, USADepartment of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USAScott Department of Urology, Baylor College of Medicine, Houston, TX 77030, USAScott Department of Urology, Baylor College of Medicine, Houston, TX 77030, USAUniversity of Wisconsin School of Medicine and Public Health, Madison, WI 53726, USAGenitourinary Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USAMolecular Oncology Research Center, Barretos Cancer Hospital, Rua Antenor Duarte Villela, 1331, Barretos, Sao Paolo-SP, 14784-400, BrazilInstitute of Human Genetics, University of Ulm, 89081 Ulm, Germany; Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, GermanyDepartment of Urology, University Hospital Center Zagreb, University of Zagreb School of Medicine, 10000 Zagreb, CroatiaDepartment of Clinical Oncology, Barretos Cancer Hospital, Rua Antenor Duarte Villela, 1331, Barretos, Sao Paolo-SP, 14784-400, BrazilThe Research Institute at Nationwide Children’s Hospital, Columbus, OH 43205, USAThe Research Institute at Nationwide Children’s Hospital, Columbus, OH 43205, USACanada’s Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, BC V5Z 4S6, CanadaThe 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, USAThe Eli and Edythe L. Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, MA 02142, USAThe Eli and Edythe L. Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, MA 02142, USACanada’s Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, BC V5Z 4S6, CanadaComputational Biology Center, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USAThe Eli and Edythe L. Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, MA 02142, USAHuman Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USAThe Eli and Edythe L. Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, MA 02142, USAVan Andel Research Institute, Grand Rapids, MI 49503, USANational Cancer Institute, NIH, Bethesda, MD 20892, USANational Human Genome Research Institute, NIH, Bethesda, MD 20892, USANational Cancer Institute, NIH, Bethesda, MD 20892, USANational Cancer Institute, NIH, Bethesda, MD 20892, USACenter for Molecular Oncology, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USAThe 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, USAThe 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, USADepartment of Biomolecular Engineering and Center for Biomolecular Science and Engineering, University of California, Santa Cruz, Santa Cruz, CA 95064, USADepartment of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USAHuman Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USAVan Andel Research Institute, Grand Rapids, MI 49503, USADivision 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, USADepartments 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 authorDepartment of Genetics, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Corresponding authorSummary: 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-375http://www.sciencedirect.com/science/article/pii/S221112471830785X |
| spellingShingle | 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 Integrated Molecular Characterization of Testicular Germ Cell Tumors Cell Reports |
| title | Integrated Molecular Characterization of Testicular Germ Cell Tumors |
| title_full | Integrated Molecular Characterization of Testicular Germ Cell Tumors |
| title_fullStr | Integrated Molecular Characterization of Testicular Germ Cell Tumors |
| title_full_unstemmed | Integrated Molecular Characterization of Testicular Germ Cell Tumors |
| title_short | Integrated Molecular Characterization of Testicular Germ Cell Tumors |
| title_sort | integrated molecular characterization of testicular germ cell tumors |
| url | http://www.sciencedirect.com/science/article/pii/S221112471830785X |
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