Integrated Molecular Characterization of Testicular Germ Cell Tumors

Cancer Genome Atlas Research Network

doi:10.1016/j.celrep.2018.05.039

Integrated Molecular Characterization of Testicular Germ Cell Tumors

Cancer Genome Atlas Research Network

Onderzoeksoutput: Bijdrage aan tijdschrift › Artikel › peer review

313 Citaten (Scopus)

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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.

Originele taal-2	Engels
Pagina's (van-tot)	3392-3406
Aantal pagina's	15
Tijdschrift	Cell reports
Volume	23
Nummer van het tijdschrift	11
DOI's	https://doi.org/10.1016/j.celrep.2018.05.039
Status	Gepubliceerd - 12 jun. 2018
Extern gepubliceerd	Ja

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10.1016/j.celrep.2018.05.039

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@article{bab356da13484f9bb45b43151ec3ed35,

title = "Integrated Molecular Characterization of Testicular Germ Cell Tumors",

abstract = "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.",

keywords = "DNA Copy Number Variations, DNA Methylation, Gene Expression Regulation, Neoplastic, Humans, Male, MicroRNAs/metabolism, Neoplasms, Germ Cell and Embryonal/classification, Proto-Oncogene Proteins c-kit/genetics, Seminoma/metabolism, Testicular Neoplasms/classification, ras Proteins/genetics",

author = "{Cancer Genome Atlas Research Network} and Hui Shen and Juliann Shih and Hollern, {Daniel P} and Linghua Wang and Reanne Bowlby and Tickoo, {Satish K} and V{\'e}steinn Thorsson and Mungall, {Andrew J} and Yulia Newton and Hegde, {Apurva M} and Joshua Armenia and Francisco S{\'a}nchez-Vega and John Pluta and Pyle, {Louise C} and Rohit Mehra and Reuter, {Victor E} and Guilherme Godoy and Jeffrey Jones and Shelley, {Carl S} and Feldman, {Darren R} and Vidal, {Daniel O} and Davor Lessel and Tomislav Kulis and C{\'a}rcano, {Flavio M} and Leraas, {Kristen M} and Lichtenberg, {Tara M} and Denise Brooks and Cherniack, {Andrew D} and Juok Cho and Heiman, {David I} and Katayoon Kasaian and Minwei Liu and Noble, {Michael S} and Liu Xi and Hailei Zhang and Wanding Zhou and ZenKlusen, {Jean C} and Hutter, {Carolyn M} and Ina Felau and Jiashan Zhang and Nikolaus Schultz and Gad Getz and Matthew Meyerson and Stuart, {Joshua M} and Rehan Akbani and Wheeler, {David A} and Laird, {Peter W} and Nathanson, {Katherine L} and Cortessis, {Victoria K} and Hoadley, {Katherine A}",

year = "2018",

month = jun,

day = "12",

doi = "10.1016/j.celrep.2018.05.039",

language = "English",

volume = "23",

pages = "3392--3406",

journal = "Cell reports",

issn = "2211-1247",

publisher = "Cell Press",

number = "11",

}

TY - JOUR

T1 - Integrated Molecular Characterization of Testicular Germ Cell Tumors

AU - Cancer Genome Atlas Research Network

AU - Shen, Hui

AU - Shih, Juliann

AU - Hollern, Daniel P

AU - Wang, Linghua

AU - Bowlby, Reanne

AU - Tickoo, Satish K

AU - Thorsson, Vésteinn

AU - Mungall, Andrew J

AU - Newton, Yulia

AU - Hegde, Apurva M

AU - Armenia, Joshua

AU - Sánchez-Vega, Francisco

AU - Pluta, John

AU - Pyle, Louise C

AU - Mehra, Rohit

AU - Reuter, Victor E

AU - Godoy, Guilherme

AU - Jones, Jeffrey

AU - Shelley, Carl S

AU - Feldman, Darren R

AU - Vidal, Daniel O

AU - Lessel, Davor

AU - Kulis, Tomislav

AU - Cárcano, Flavio M

AU - Leraas, Kristen M

AU - Lichtenberg, Tara M

AU - Brooks, Denise

AU - Cherniack, Andrew D

AU - Cho, Juok

AU - Heiman, David I

AU - Kasaian, Katayoon

AU - Liu, Minwei

AU - Noble, Michael S

AU - Xi, Liu

AU - Zhang, Hailei

AU - Zhou, Wanding

AU - ZenKlusen, Jean C

AU - Hutter, Carolyn M

AU - Felau, Ina

AU - Zhang, Jiashan

AU - Schultz, Nikolaus

AU - Getz, Gad

AU - Meyerson, Matthew

AU - Stuart, Joshua M

AU - Akbani, Rehan

AU - Wheeler, David A

AU - Laird, Peter W

AU - Nathanson, Katherine L

AU - Cortessis, Victoria K

AU - Hoadley, Katherine A

PY - 2018/6/12

Y1 - 2018/6/12

N2 - 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.

AB - 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.

KW - DNA Copy Number Variations

KW - DNA Methylation

KW - Gene Expression Regulation, Neoplastic

KW - Humans

KW - Male

KW - MicroRNAs/metabolism

KW - Neoplasms, Germ Cell and Embryonal/classification

KW - Proto-Oncogene Proteins c-kit/genetics

KW - Seminoma/metabolism

KW - Testicular Neoplasms/classification

KW - ras Proteins/genetics

UR - http://www.scopus.com/inward/record.url?scp=85048288974&partnerID=8YFLogxK

U2 - 10.1016/j.celrep.2018.05.039

DO - 10.1016/j.celrep.2018.05.039

M3 - Article

C2 - 29898407

SN - 2211-1247

VL - 23

SP - 3392

EP - 3406

JO - Cell reports

JF - Cell reports

IS - 11

ER -

Integrated Molecular Characterization of Testicular Germ Cell Tumors

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