Integrated Molecular Characterization of Testicular Germ Cell Tumors

The Cancer Genome Atlas Research Network

    Research output: Contribution to journalArticle

    52 Citations (Scopus)

    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. 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.

    Original languageEnglish (US)
    Pages (from-to)3392-3406
    Number of pages15
    JournalCell Reports
    Volume23
    Issue number11
    DOIs
    StatePublished - Jun 12 2018

    Fingerprint

    Seminoma
    Tumors
    Cells
    Embryonal Carcinoma
    Mutation
    Teratoma
    MicroRNAs
    Epigenomics
    Biomarkers
    Endodermal Sinus Tumor
    Molecular Pathology
    Aneuploidy
    DNA Methylation
    Proteomics
    Methylation
    Histology
    Infiltration
    Testicular Germ Cell Tumor
    Assays
    DNA

    Keywords

    • copy number
    • DNA methylation
    • exome sequencing
    • KIT
    • miR-375
    • nonseminoma
    • seminoma
    • testicular germ cell tumors
    • The Cancer Genome Atlas

    ASJC Scopus subject areas

    • Biochemistry, Genetics and Molecular Biology(all)

    Cite this

    Integrated Molecular Characterization of Testicular Germ Cell Tumors. / The Cancer Genome Atlas Research Network.

    In: Cell Reports, Vol. 23, No. 11, 12.06.2018, p. 3392-3406.

    Research output: Contribution to journalArticle

    The Cancer Genome Atlas Research Network 2018, 'Integrated Molecular Characterization of Testicular Germ Cell Tumors', Cell Reports, vol. 23, no. 11, pp. 3392-3406. https://doi.org/10.1016/j.celrep.2018.05.039
    The Cancer Genome Atlas Research Network. / Integrated Molecular Characterization of Testicular Germ Cell Tumors. In: Cell Reports. 2018 ; Vol. 23, No. 11. pp. 3392-3406.
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    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. 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.",
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    AU - The Cancer Genome Atlas Research Network

    AU - Shen, Hui

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    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

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    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 - Wang, Linghua

    AU - Xi, Liu

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    AU - Hughes, Daniel

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    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. 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.

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    KW - DNA methylation

    KW - exome sequencing

    KW - KIT

    KW - miR-375

    KW - nonseminoma

    KW - seminoma

    KW - testicular germ cell tumors

    KW - The Cancer Genome Atlas

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