Integrated Molecular Characterization of Testicular Germ Cell Tumors

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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.

In Brief

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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Most cited references 41

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CTdatabase: a knowledge-base of high-throughput and curated data on cancer-testis antigens

Luiz Gonzaga Almeida, Noboru J. Sakabe, Alice deOliveira … (2009)

The potency of the immune response has still to be harnessed effectively to combat human cancers. However, the discovery of T-cell targets in melanomas and other tumors has raised the possibility that cancer vaccines can be used to induce a therapeutically effective immune response against cancer. The targets, cancer-testis (CT) antigens, are immunogenic proteins preferentially expressed in normal gametogenic tissues and different histological types of tumors. Therapeutic cancer vaccines directed against CT antigens are currently in late-stage clinical trials testing whether they can delay or prevent recurrence of lung cancer and melanoma following surgical removal of primary tumors. CT antigens constitute a large, but ill-defined, family of proteins that exhibit a remarkably restricted expression. Currently, there is a considerable amount of information about these proteins, but the data are scattered through the literature and in several bioinformatic databases. The database presented here, CTdatabase (http://www.cta.lncc.br), unifies this knowledge to facilitate both the mining of the existing deluge of data, and the identification of proteins alleged to be CT antigens, but that do not have their characteristic restricted expression pattern. CTdatabase is more than a repository of CT antigen data, since all the available information was carefully curated and annotated with most data being specifically processed for CT antigens and stored locally. Starting from a compilation of known CT antigens, CTdatabase provides basic information including gene names and aliases, RefSeq accession numbers, genomic location, known splicing variants, gene duplications and additional family members. Gene expression at the mRNA level in normal and tumor tissues has been collated from publicly available data obtained by several different technologies. Manually curated data related to mRNA and protein expression, and antigen-specific immune responses in cancer patients are also available, together with links to PubMed for relevant CT antigen articles.

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DNA methylation screening identifies driver epigenetic events of cancer cell survival.

Daniel D. De Carvalho, Shikhar Sharma, Jueng Soo You … (2012)

Cancer cells typically exhibit aberrant DNA methylation patterns that can drive malignant transformation. Whether cancer cells are dependent on these abnormal epigenetic modifications remains elusive. We used experimental and bioinformatic approaches to unveil genomic regions that require DNA methylation for survival of cancer cells. First, we surveyed the residual DNA methylation profiles in cancer cells with highly impaired DNA methyltransferases. Then, we clustered these profiles according to their DNA methylation status in primary normal and tumor tissues. Finally, we used gene expression meta-analysis to identify regions that are dependent on DNA methylation-mediated gene silencing. We further showed experimentally that these genes must be silenced by DNA methylation for cancer cell survival, suggesting these are key epigenetic events associated with tumorigenesis. Copyright © 2012 Elsevier Inc. All rights reserved.

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Circulating serum miRNA (miR-367-3p, miR-371a-3p, miR-372-3p and miR-373-3p) as biomarkers in patients with testicular germ cell cancer.

Isabella Syring, Joanna Bartels, Stefan Holdenrieder … (2015)

Classic serum tumor markers (human chorionic gonadotropin, α1-fetoprotein and lactate dehydrogenase) have an important role in managing testicular germ cell tumor. Since only 60% of all patients with testicular germ cell tumor have elevations of these markers, there is a need for new biomarkers with greater sensitivity/specificity. miRNAs are deregulated in cancer and could serve as noninvasive serum biomarkers. We explored the role of serum miRNAs as a novel biomarker in patients with testicular germ cell tumor.

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Author and article information

Journal

Journal ID (nlm-journal-id): 101573691

Journal ID (pubmed-jr-id): 39703

Journal ID (nlm-ta): Cell Rep

Journal ID (iso-abbrev): Cell Rep

Title: Cell reports

ISSN (Electronic): 2211-1247

Publication date Nihms-submitted: 27 June 2018

Publication date (Print): 12 June 2018

Publication date PMC-release: 03 August 2018

Volume: 23

Issue: 11

Pages: 3392-3406

Affiliations

[1 ]Van Andel Research Institute, Grand Rapids, MI 49503, USA

[2 ]The Eli and Edythe L. Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, MA 02142, USA

[3 ]Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA

[4 ]Tufts University School of Medicine, 136 Harrison Avenue, Boston, MA 02111, USA

[5 ]Department of Genetics, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA

[6 ]Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA

[7 ]Department of Genomic Medicine, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA

[8 ]Canada’s Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, BC V5Z 4S6, Canada

[9 ]Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA

[10 ]Institute for Systems Biology, Seattle, WA 98109, USA

[11 ]Department of Biomolecular Engineering and Center for Biomolecular Science and Engineering, University of California, Santa Cruz, Santa Cruz, CA 95064, USA

[12 ]Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA

[13 ]Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA

[14 ]Division of Translational Medicine and Human Genetics, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19105, USA

[15 ]Division of Genetics and Metabolism, Department of Pediatrics, Children’s Hospital of Philadelphia, Philadelphia, PA 19104, USA

[16 ]University of Michigan Hospital and Health Systems, 2G332 UH, 1500 East Medical Center Drive, Ann Arbor, MI 48109, USA

[17 ]Scott Department of Urology, Baylor College of Medicine, Houston, TX 77030, USA

[18 ]University of Wisconsin School of Medicine and Public Health, Madison, WI 53726, USA

[19 ]Genitourinary Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA

[20 ]Molecular Oncology Research Center, Barretos Cancer Hospital, Rua Antenor Duarte Villela, 1331, Barretos, Sao Paolo-SP, 14784-400, Brazil

[21 ]Institute of Human Genetics, University of Ulm, 89081 Ulm, Germany

[22 ]Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany

[23 ]Department of Urology, University Hospital Center Zagreb, University of Zagreb School of Medicine, 10000 Zagreb, Croatia

[24 ]Department of Clinical Oncology, Barretos Cancer Hospital, Rua Antenor Duarte Villela, 1331, Barretos, Sao Paolo-SP, 14784-400, Brazil

[25 ]The Research Institute at Nationwide Children’s Hospital, Columbus, OH 43205, USA

[26 ]Computational Biology Center, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA

[27 ]National Cancer Institute, NIH, Bethesda, MD 20892, USA

[28 ]National Human Genome Research Institute, NIH, Bethesda, MD 20892, USA

[29 ]Massachusetts General Hospital Cancer Center and Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA

[30 ]Abramson Cancer Center, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA

[31 ]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

Author notes

[* ]Correspondence: cortessis_v@ 123456med.usc.edu (V.K.C.), hoadley@ 123456med.unc.edu (K.A.H.)

[32]

These authors contributed equally

[33]

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Article

Manuscript ID: NIHMS977848

DOI: 10.1016/j.celrep.2018.05.039

PMC ID: 6075738

PubMed ID: 29898407

SO-VID: a17ed8d7-221c-4da2-bd3d-4a0c4fbac4f2

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This is an open access article under the CC BY license ( http://creativecommons.org/licenses/by/4.0/).

Integrated Molecular Characterization of Testicular Germ Cell Tumors

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In Brief

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Evolutionary Cell Biology

Most cited references 41

CTdatabase: a knowledge-base of high-throughput and curated data on cancer-testis antigens

DNA methylation screening identifies driver epigenetic events of cancer cell survival.

Circulating serum miRNA (miR-367-3p, miR-371a-3p, miR-372-3p and miR-373-3p) as biomarkers in patients with testicular germ cell cancer.

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