Abstract

Germ-cell tumours (GCTs) are derived from germ cells and occur most frequently in the testes1,2. GCTs are histologically heterogeneous and distinctly curable with chemotherapy3. Gains of chromosome arm 12p and aneuploidy are nearly universal in GCTs4,5,6, but specific somatic genomic features driving tumour initiation, chemosensitivity and progression are incompletely characterized. Here, using clinical whole-exome and transcriptome sequencing of precursor, primary (testicular and mediastinal) and chemoresistant metastatic human GCTs, we show that the primary somatic feature of GCTs is highly recurrent chromosome arm level amplifications and reciprocal deletions (reciprocal loss of heterozygosity), variations that are significantly enriched in GCTs compared to 19 other cancer types. These tumours also acquire KRAS mutations during the development from precursor to primary disease, and primary testicular GCTs (TGCTs) are uniformly wild type for TP53. In addition, by functional measurement of apoptotic signalling (BH3 profiling) of fresh tumour and adjacent tissue7, we find that primary TGCTs have high mitochondrial priming that facilitates chemotherapy-induced apoptosis. Finally, by phylogenetic analysis of serial TGCTs that emerge with chemotherapy resistance, we show how TGCTs gain additional reciprocal loss of heterozygosity and that this is associated with loss of pluripotency markers (NANOG and POU5F1)8,9 in chemoresistant teratomas or transformed carcinomas. Our results demonstrate the distinct genomic features underlying the origins of this disease and associated with the chemosensitivity phenotype, as well as the rare progression to chemoresistance. These results identify the convergence of cancer genomics, mitochondrial priming and GCT evolution, and may provide insights into chemosensitivity and resistance in other cancers.

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Acknowledgements

We thank the patients for contributing to this study, and H.Taylor-Weiner for feedback on ES cells. This work was supported by NIH U54 HG003067, NIH 1K08 CA188615 (E.M.V.), Damon Runyon Clinical Investigator Award (E.M.V.), Shawmut Design and Construction Pan Mass Challenge Team (C.S.), and Giovino Jimmy Fund Golf Tournament (C.S.).

Author information

Author notes

    • Amaro Taylor-Weiner
    •  & Travis Zack

    These authors contributed equally to this work.

    • Christopher Sweeney
    •  & Eliezer M Van Allen

    These authors jointly supervised this work.

Affiliations

  1. Division of Medical Sciences, Harvard University, Boston, Massachusetts 02115, USA

    • Amaro Taylor-Weiner
    •  & Travis Zack
  2. Cancer Program, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA

    • Amaro Taylor-Weiner
    • , G. Celine Han
    • , Ali Amin-Mansour
    • , Steven E. Schumacher
    • , Stacey Gabriel
    • , Rameen Beroukhim
    • , Gad Getz
    • , Scott L. Carter
    •  & Eliezer M Van Allen
  3. Health Sciences and Technology, Harvard Medical School, Boston, Massachusetts 02115, USA

    • Travis Zack
  4. Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA

    • Elizabeth O’Donnell
    • , Jennifer L. Guerriero
    • , Brandon Bernard
    • , G. Celine Han
    • , Rameen Beroukhim
    • , Anthony Letai
    • , Christopher Sweeney
    •  & Eliezer M Van Allen
  5. Department of Medical Oncology, Massachusetts General Hospital, Boston, Massachusetts 02114, USA

    • Elizabeth O’Donnell
  6. Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, USA

    • Anita Reddy
  7. Division of Genetics and Genomics, Department of Medicine, Boston Children’s Hospital, Massachusetts 02115, USA

    • Saud AlDubayan
  8. Department of Medicine, King Saud bin Abdulaziz University for Health Sciences, Saudi Arabia

    • Saud AlDubayan
  9. Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA

  10. Division of Genetics and Epidemiology, The Institute of Cancer Research, Fulham Road, London SW3 6JB, UK

    • Kevin Litchfield
    •  & Clare Turnbull
  11. William Harvey Research Institute, Queen Mary University London, Charterhouse Square, London EC1M 6BQ, UK

    • Kevin Litchfield
    •  & Clare Turnbull
  12. Cancer Center and Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts 02114, USA

    • Gad Getz
  13. Center for Cancer Precision Medicine, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA

    • Scott L. Carter
    •  & Eliezer M Van Allen
  14. Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215 , USA

    • Scott L. Carter
  15. Harvard T.H. Chan School of Public Health, Boston, Massachusetts 02115, USA

    • Scott L. Carter
  16. Department of Pathology, Brigham and Women’s Hospital, Boston, Massachusetts 02115, USA

    • Michelle S. Hirsch

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Contributions

A.T.-W., T.Z., B.B., G.C.H., S.A., A.A.-M. and E.M.V. performed genomic analysis of discovery cohort. A.T.-W., T.Z., B.B., E.O., M.H., C.S. and E.M.V performed clinical integration and analysis. J.L.G. and A.L. performed BH3 profiling experiments. S.S., S.L.C., R.B. and G.G. contributed methodology and analysis review. A.R. and E.M.V. performed biological review of genomic findings. S.G. performed sequencing assays. A.T.-W., T.Z., K.L., C.T. and E.M.V. performed genomic analysis of validation cohort. M.H. performed pathology and histological evaluation of clinical samples. A.T.-W., T.Z., B.B., C.S. and E.M.V. prepared manuscript and figures.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Eliezer M Van Allen.

Reviewer Information Nature thanks K. Nathanson and the other anonymous reviewer(s) for their contribution to the peer review of this work.

Extended data

Supplementary information

Excel files

  1. 1.

    Supplementary Table 1

    Clinical and genomic overview of GCT cohort. This table lists histological subclass, vital status, mutation load, and location of the primary and initially sequenced metastases shown in figure 1.

  2. 2.

    Supplementary Table 2

    Summary clinical data. This table lists aggregate summary phenotypic data, including therapies and response, for this cohort.

  3. 3.

    Supplementary Table 3

    Mutation significance analysis. Table of significant (q < 0.2) genes uncovered with MutSigCV run on the discovery cohort.

  4. 4.

    Supplementary Table 4

    Mutation data for all samples. All mutations and small insertions and deletions called in this cohort.

  5. 5.

    Supplementary Table 6

    ABSOLUTE purity and ploidy solutions. This table lists purity, ploidy and genome doubling status of each tumor as assessed by ABSOLUTE.

  6. 6.

    Supplementary Table 7

    Gene expression data. This table has transcript per million expression values by sample for TP53, NANOG and POU5F1.

  7. 7.

    Supplementary Table 8

    Detailed clinical annotations for multi-regional sampling subset. This table lists treatment regimen, location, and histological subtype of each sample in figure 4.

Text files

  1. 1.

    Supplementary Table 5

    ABSOLUTE allelic segmented copy-number data. Allelic copy number data used to perform deconstructions and construct phylogenetic trees.

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DOI

https://doi.org/10.1038/nature20596

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