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Small cell carcinoma of the ovary, hypercalcemic type, displays frequent inactivating germline and somatic mutations in SMARCA4

Nature Genetics volume 46, pages 427–429 (2014)Cite this article

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A Corrigendum to this article was published on 26 June 2014

A Corrigendum to this article was published on 26 June 2014

This article has been updated

Abstract

Small cell carcinoma of the ovary of hypercalcemic type (SCCOHT) is an extremely rare, aggressive cancer affecting children and young women. We identified germline and somatic inactivating mutations in the SWI/SNF chromatin-remodeling gene SMARCA4 in 69% (9/13) of SCCOHT cases in addition to SMARCA4 protein loss in 82% (14/17) of SCCOHT tumors but in only 0.4% (2/485) of other primary ovarian tumors. These data implicate SMARCA4 in SCCOHT oncogenesis.

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Figure 1: Inactivating germline and somatic SMARCA4 mutations identified in SCCOHT.

Change history

  • 13 June 2014

    In the version of this article initially published, there were errors in the numbers of tumors reported in the text. The abstract reports SMARCA4 mutations in 75% (9/12) of tumors. The correct numbers are 69% (9/13) of tumors. The main text reports immunohistochemical analysis of 15 tumors, with 6 tumors overlapping with the 12 cases sequenced. These should have been reported as 17 tumors, 8 of which were overlapping. The errors do not affect any of the analyses or conclusions in the paper. In addition, a secondary affiliation for author Pilar Ramos was erroneously omitted and should read "School of Life Sciences, Arizona State University, Tempe, Arizona, USA." The errors have been corrected in the HTML and PDF versions of the article.

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Acknowledgements

We particularly thank the families and patients who joined this institutional review board (IRB)-approved study for their critical contributions. We also thank the faculty and staff at TGen from the Macromolecular Analysis & Processing Center (G. Hostetter and J. LoBello) and the Office of Research Compliance & Quality Management (L. Nordstrom, S. Althoff and S. Buchholtz); the Children's Oncology Group for their samples; and B. Vanderhyden (University of Ottawa and Ottawa Hospital Research Institute) for BIN-67 cells. This study was supported by grants from the Marsha Rivkin Center for Ovarian Cancer Research, the Anne Rita Monahan Foundation, the Ovarian Cancer Alliance of Arizona, the Small Cell Ovarian Cancer Foundation and philanthropic support to the TGen Foundation. Further support was provided to A.N.K. and D.G.H. by the Terry Fox Research Initiative New Frontiers Program in Cancer and to A.N.K. by the Molecular Oncologic Pathology Fellowship of the Canadian Institutes of Health Research.

Author information

Author notes

  1. Pilar Ramos and Anthony N Karnezis: These authors contributed equally to this work.

  2. David G Huntsman and Jeffrey M Trent: These authors jointly directed this work.

  3. dhuntsma@bccancer.bc.ca

  4. jtrent@tgen.org

Authors and Affiliations

  1. Division of Integrated Cancer Genomics, Translational Genomics Research Institute (TGen), Phoenix, Arizona, USA

    Pilar Ramos, David W Craig, Aleksandar Sekulic, Megan L Russell, William P D Hendricks, Jason J Corneveaux, Michael T Barrett, Jeffrey Kiefer, Victoria L Zismann, Troy A McEachron, Bodour Salhia, Heather E Cunliffe, David G Huntsman & Jeffrey M Trent

  2. School of Life Sciences, Arizona State University, Tempe, Arizona, USA

    Pilar Ramos & Jeffrey M Trent

  3. Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada

    Anthony N Karnezis, Sohrab P Shah & David G Huntsman

  4. Centre for Translational and Applied Genomics, British Columbia Cancer Agency, Vancouver, British Columbia, Canada

    Anthony N Karnezis, Leah M Prentice & David G Huntsman

  5. Department of Dermatology, Mayo Clinic, Scottsdale, Arizona, USA

    Aleksandar Sekulic

  6. Department of Molecular Oncology, British Columbia Cancer Agency, Vancouver, British Columbia, Canada

    Karey Shumansky, Yidong Yang & Sohrab P Shah

  7. Canada's Michael Smith Genome Sciences Centre, British Columbia Cancer Agency, Vancouver, British Columbia, Canada

    Marco A Marra

  8. Department of Pathology, Hospital de la Santa Creu i Sant Pau, Autonomous University of Barcelona, Barcelona, Spain

    Jaime Prat & Emanuela D'Angelo

  9. Department of Pathology, University Health Network, Toronto, Ontario, Canada

    Blaise A Clarke

  10. Department of Pediatric Hematology-Oncology, Children's Hospital of Alabama, University of Alabama at Birmingham, Birmingham, Alabama, USA

    Joseph G Pressey

  11. Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Creighton University School of Medicine and St. Joseph's Hospital and Medical Center, Phoenix, Arizona, USA

    John H Farley

  12. Evergreen Hematology and Oncology, Spokane, Washington, USA

    Stephen P Anthony

  13. Department of Pathology, Johns Hopkins University, Baltimore, Maryland, USA

    Richard B S Roden

  14. Department of Pathology, University of Otago, Dunedin, New Zealand

    Heather E Cunliffe

Authors
  1. Pilar Ramos
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  2. Anthony N Karnezis
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  3. David W Craig
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  4. Aleksandar Sekulic
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  5. Megan L Russell
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  6. William P D Hendricks
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  7. Jason J Corneveaux
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  8. Michael T Barrett
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  9. Karey Shumansky
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  10. Yidong Yang
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  11. Sohrab P Shah
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  12. Leah M Prentice
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  13. Marco A Marra
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  14. Jeffrey Kiefer
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  15. Victoria L Zismann
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  16. Troy A McEachron
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  17. Bodour Salhia
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  18. Jaime Prat
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  19. Emanuela D'Angelo
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  20. Blaise A Clarke
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  21. Joseph G Pressey
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  22. John H Farley
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  23. Stephen P Anthony
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  24. Richard B S Roden
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  25. Heather E Cunliffe
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  26. David G Huntsman
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  27. Jeffrey M Trent
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Contributions

Study concept and design: P.R., A.N.K., H.E.C., J.M.T. and D.G.H. Acquisition of data: P.R., A.N.K., M.L.R., J.J.C., B.S. and H.E.C. Sample contribution: J.P., E.D., B.A.C., J.G.P., J.H.F., S.P.A. and R.B.S.R. Data analysis: P.R., A.N.K., A.S., W.P.D.H., M.T.B., J.K., V.L.Z., B.S., T.A.M., J.M.T. and D.G.H. Bioinformatics data analysis: D.W.C., M.L.R., J.J.C., K.S., Y.Y., S.P.S., L.M.P. and M.A.M. Drafting of the manuscript: P.R., A.N.K., A.S., W.P.D.H., J.M.T. and D.G.H.

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The authors declare no competing financial interests.

Integrated supplementary information

Supplementary Figure 1 LOH analysis in SCCOHT tumors with SMARCA4 mutations.

LOH analysis was performed using bcbio-nextgen 0.7.7a-e91123c to map reads with BWA 0.7.5a to GRCh37 and freebayes v0.9.10-11 for joint variant calling restricted to chr. 19: 10,667,750–11,554,548. The heat map shows SNPs with a call rate of 0.2. No evidence of LOH was observed.

Supplementary Figure 2 Genome view of SMARCA4 450K methylation data.

The top panel is a scatter plot displaying differential β values for all 44 SMARCA4 CpG probes in eight SCCOHT samples. Only two probes demonstrate differential hypomethylation (indicated by a red box). The upper limit of the y axis does not exceed 0.11, indicative of a lack of differential hypermethylation for any probe.

Supplementary Figure 3 SMARCA4 methylation status in SCCOHT tumors and normal fallopian tube tissues.

Vertical scatter plot of the average β values for 44 SMARCA4 450K CpG methylation probes in 8 SCCOHTs and 2 pools of normal fallopian tissue. There is no significant difference in SMARCA4 methylation between normal tissue and SCCOHT.

Supplementary Figure 4 SMARCA4 immunohistochemistry in normal premenopausal ovary and fallopian tube.

H&E-stained sections (A, C, E) and SMARCA4 immunohistochemistry (B, D, F) demonstrating strong, uniform positive nuclear staining in oocytes (B), granulosa cells of primordial (B) and secondary (D) follicles, theca cells (D) and secretory and ciliated cells throughout the fallopian tube ampulla (F) and fimbria (data not shown). In contrast, the ovarian stroma stains weakly (B) or is negative (data not shown). 400× magnification. Scale bars, 50 μm.

Supplementary information

Supplementary Text and Figures

Supplementary Note, Supplementary Figures 1–4 and Supplementary Tables 1 and 3 (PDF 1937 kb)

Supplementary Table 2

Summary of whole-genome and exome sequencing metrics. (XLS 499 kb)

Supplementary Table 4

SMARCA4 immunohistochemical analysis in primary ovarian and adnexal epithelial, sex cord stromal and germ cell tumors. (XLS 23 kb)

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Ramos, P., Karnezis, A., Craig, D. et al. Small cell carcinoma of the ovary, hypercalcemic type, displays frequent inactivating germline and somatic mutations in SMARCA4. Nat Genet 46, 427–429 (2014). https://doi.org/10.1038/ng.2928

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