Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

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

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


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.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

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.


  1. Young, R.H., Oliva, E. & Scully, R.E. Am. J. Surg. Pathol. 18, 1102–1116 (1994).

    Article  CAS  Google Scholar 

  2. Florell, S.R., Bruggers, C.S., Matlak, M., Young, R.H. & Lowichik, A. Med. Pediatr. Oncol. 32, 304–307 (1999).

    Article  CAS  Google Scholar 

  3. Shrimali, R.K., Correa, P.D. & Reed, N.S. Med. Oncol. 28, 766–770 (2011).

    Article  CAS  Google Scholar 

  4. Estel, R., Hackethal, A., Kalder, M. & Munstedt, K. Arch. Gynecol. Obstet. 284, 1277–1282 (2011).

    Article  Google Scholar 

  5. McCluggage, W.G., Oliva, E., Connolly, L.E., McBride, H.A. & Young, R.H. Int. J. Gynecol. Pathol. 23, 330–336 (2004).

    Article  CAS  Google Scholar 

  6. Gamwell, L.F. et al. Orphanet J. Rare Dis. 8, 33 (2013).

    Article  Google Scholar 

  7. Kupryjańczyk, J. et al. Pol. J. Pathol. 64, 238–246 (2013).

    Article  Google Scholar 

  8. Martinez-Borges, A.R. et al. Pediatr. Blood Cancer 53, 1334–1336 (2009).

    Article  Google Scholar 

  9. McDonald, J.M. et al. J. Pediatr. Surg. 47, 588–592 (2012).

    Article  Google Scholar 

  10. Eaton, K.W., Tooke, L.S., Wainwright, L.M., Judkins, A.R. & Biegel, J.A. Pediatr. Blood Cancer 56, 7–15 (2011).

    Article  Google Scholar 

  11. Serber, D.W. et al. PLoS ONE 7, e31346 (2012).

    Article  CAS  Google Scholar 

  12. Wilson, B.G. et al. Mol. Cell. Biol. 34, 1136–1144 (2014).

    Article  Google Scholar 

  13. Oike, T. et al. Cancer Res. 73, 5508–5518 (2013).

    Article  CAS  Google Scholar 

  14. Hoffman, G.R. et al. Proc. Natl. Acad. Sci. USA 111, 3128–3133 (2014).

    Article  CAS  Google Scholar 

  15. Kononen, J. et al. Nat. Med. 4, 844–847 (1998).

    Article  CAS  Google Scholar 

Download references


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

Authors and Affiliations



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.

Ethics declarations

Competing interests

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)

Rights and permissions

Reprints and Permissions

About this article

Cite this article

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).

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI:

This article is cited by


Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing