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Addendum

Loss of the tumor suppressor SMARCA4 in small cell carcinoma of the ovary, hypercalcemic type (SCCOHT)

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Article: e967148 | Received 12 Jul 2014, Accepted 09 Nov 2014, Published online: 03 Nov 2014
 

Abstract

Small cell carcinoma of the ovary, hypercalcemic type (SCCOHT), is a rare and understudied cancer with a dismal prognosis. SCCOHT's infrequency has hindered empirical study of its biology and clinical management. However, we and others have recently identified inactivating mutations in the SWI/SNF chromatin remodeling gene SMARCA4 with concomitant loss of SMARCA4 protein in the majority of SCCOHT tumors.Citation1–4 Here we summarize these findings and report SMARCA4 status by targeted sequencing and/or immunohistochemistry (IHC) in an additional 12 SCCOHT tumors, 3 matched germlines, and the cell line SCCOHT-1. We also report the identification of a homozygous inactivating mutation in the gene SMARCB1 in one SCCOHT tumor with wild-type SMARCA4, suggesting that SMARCB1 inactivation may also play a role in the pathogenesis of SCCOHT. To date, SMARCA4 mutations and protein loss have been reported in the majority of 69 SCCOHT cases (including 2 cell lines). These data firmly establish SMARCA4 as a tumor suppressor whose loss promotes the development of SCCOHT, setting the stage for rapid advancement in the biological understanding, diagnosis, and treatment of this rare tumor type.

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Disclosure of Potential Conflicts of Interest

No conflicts of interest were disclosed.

Acknowledgments

We particularly thank the families and patients who joined this IRB-approved study for their critical contributions. We further thank Scottsdale Healthcare for institutional support and clinical leadership in addition to that provided by many other physicians: Drs. Jaime Prat, Emanuela D’Angelo, Blaise Clark, Joseph Pressey, and Richard Roden. We also thank the faculty and staff at TGen of the Macromolecular Analysis & Processing Center (Drs. Hostetter and LoBello), and the Office of Research Compliance & Quality Management (Lora Nordstrom, Stephanie Althoff, and Stephanie Buchholtz); Children's Oncology Group for sample collection and Drs. Ralf Haas and Barbara Vanderhyden for establishing and sharing the SCCOHT-1 and BIN-67 cells, respectively.

Funding

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 Foster and Lynn Friess. Further support was provided to Yemin Wang by the Michael Smith Foundation for Health Research and to Anthony N. Karnezis and David G. Huntsman by the Terry Fox Research Initiative New Frontiers Program in Cancer.

Supplemental Material

Supplemental data for this article can be accessed on the publisher's website.