Abstract LB-89: Germ-line and somatic SMARCA4 mutations characterize small cell carcinoma of the ovary, hypercalcemic type
Authors: Witkowski Leora , Carrot-Zhang Jian , Albrecht Steffen , Hamel Nancy , Tomiak Eva , Grynspan David , Saloustros Emmanouil , Gilpin Catherine , Silva-Smith Rachel , Plourde François , Rivera Barbara , Castellsagué Ester , Wu Mona , Fahiminiya Somayyeh , Nadaf Javad , Saskin Avi , Arseneault Madeleine , Karabakhtsian Rouzan G. , Reilly Elizabeth A. , Ueland Frederick R. , Margiolaki Anna , Pavlakis Kitty , Castellino Sharon M. , Lamovec Janez , Roth Lawrence M. , Ulbright Thomas M. , Bender Tracey , Longy Michel , Berchuck Andrew , Tischkowitz Marc , Siebert Reiner , Nagel Inga , Georgoulias Vassilis , Stewart Colin J.r. , McCluggage Glenn , Arseneau Jocelyne , Clarke Blaise A. , Riazalhosseini Yasser , Hasselblatt Martin , Majewski Jacek , Foulkes William D. 
Published: May 2015

Abstract
Small-cell carcinoma of the ovary, hypercalcemic type (SCCOHT) is an aggressive tumor and the most common type of undifferentiated ovarian malignancy presenting at less than 40 years of age. Its cause and histogenesis remain unknown. We sequenced the exomes of individuals from three familial cases of SCCOHT. Subsequently, we used whole exome sequencing, Sanger sequencing and immunohistochemistry to analyze germline and tumor DNA from three additional familial cases, 35 non-familial cases and one SCCOHT cell line (BIN-67). DNA sequencing revealed likely deleterious germ-line mutations in the chromatin remodeling gene SMARCA4 in all four familial cases of SCCOHT where DNA was available. This was accompanied by either a somatic mutation or loss of the wild-type allele in the tumor. BIN-67 contained bi-allelic deleterious mutations in SMARCA4. Sequencing of 24 non-familial pathologically-confirmed SCCOHT cases revealed at least one germ-line or somatic likely deleterious SMARCA4 mutation in 22 cases. Immunohistochemical (IHC) analyses of these and an additional 11 tumors showed loss of BRG1 protein in 38/40 cases. Our findings identify alterations in SMARCA4 as a major cause of SCCOHT, which could pave the way for genetic counseling and new treatment approaches.
Citation Format: Leora Witkowski, Jian Carrot-Zhang, Steffen Albrecht, Nancy Hamel, Eva Tomiak, David Grynspan, Emmanouil Saloustros, Catherine Gilpin, Rachel Silva-Smith, François Plourde, Barbara Rivera, Ester Castellsagué, Mona Wu, Somayyeh Fahiminiya, Javad Nadaf, Avi Saskin, Madeleine Arseneault, Rouzan G. Karabakhtsian, Elizabeth A. Reilly, Frederick R. Ueland, Anna Margiolaki, Kitty Pavlakis, Sharon M. Castellino, Janez Lamovec, Lawrence M. Roth, Thomas M. Ulbright, Tracey Bender, Michel Longy, Andrew Berchuck, Marc Tischkowitz, Reiner Siebert, Inga Nagel, Vassilis Georgoulias, Colin J.r. Stewart, Glenn McCluggage, Jocelyne Arseneau, Blaise A. Clarke, Yasser Riazalhosseini, Martin Hasselblatt, Jacek Majewski, William D. Foulkes. Germ-line and somatic SMARCA4 mutations characterize small cell carcinoma of the ovary, hypercalcemic type. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr LB-89. doi:10.1158/1538-7445.AM2014-LB-89