title: Dual loss of the SWI/SNF complex ATPases SMARCA4/BRG1 and SMARCA2/BRM is highly sensitive and specific for small cell carcinoma of the ovary, hypercalcaemic type.
abstract: Small cell carcinoma of the ovary, hypercalcaemic type (SCCOHT) is a lethal and sometimes familial ovarian tumour of young women and children. We and others recently discovered that over 90% of SCCOHTs harbour inactivating mutations in the chromatin remodelling gene SMARCA4 with concomitant loss of its encoded protein SMARCA4 (BRG1), one of two mutually exclusive ATPases of the SWI/SNF chromatin remodelling complex. To determine the specificity of SMARCA4 loss for SCCOHT, we examined the expression of SMARCA4 by immunohistochemistry in more than 3000 primary gynaecological tumours. Among ovarian tumours, it was only absent in clear cell carcinoma (15 of 360, 4%). In the uterus, it was absent in endometrial stromal sarcomas (4 of 52, 8%) and high-grade endometrioid carcinomas (2 of 338, 1%). Recent studies have shown that SMARCA2 (BRM), the other mutually exclusive ATPase of the SWI/SNF complex, is necessary for survival of tumour cells lacking SMARCA4. Therefore, we examined SMARCA2 expression and discovered that all SMARCA4-negative SCCOHTs also lacked SMARCA2 protein by IHC, including the SCCOHT cell lines BIN67 and SCCOHT1. Among ovarian tumours, the SMARCA4/SMARCA2 dual loss phenotype appears completely specific for SCCOHT. SMARCA2 loss was not due to mutation but rather from an absence of mRNA expression, which was restored by treatment with the histone deacetylase inhibitor trichostatin A. Re-expression of SMARCA4 or SMARCA2 inhibited the growth of BIN67 and SCCOHT1 cell lines. Our results indicate that SMARCA4 loss, either alone or with SMARCA2, is highly sensitive and specific for SCCOHT and that restoration of either SWI/SNF ATPase can inhibit the growth of SCCOHT cell lines.
authors.affiliation: Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Anthony N
authors.initials: AN
authors.lastname: Karnezis
authors.affiliation: Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Yemin
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Division of Integrated Cancer Genomics, Translational Genomics Research Institute (TGen), Phoenix, AZ, USA.
authors.forename: Pilar
authors.initials: P
authors.lastname: Ramos
authors.affiliation: Division of Integrated Cancer Genomics, Translational Genomics Research Institute (TGen), Phoenix, AZ, USA.
authors.forename: William Pd
authors.initials: WP
authors.lastname: Hendricks
authors.affiliation: Department of Pathology, Massachusetts General Hospital, Boston, MA, USA.
authors.forename: Esther
authors.initials: E
authors.lastname: Oliva
authors.affiliation: Department of Pathology, Hospital de la Santa Creu i Sant Pau, Autonomous University of Barcelona, Barcelona, Spain.
authors.forename: Emanuela
authors.initials: E
authors.lastname: D'Angelo
authors.affiliation: Department of Pathology, Hospital de la Santa Creu i Sant Pau, Autonomous University of Barcelona, Barcelona, Spain.
authors.forename: Jaime
authors.initials: J
authors.lastname: Prat
authors.affiliation: Department of Pathology, Brigham and Women's Hospital, Boston, MA, USA.
authors.forename: Marisa R
authors.initials: MR
authors.lastname: Nucci
authors.affiliation: Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Torsten O
authors.initials: TO
authors.lastname: Nielsen
authors.affiliation: Genetic Pathology Evaluation Centre, Vancouver General Hospital, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Christine
authors.initials: C
authors.lastname: Chow
authors.affiliation: Genetic Pathology Evaluation Centre, Vancouver General Hospital, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Samuel
authors.initials: S
authors.lastname: Leung
authors.affiliation: Synlab MVZ Pathologie, Mannheim, Germany.
authors.forename: Friedrich
authors.initials: F
authors.lastname: Kommoss
authors.affiliation: Department of Obstetrics and Gynecology, University Hospital of Tuebingen, Tuebingen, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Kommoss
authors.affiliation: The James Homer Wright Pathology Laboratories, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Annacarolina
authors.initials: A
authors.lastname: Silva
authors.affiliation: Department of Pathology, The Johns Hopkins Hospital, Baltimore, MD, USA.
authors.forename: Brigitte M
authors.initials: BM
authors.lastname: Ronnett
authors.affiliation: Department of Anatomic Pathology, University of California San Francisco, San Francisco, CA, USA.
authors.forename: Joseph T
authors.initials: JT
authors.lastname: Rabban
authors.affiliation: Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia.
authors.forename: David D
authors.initials: DD
authors.lastname: Bowtell
authors.affiliation: Department of Pathology and Laboratory Medicine, Lineberger Cancer Center, University of North Carolina, Chapel Hill, NC, USA.
authors.forename: Bernard E
authors.initials: BE
authors.lastname: Weissman
authors.affiliation: Division of Integrated Cancer Genomics, Translational Genomics Research Institute (TGen), Phoenix, AZ, USA.
authors.forename: Jeffrey M
authors.initials: JM
authors.lastname: Trent
authors.affiliation: Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada.
authors.forename: C Blake
authors.initials: CB
authors.lastname: Gilks
authors.affiliation: Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada.|Genetic Pathology Evaluation Centre, Vancouver General Hospital, University of British Columbia, Vancouver, BC, Canada.|Department of Molecular Oncology, British Columbia Cancer Research Centre, Vancouver, BC, Canada.
authors.forename: David G
authors.initials: DG
authors.lastname: Huntsman
mesh_terms: D000251:Adenosine Triphosphatases / Q000378:metabolism; D014408:Biomarkers, Tumor / Q000378:metabolism*; D018288:Carcinoma, Small Cell / Q000175:diagnosis / Q000235:genetics*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000502:physiology; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D002868:Chromosomal Proteins, Non-Histone / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D004265:DNA Helicases / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D005260:Female; D020868:Gene Silencing / Q000502:physiology; D006801:Humans; D006934:Hypercalcemia / Q000235:genetics; D007150:Immunohistochemistry; D009154:Mutation / Q000235:genetics; D009687:Nuclear Proteins / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D010051:Ovarian Neoplasms / Q000175:diagnosis* / Q000235:genetics; D000071796:SMARCB1 Protein; D014157:Transcription Factors / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism
chemical_list: D014408:Biomarkers, Tumor; D002868:Chromosomal Proteins, Non-Histone; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; C084011:SMARCA2 protein, human; D000071796:SMARCB1 Protein; C513266:SMARCB1 protein, human; D014157:Transcription Factors; D000251:Adenosine Triphosphatases; C084108:SMARCA4 protein, human; D004265:DNA Helicases
keywords: HDAC inhibitor; SMARCA2/BRM; SMARCA4/BRG1; SMARCB1/INI1; SWI/SNF; epigenetic silencing; hypercalcaemic type; rhabdoid tumour; small cell carcinoma; trichostatin A