title: Loss of the tumor suppressor SMARCA4 in small cell carcinoma of the ovary, hypercalcemic type (SCCOHT).
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.(1-4) 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.
authors.affiliation: Division of Integrated Cancer Genomics; Translational Genomics Research Institute (TGen); Phoenix, AZ USA; School of Life Sciences; Arizona State University; Tempe, AZ USA.
authors.forename: Pilar
authors.initials: P
authors.lastname: Ramos
authors.affiliation: Department of Pathology and Laboratory Medicine; The University of British Columbia; Vancouver, BC Canada; Centre for Translational and Applied Genomics; British Columbia Cancer Agency; Vancouver, BC Canada.
authors.forename: Anthony N
authors.initials: AN
authors.lastname: Karnezis
authors.affiliation: Division of Integrated Cancer Genomics; Translational Genomics Research Institute (TGen) ; Phoenix, AZ USA.
authors.forename: William P D
authors.initials: WP
authors.lastname: Hendricks
authors.affiliation: Department of Pathology and Laboratory Medicine; The University of British Columbia; Vancouver, BC Canada; Centre for Translational and Applied Genomics; British Columbia Cancer Agency; Vancouver, BC Canada.
authors.forename: Yemin
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Collaborative Bioinformatics Center; Translational Genomics Research Institute (TGen) ; Phoenix, AZ USA.
authors.forename: Waibhav
authors.initials: W
authors.lastname: Tembe
authors.affiliation: Division of Integrated Cancer Genomics; Translational Genomics Research Institute (TGen) ; Phoenix, AZ USA.
authors.forename: Victoria L
authors.initials: VL
authors.lastname: Zismann
authors.affiliation: Collaborative Bioinformatics Center; Translational Genomics Research Institute (TGen) ; Phoenix, AZ USA.
authors.forename: Christophe
authors.initials: C
authors.lastname: Legendre
authors.affiliation: Division of Integrated Cancer Genomics; Translational Genomics Research Institute (TGen) ; Phoenix, AZ USA.
authors.forename: Winnie S
authors.initials: WS
authors.lastname: Liang
authors.affiliation: Division of Integrated Cancer Genomics; Translational Genomics Research Institute (TGen) ; Phoenix, AZ USA.
authors.forename: Megan L
authors.initials: ML
authors.lastname: Russell
authors.affiliation: Division of Integrated Cancer Genomics; Translational Genomics Research Institute (TGen) ; Phoenix, AZ USA.
authors.forename: David W
authors.initials: DW
authors.lastname: Craig
authors.affiliation: Department of Obstetrics and Gynecology; Creighton University School of Medicine; St. Joseph's Hospital and Medical Center ; Phoenix, AZ USA.
authors.forename: John H
authors.initials: JH
authors.lastname: Farley
authors.affiliation: Department of Obstetrics and Gynecology; Creighton University School of Medicine; St. Joseph's Hospital and Medical Center ; Phoenix, AZ USA.
authors.forename: Bradley J
authors.initials: BJ
authors.lastname: Monk
authors.affiliation: Evergreen Hematology and Oncology ; Spokane, WA USA.
authors.forename: Stephen P
authors.initials: SP
authors.lastname: Anthony
authors.affiliation: Division of Integrated Cancer Genomics; Translational Genomics Research Institute (TGen); Phoenix, AZ USA; Department of Dermatology; Mayo Clinic; Scottsdale, AZ USA.
authors.forename: Aleksandar
authors.initials: A
authors.lastname: Sekulic
authors.affiliation: Department of Pathology; Dunedin School of Medicine; University of Otago ; Dunedin, New Zealand.
authors.forename: Heather E
authors.initials: HE
authors.lastname: Cunliffe
authors.affiliation: Department of Pathology and Laboratory Medicine; The University of British Columbia; Vancouver, BC Canada; Centre for Translational and Applied Genomics; British Columbia Cancer Agency; Vancouver, BC Canada.
authors.forename: David G
authors.initials: DG
authors.lastname: Huntsman
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
keywords: BRG1; SMARCA4; SMARCB1; SNF5; SWI/SNF; chromatin remodeling; ovarian cancer; small cell carcinoma of the ovary hypercalcemic type (SCCOHT); tumorigenesis