title: Germline and somatic SMARCA4 mutations characterize small cell carcinoma of the ovary, hypercalcemic type.
abstract: Small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) is the most common undifferentiated ovarian malignancy in women under 40 years of age. We sequenced the exomes of six individuals from three families with SCCOHT. After discovering segregating deleterious germline mutations in SMARCA4 in all three families, we tested DNA from a fourth affected family, which also carried a segregating SMARCA4 germline mutation. All the familial tumors sequenced harbored either a somatic mutation or loss of the wild-type allele. Immunohistochemical analysis of these cases and additional familial and non-familial cases showed loss of SMARCA4 (BRG1) protein in 38 of 40 tumors overall. Sequencing of cases with available DNA identified at least one germline or somatic deleterious SMARCA4 mutation in 30 of 32 cases. Additionally, the SCCOHT cell line BIN-67 had biallelic deleterious mutations in SMARCA4. Our findings identify alterations in SMARCA4 as the major cause of SCCOHT, which could lead to improvements in genetic counseling and new treatment approaches.
authors.affiliation: 1] Program in Cancer Genetics, Department of Oncology and Human Genetics, McGill University, Montreal, Quebec, Canada. [2] Department of Human Genetics, McGill University, Montreal, Quebec, Canada. [3].
authors.forename: Leora
authors.initials: L
authors.lastname: Witkowski
authors.affiliation: 1] Department of Human Genetics, McGill University, Montreal, Quebec, Canada. [2] McGill University and Génome Québec Innovation Centre, Montreal, Quebec, Canada. [3].
authors.forename: Jian
authors.initials: J
authors.lastname: Carrot-Zhang
authors.affiliation: Department of Pathology, Montreal Children's Hospital, McGill University Health Centre, McGill University, Montreal, Quebec, Canada.
authors.forename: Steffen
authors.initials: S
authors.lastname: Albrecht
authors.affiliation: 1] Department of Human Genetics, McGill University, Montreal, Quebec, Canada. [2] McGill University and Génome Québec Innovation Centre, Montreal, Quebec, Canada.
authors.forename: Somayyeh
authors.initials: S
authors.lastname: Fahiminiya
authors.affiliation: 1] Program in Cancer Genetics, Department of Oncology and Human Genetics, McGill University, Montreal, Quebec, Canada. [2] Department of Medical Genetics, Research Institute, McGill University Health Centre, Montreal, Quebec, Canada.
authors.forename: Nancy
authors.initials: N
authors.lastname: Hamel
authors.affiliation: Department of Genetics, Children's Hospital of Eastern Ontario, University of Ottawa, Ottawa, Ontario, Canada.
authors.forename: Eva
authors.initials: E
authors.lastname: Tomiak
authors.affiliation: Department of Pathology and Laboratory Medicine, Children's Hospital of Eastern Ontario, University of Ottawa, Ottawa, Ontario, Canada.
authors.forename: David
authors.initials: D
authors.lastname: Grynspan
authors.affiliation: Hereditary Cancer Clinic, Department of Medical Oncology, University Hospital of Heraklion, Heraklion, Greece.
authors.forename: Emmanouil
authors.initials: E
authors.lastname: Saloustros
authors.affiliation: 1] Department of Human Genetics, McGill University, Montreal, Quebec, Canada. [2] McGill University and Génome Québec Innovation Centre, Montreal, Quebec, Canada.
authors.forename: Javad
authors.initials: J
authors.lastname: Nadaf
authors.affiliation: 1] Program in Cancer Genetics, Department of Oncology and Human Genetics, McGill University, Montreal, Quebec, Canada. [2] Department of Human Genetics, McGill University, Montreal, Quebec, Canada.
authors.forename: Barbara
authors.initials: B
authors.lastname: Rivera
authors.affiliation: Department of Genetics, Children's Hospital of Eastern Ontario, University of Ottawa, Ottawa, Ontario, Canada.
authors.forename: Catherine
authors.initials: C
authors.lastname: Gilpin
authors.affiliation: 1] Program in Cancer Genetics, Department of Oncology and Human Genetics, McGill University, Montreal, Quebec, Canada. [2] Department of Human Genetics, McGill University, Montreal, Quebec, Canada.
authors.forename: Ester
authors.initials: E
authors.lastname: Castellsagué
authors.affiliation: 1] Program in Cancer Genetics, Department of Oncology and Human Genetics, McGill University, Montreal, Quebec, Canada. [2] Department of Medical Genetics, Lady Davis Institute and Segal Cancer Centre, Jewish General Hospital, McGill University, Montreal, Quebec, Canada.
authors.forename: Rachel
authors.initials: R
authors.lastname: Silva-Smith
authors.affiliation: 1] Program in Cancer Genetics, Department of Oncology and Human Genetics, McGill University, Montreal, Quebec, Canada. [2] Department of Medical Genetics, Lady Davis Institute and Segal Cancer Centre, Jewish General Hospital, McGill University, Montreal, Quebec, Canada.
authors.forename: François
authors.initials: F
authors.lastname: Plourde
authors.affiliation: 1] Program in Cancer Genetics, Department of Oncology and Human Genetics, McGill University, Montreal, Quebec, Canada. [2] Department of Human Genetics, McGill University, Montreal, Quebec, Canada.
authors.forename: Mona
authors.initials: M
authors.lastname: Wu
authors.affiliation: Department of Human Genetics, McGill University, Montreal, Quebec, Canada.
authors.forename: Avi
authors.initials: A
authors.lastname: Saskin
authors.affiliation: 1] Department of Human Genetics, McGill University, Montreal, Quebec, Canada. [2] McGill University and Génome Québec Innovation Centre, Montreal, Quebec, Canada.
authors.forename: Madeleine
authors.initials: M
authors.lastname: Arseneault
authors.affiliation: 1] Department of Pathology and Laboratory Medicine, Markey Cancer Center, University of Kentucky, Lexington, Kentucky, USA. [2].
authors.forename: Rouzan G
authors.initials: RG
authors.lastname: Karabakhtsian
authors.affiliation: Department of Pathology and Laboratory Medicine, Markey Cancer Center, University of Kentucky, Lexington, Kentucky, USA.
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Reilly
authors.affiliation: Department of Pathology and Laboratory Medicine, Markey Cancer Center, University of Kentucky, Lexington, Kentucky, USA.
authors.forename: Frederick R
authors.initials: FR
authors.lastname: Ueland
authors.affiliation: Hereditary Cancer Clinic, Department of Medical Oncology, University Hospital of Heraklion, Heraklion, Greece.
authors.forename: Anna
authors.initials: A
authors.lastname: Margiolaki
authors.affiliation: Pathology Department, National and Kapodistrian University of Athens, Athens, Greece.
authors.forename: Kitty
authors.initials: K
authors.lastname: Pavlakis
authors.affiliation: Department of Pediatrics, Hematology/Oncology, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA.
authors.forename: Sharon M
authors.initials: SM
authors.lastname: Castellino
authors.affiliation: Department of Pathology, Institute of Oncology, Ljubljana, Slovenia.
authors.forename: Janez
authors.initials: J
authors.lastname: Lamovec
authors.affiliation: Department of Medical Oncology, Princess Margaret Cancer Centre, Toronto, Ontario, Canada.
authors.forename: Helen J
authors.initials: HJ
authors.lastname: Mackay
authors.affiliation: Department of Pathology, Indiana University School of Medicine, Indianapolis, Indiana, USA.
authors.forename: Lawrence M
authors.initials: LM
authors.lastname: Roth
authors.affiliation: Department of Pathology, Indiana University School of Medicine, Indianapolis, Indiana, USA.
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Ulbright
authors.affiliation: Department of Pathology, Indiana University School of Medicine, Indianapolis, Indiana, USA.
authors.forename: Tracey A
authors.initials: TA
authors.lastname: Bender
authors.affiliation: Hereditary Cancer Clinic, Department of Medical Oncology, University Hospital of Heraklion, Heraklion, Greece.
authors.forename: Vassilis
authors.initials: V
authors.lastname: Georgoulias
authors.affiliation: Institut Bergonié, Unité d'Oncogénétique, Bordeaux, France.
authors.forename: Michel
authors.initials: M
authors.lastname: Longy
authors.affiliation: Division of Gynecologic Oncology, Duke University Medical Center, Durham, North Carolina, USA.
authors.forename: Andrew
authors.initials: A
authors.lastname: Berchuck
authors.affiliation: Department of Medical Genetics, University of Cambridge, Cambridge, UK.
authors.forename: Marc
authors.initials: M
authors.lastname: Tischkowitz
authors.affiliation: Institute of Human Genetics, Christian Albrechts University Kiel and University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany.
authors.forename: Inga
authors.initials: I
authors.lastname: Nagel
authors.affiliation: Institute of Human Genetics, Christian Albrechts University Kiel and University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany.
authors.forename: Reiner
authors.initials: R
authors.lastname: Siebert
authors.affiliation: School for Women's and Infants' Health, University of Western Australia, Perth, Western Australia, Australia.
authors.forename: Colin J R
authors.initials: CJ
authors.lastname: Stewart
authors.affiliation: Department of Pathology, Royal Victoria Hospital, McGill University Health Centre, McGill University, Montreal, Quebec, Canada.
authors.forename: Jocelyne
authors.initials: J
authors.lastname: Arseneau
authors.affiliation: Department of Pathology, Royal Group of Hospitals Trust, Belfast, UK.
authors.forename: W Glenn
authors.initials: WG
authors.lastname: McCluggage
authors.affiliation: Department of Pathology Laboratory Medicine Program, University Health Network, Toronto, Ontario, Canada.
authors.forename: Blaise A
authors.initials: BA
authors.lastname: Clarke
authors.affiliation: 1] Department of Human Genetics, McGill University, Montreal, Quebec, Canada. [2] McGill University and Génome Québec Innovation Centre, Montreal, Quebec, Canada.
authors.forename: Yasser
authors.initials: Y
authors.lastname: Riazalhosseini
authors.affiliation: Institute of Neuropathology, University Hospital-Münster, Münster, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Hasselblatt
authors.affiliation: 1] Department of Human Genetics, McGill University, Montreal, Quebec, Canada. [2] McGill University and Génome Québec Innovation Centre, Montreal, Quebec, Canada.
authors.forename: Jacek
authors.initials: J
authors.lastname: Majewski
authors.affiliation: 1] Program in Cancer Genetics, Department of Oncology and Human Genetics, McGill University, Montreal, Quebec, Canada. [2] Department of Medical Genetics, Lady Davis Institute and Segal Cancer Centre, Jewish General Hospital, McGill University, Montreal, Quebec, Canada. [3] Department of Human Genetics, McGill University, Montreal, Quebec, Canada. [4] Department of Medical Genetics, Research Institute, McGill University Health Centre, Montreal, Quebec, Canada.
authors.forename: William D
authors.identifier: 0000000174274651
authors.initials: WD
authors.lastname: Foulkes
mesh_terms: D001483:Base Sequence; D018288:Carcinoma, Small Cell / Q000235:genetics*; D045744:Cell Line, Tumor; D004265:DNA Helicases / Q000235:genetics*; D059472:Exome / Q000235:genetics; D005260:Female; D040461:Gene Components; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D017404:In Situ Hybridization, Fluorescence; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D009687:Nuclear Proteins / Q000235:genetics*; D010051:Ovarian Neoplasms / Q000235:genetics*; D017422:Sequence Analysis, DNA; D014157:Transcription Factors / Q000235:genetics*
chemical_list: D009687:Nuclear Proteins; D014157:Transcription Factors; C084108:SMARCA4 protein, human; D004265:DNA Helicases