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Nat Genet. 2014 May;46(5):438-43. doi: 10.1038/ng.2931. Epub 2014 Mar 23.

Germline and somatic SMARCA4 mutations characterize small cell carcinoma of the ovary, hypercalcemic type.

Author information

1
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].
2
1] Department of Human Genetics, McGill University, Montreal, Quebec, Canada. [2] McGill University and Génome Québec Innovation Centre, Montreal, Quebec, Canada. [3].
3
Department of Pathology, Montreal Children's Hospital, McGill University Health Centre, McGill University, Montreal, Quebec, Canada.
4
1] Department of Human Genetics, McGill University, Montreal, Quebec, Canada. [2] McGill University and Génome Québec Innovation Centre, Montreal, Quebec, Canada.
5
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.
6
Department of Genetics, Children's Hospital of Eastern Ontario, University of Ottawa, Ottawa, Ontario, Canada.
7
Department of Pathology and Laboratory Medicine, Children's Hospital of Eastern Ontario, University of Ottawa, Ottawa, Ontario, Canada.
8
Hereditary Cancer Clinic, Department of Medical Oncology, University Hospital of Heraklion, Heraklion, Greece.
9
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.
10
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.
11
Department of Human Genetics, McGill University, Montreal, Quebec, Canada.
12
1] Department of Pathology and Laboratory Medicine, Markey Cancer Center, University of Kentucky, Lexington, Kentucky, USA. [2].
13
Department of Pathology and Laboratory Medicine, Markey Cancer Center, University of Kentucky, Lexington, Kentucky, USA.
14
Pathology Department, National and Kapodistrian University of Athens, Athens, Greece.
15
Department of Pediatrics, Hematology/Oncology, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA.
16
Department of Pathology, Institute of Oncology, Ljubljana, Slovenia.
17
Department of Medical Oncology, Princess Margaret Cancer Centre, Toronto, Ontario, Canada.
18
Department of Pathology, Indiana University School of Medicine, Indianapolis, Indiana, USA.
19
Institut Bergonié, Unité d'Oncogénétique, Bordeaux, France.
20
Division of Gynecologic Oncology, Duke University Medical Center, Durham, North Carolina, USA.
21
Department of Medical Genetics, University of Cambridge, Cambridge, UK.
22
Institute of Human Genetics, Christian Albrechts University Kiel and University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany.
23
School for Women's and Infants' Health, University of Western Australia, Perth, Western Australia, Australia.
24
Department of Pathology, Royal Victoria Hospital, McGill University Health Centre, McGill University, Montreal, Quebec, Canada.
25
Department of Pathology, Royal Group of Hospitals Trust, Belfast, UK.
26
Department of Pathology Laboratory Medicine Program, University Health Network, Toronto, Ontario, Canada.
27
Institute of Neuropathology, University Hospital-Münster, Münster, Germany.
28
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.

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.

Comment in

PMID:
24658002
DOI:
10.1038/ng.2931
[Indexed for MEDLINE]

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