title: Concurrent ARID1A and ARID1B inactivation in endometrial and ovarian dedifferentiated carcinomas.
abstract: Dedifferentiated carcinoma of the endometrium or the ovary is an aggressive epithelial malignancy that comprises an endometrioid carcinoma together with an undifferentiated carcinoma. We recently reported that inactivation of BRG1 or INI1, core subunits of the switch/sucrose non-fermenting (SWI/SNF) complex, was the likely molecular event underlying dedifferentiation in about half of dedifferentiated carcinomas. In this study, we performed a genomic screen that included other members of the SWI/SNF complex to better delineate the molecular basis in the remainder of these tumours. We identified concurrent inactivating mutations involving ARID1A and ARID1B in 12 of 24 BRG1/INI1-intact, 0 of 3 INI1-deficient and 0 of 16 BRG1-deficient dedifferentiated carcinomas. All ARID1A and ARID1B co-mutated tumours displayed loss of ARID1A expression in the undifferentiated component with 11 of 12 tumours also displaying absent staining in the endometrioid component. ARID1B expression was absent in the undifferentiated component in all 12 tumours, whereas the corresponding endometrioid component showed intact expression. Clinically, ARID1A/ARID1B co-inactivated tumours showed similar aggressive behaviour to BRG1 or INI1-inactivated tumours. Given that ARID1A and ARID1B are the only known DNA-binding subunits of the SWI/SNF-A complex, additional inactivation of ARID1B in an ARID1A-deficient background appears to represent an alternative mechanism of disruption of SWI/SNF-mediated transcriptional regulation, resulting in arrested cellular differentiation in endometrial and ovarian endometrioid cancer.
authors: Department of Oncology, University of Alberta, Edmonton, Alberta, Canada.
authors: Mackenzie
authors: M
authors: Coatham
authors: Department of Laboratory Medicine and Pathology, Royal Alexandra Hospital and University of Alberta, Edmonton, Alberta, Canada.
authors: Xiaodong
authors: X
authors: Li
authors: Department of Pathology and Laboratory Medicine, and Genetic Pathology Evaluation Center, Vancouver General Hospital and University of British Columbia, Vancouver, British Columbia, Canada.
authors: Anthony N
authors: AN
authors: Karnezis
authors: Department of Pathology and Laboratory Medicine, and Genetic Pathology Evaluation Center, Vancouver General Hospital and University of British Columbia, Vancouver, British Columbia, Canada.|Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors: Lien N
authors: LN
authors: Hoang
authors: Department of Pathology and Laboratory Medicine, and Genetic Pathology Evaluation Center, Vancouver General Hospital and University of British Columbia, Vancouver, British Columbia, Canada.
authors: Basile
authors: B
authors: Tessier-Cloutier
authors: Department of Laboratory Medicine and Pathology, Royal Alexandra Hospital and University of Alberta, Edmonton, Alberta, Canada.
authors: Bo
authors: B
authors: Meng
authors: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors: Robert A
authors: RA
authors: Soslow
authors: Department of Pathology and Laboratory Medicine, and Genetic Pathology Evaluation Center, Vancouver General Hospital and University of British Columbia, Vancouver, British Columbia, Canada.
authors: C
authors: C
authors: Blake Gilks
authors: Department of Pathology and Laboratory Medicine, and Genetic Pathology Evaluation Center, Vancouver General Hospital and University of British Columbia, Vancouver, British Columbia, Canada.
authors: David G
authors: DG
authors: Huntsman
authors: Department of Histopathology, King Edward Memorial Hospital and School for Women's and Infants' Health, University of Western Australia, Perth, Western Australia, Australia.
authors: Colin J R
authors: CJ
authors: Stewart
authors: Department of Oncology, University of Alberta, Edmonton, Alberta, Canada.
authors: Lynne M
authors: LM
authors: Postovit
authors: Department of Pathology and Laboratory Medicine, Calgary Laboratory Services and University of Calgary, Calgary, Alberta, Canada.
authors: Martin
authors: M
authors: Köbel
authors: Department of Laboratory Medicine and Pathology, Royal Alexandra Hospital and University of Alberta, Edmonton, Alberta, Canada.
authors: Cheng-Han
authors: CH
authors: Lee
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000235:genetics; D018269:Carcinoma, Endometrioid / Q000235:genetics* / Q000473:pathology; D004268:DNA-Binding Proteins / Q000235:genetics*; D016889:Endometrial Neoplasms / Q000235:genetics* / Q000473:pathology; D005260:Female; D006801:Humans; D008875:Middle Aged; D009687:Nuclear Proteins / Q000235:genetics*; D010051:Ovarian Neoplasms / Q000235:genetics* / Q000473:pathology; D014157:Transcription Factors / Q000235:genetics*
chemical_list: C112476:ARID1A protein, human; C497837:ARID1B protein, human; D014408:Biomarkers, Tumor; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D014157:Transcription Factors