title: Loss of switch/sucrose non-fermenting complex protein expression is associated with dedifferentiation in endometrial carcinomas.
abstract: Dedifferentiated endometrial carcinoma is an aggressive type of endometrial cancer that contains a mix of low-grade endometrioid and undifferentiated carcinoma components. We performed targeted sequencing of eight dedifferentiated carcinomas and identified somatic frameshift/nonsense mutations in SMARCA4, a core ATPase of the switch/sucrose non-fermenting (SWI/SNF) complex, in the undifferentiated components of four tumors. Immunohistochemical analysis confirmed the loss of SMARCA4 in the undifferentiated component of these four SMARCA4-mutated cases, whereas the corresponding low-grade endometrioid component showed retained SMARCA4 expression. An expanded survey of other members of the SWI/SNF complex showed SMARCB1 loss in the undifferentiated component of two SMARCA4-intact tumors, and all SMARCA4- or SMARCB1-deficient tumors showed concomitant loss of expression of SMARCA2. We subsequently examined the expression of SMARCA2, SMARCA4, and SMARCB1 in an additional set of 22 centrally reviewed dedifferentiated carcinomas and 31 grade 3 endometrioid carcinomas. Combining the results from the index and the expansion set, 15 of 30 (50%) of the dedifferentiated carcinomas examined showed either concurrent SMARCA4 and SMARCA2 loss (37%) or concurrent SMARCB1 and SMARCA2 loss (13%) in the undifferentiated component. The loss of SMARCA4 or SMARCB1 was mutually exclusive. All 31 grade 3 endometrioid carcinomas showed intact expression of these core SWI/SNF proteins. The majority (73%) of the SMARCA4/SMARCA2-deficient and half of SMARCB1/SMARCA2-deficient undifferentiated component developed in a mismatch repair-deficient molecular context. The observed spatial association between SWI/SNF protein loss and histologic dedifferentiation suggests that inactivation of these core SWI/SNF proteins may contribute to the development of dedifferentiated endometrial carcinoma.
authors.affiliation: Department of Pathology and Laboratory Medicine, and Genetic Pathology Evaluation Center, Vancouver General Hospital and 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, and Genetic Pathology Evaluation Center, Vancouver General Hospital and University of British Columbia, Vancouver, BC, Canada.
authors.forename: Lien N
authors.initials: LN
authors.lastname: Hoang
authors.affiliation: Department of Oncology, University of Alberta, Edmonton, AB, Canada.|Department of Obstetrics and Gynecology, University of Alberta, Edmonton, AB, Canada.
authors.forename: Mackenzie
authors.initials: M
authors.lastname: Coatham
authors.affiliation: Department of Obstetrics and Gynecology, University of Alberta, Edmonton, AB, Canada.
authors.forename: Sarah
authors.initials: S
authors.lastname: Ravn
authors.affiliation: Department of Pathology and Laboratory Medicine, and Genetic Pathology Evaluation Center, Vancouver General Hospital and University of British Columbia, Vancouver, BC, Canada.
authors.forename: Noorah
authors.initials: N
authors.lastname: Almadani
authors.affiliation: Department of Pathology and Laboratory Medicine, and Genetic Pathology Evaluation Center, Vancouver General Hospital and University of British Columbia, Vancouver, BC, Canada.
authors.forename: Basile
authors.initials: B
authors.lastname: Tessier-Cloutier
authors.affiliation: Department of Pathology and Laboratory Medicine, and Genetic Pathology Evaluation Center, Vancouver General Hospital and University of British Columbia, Vancouver, BC, Canada.|Department of Laboratory Medicine, Pathology, and Medical Genetics, Royal Jubilee Hospital, Victoria, BC, Canada.
authors.forename: Julie
authors.initials: J
authors.lastname: Irving
authors.affiliation: Department of Laboratory Medicine and Pathology, Royal Alexandra Hospital and University of Alberta, Edmonton, AB, Canada.
authors.forename: Bo
authors.initials: B
authors.lastname: Meng
authors.affiliation: Department of Laboratory Medicine and Pathology, Royal Alexandra Hospital and University of Alberta, Edmonton, AB, Canada.
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Li
authors.affiliation: Department of Pathology and Laboratory Medicine, and Genetic Pathology Evaluation Center, Vancouver General Hospital and University of British Columbia, Vancouver, BC, Canada.
authors.forename: Christine
authors.initials: C
authors.lastname: Chow
authors.affiliation: Department of Obstetrics and Gynecology, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Jessica
authors.initials: J
authors.lastname: McAlpine
authors.affiliation: Department of Pathology, National Taiwan University Hospital and College of Medicine, Taipei, Taiwan.
authors.forename: Kuan-Ting
authors.initials: KT
authors.lastname: Kuo
authors.affiliation: Department of Pathology, National Taiwan University Hospital and College of Medicine, Taipei, Taiwan.
authors.forename: Tsui-Lien
authors.initials: TL
authors.lastname: Mao
authors.affiliation: Department of Pathology and Laboratory Medicine, The Ottawa Hospital, Ottawa, ON, Canada.
authors.forename: Bojana
authors.initials: B
authors.lastname: Djordjevic
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Soslow
authors.affiliation: Department of Pathology and Laboratory Medicine, and Genetic Pathology Evaluation Center, Vancouver General Hospital and University of British Columbia, Vancouver, BC, Canada.
authors.forename: David G
authors.initials: DG
authors.lastname: Huntsman
authors.affiliation: Department of Pathology and Laboratory Medicine, and Genetic Pathology Evaluation Center, Vancouver General Hospital and University of British Columbia, Vancouver, BC, Canada.
authors.forename: C
authors.initials: C
authors.lastname: Blake Gilks
authors.affiliation: Department of Pathology and Laboratory Medicine, Calgary Laboratory Services and University of Calgary, Calgary, AB, Canada.
authors.forename: Martin
authors.initials: M
authors.lastname: Köbel
authors.affiliation: Department of Laboratory Medicine and Pathology, Royal Alexandra Hospital and University of Alberta, Edmonton, AB, Canada.
authors.forename: Cheng-Han
authors.initials: CH
authors.lastname: Lee
mesh_terms: D000368:Aged; D054337:Cell Dedifferentiation / Q000502:physiology*; D002868:Chromosomal Proteins, Non-Histone / Q000096:biosynthesis* / Q000235:genetics; D004252:DNA Mutational Analysis; D016889:Endometrial Neoplasms / Q000235:genetics / Q000401:mortality / Q000473:pathology*; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D046888:Tissue Array Analysis; D014157:Transcription Factors / Q000096:biosynthesis* / Q000235:genetics
chemical_list: D002868:Chromosomal Proteins, Non-Histone; C445179:SWI-SNF-B chromatin-remodeling complex; D014157:Transcription Factors