Loss of switch/sucrose non-fermenting complex protein expression is associated with dedifferentiation in endometrial carcinomas
Journal
Modern Pathology
Journal Volume
29
Journal Issue
3
Pages
302-314
Date Issued
2016
Author(s)
Karnezis A.N.
Hoang L.N.
Coatham M.
Ravn S.
Almadani N.
Tessier-Cloutier B.
Irving J.
Meng B.
Li X.
Chow C.
McAlpine J.
Djordjevic B.
Soslow R.A.
Huntsman D.G.
Blake Gilks C.
Köbel M.
Lee C.-H.
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. ? 2016 USCAP, Inc.
SDGs
Other Subjects
BRG1 protein; BRM protein; mismatch repair protein; protein; protein SWI; SMARCB1 protein; transcription factor SNF; unclassified drug; nonhistone protein; SWI-SNF-B chromatin-remodeling complex; transcription factor; adult; aged; amplicon; Article; cancer adjuvant therapy; clinical article; clinical feature; cohort analysis; comparative study; controlled study; dedifferentiated endometrial carcinoma; disease specific survival; endometrioid carcinoma; endometrium carcinoma; female; frameshift mutation; human; human tissue; immunohistochemistry; middle aged; mismatch repair; missense mutation; mitosis rate; next generation sequencing; nonsense mutation; outcome assessment; priority journal; protein depletion; protein expression; tumor necrosis; undifferentiated carcinoma; biosynthesis; cell dedifferentiation; DNA microarray; dna mutational analysis; endometrium tumor; genetics; Kaplan Meier method; mortality; pathology; physiology; tissue microarray; Aged; Cell Dedifferentiation; Chromosomal Proteins, Non-Histone; DNA Mutational Analysis; Endometrial Neoplasms; Female; Humans; Immunohistochemistry; Kaplan-Meier Estimate; Middle Aged; Oligonucleotide Array Sequence Analysis; Tissue Array Analysis; Transcription Factors
Publisher
Nature Publishing Group
Type
journal article