Loss of switch/sucrose non-fermenting complex protein expression is associated with dedifferentiation in endometrial carcinomas. Academic Article uri icon

Overview

MeSH

  • Aged
  • DNA Mutational Analysis
  • Female
  • Humans
  • Immunohistochemistry
  • Kaplan-Meier Estimate
  • Middle Aged
  • Oligonucleotide Array Sequence Analysis
  • Tissue Array Analysis

MeSH Major

  • Cell Dedifferentiation
  • Chromosomal Proteins, Non-Histone
  • Endometrial Neoplasms
  • Transcription Factors

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.

publication date

  • March 2016

has subject area

  • 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

Research

keywords

  • Journal Article

Identity

Language

  • eng

PubMed Central ID

  • PMC4980656

Digital Object Identifier (DOI)

  • 10.1038/modpathol.2015.155

PubMed ID

  • 26743474

Additional Document Info

start page

  • 302

end page

  • 314

volume

  • 29

number

  • 3