| Abstract: |
Undifferentiated endometrial carcinoma is an aggressive type of endometrial carcinoma that typically presents with advanced stage disease and rapid clinical progression. In contrast to dedifferentiated endometrial carcinoma, undifferentiated carcinoma lacks a concurrent differentiated (typically low-grade endometrioid) carcinoma component, though the undifferentiated component of dedifferentiated carcinoma is similar histologically and immunophenotypically to pure undifferentiated carcinoma. We recently identified 3 mutually exclusive mechanisms of switch/sucrose nonfermentable (SWI/SNF) complex inactivation (BRG1 inactivation, INI1 inactivation or ARID1A/ARID1B co-inactivation) that are associated with histologic dedifferentiation in the majority of dedifferentiated endometrial carcinoma. In the current study, we aimed to determine by immunohistochemistry whether these patterns of SWI/SNF inactivation also occur in undifferentiated endometrial carcinomas. Of the 34 undifferentiated carcinomas examined, 17 (50%) exhibited SWI/SNF complex inactivation, with 11 tumors showing complete loss of both ARID1A and ARID1B, 5 showing complete loss of BRG1 and 1 showing complete loss of INI1. Ten of the remaining 17 undifferentiated carcinomas showed the following alterations: 5 tumors (15%) showed loss of ARID1A only with intact ARID1B, BRG1, and INI1 expression, 4 tumors (12%) showed mutated patterns of p53 staining with intact SWI/SNF protein expression, and 1 tumor (3%) harbored a POLE exonuclease domain mutation (P286R). SWI/SNF complex-inactivated tumors presented more frequently with extrauterine disease spread than those with intact expression (88% vs. 41%, respectively). In addition, patients with SWI/SNF complex-inactivated tumors had a significantly worse disease-specific survival (P=0.02). The findings here demonstrate frequent SWI/SNF complex inactivation in undifferentiated endometrial carcinomas, which has future implications regarding therapies that target chromatin remodelling and epigenetic control. Copyright © 2017 Wolters Kluwer Health, Inc. All rights reserved. |
| Keywords: |
immunohistochemistry; adult; aged; aged, 80 and over; middle aged; dna binding protein; genetics; mutation; dna-binding proteins; follow up; follow-up studies; endometrial cancer; undifferentiated carcinoma; endometrial neoplasms; metabolism; nuclear protein; transcription factor; pathology; protein p53; tumor marker; transcription factors; nuclear proteins; tumor suppressor protein p53; endometrium tumor; dna helicases; dna helicase; dna directed dna polymerase alpha; smarcb1; smarcb1 protein, human; dna polymerase ii; very elderly; arid1a; humans; human; female; smarcb1 protein; smarca4; biomarkers, tumor; smarca4 protein, human; swi/snf related matrix associated actin dependent regulator of chromatin subfamily b member 1; arid1b; arid1a protein, human; arid1b protein, human; pole protein, human; poly adp ribose binding protein; poly-adp-ribose binding proteins
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