The clinicopathologic significance of p53 and BAF-250a (ARID1A) expression in clear cell carcinoma of the endometrium

Abstract

TP53 mutation (and associated p53 protein overexpression) is probably a negative prognostic marker in endometrial cancers, but its relevance in the rarer histologic subtypes, including clear cell carcinomas, has not been delineated. Preclinical studies suggest functional interactions between p53 and the BAF250a protein, the product of a tumor suppressor gene ARID1A that is frequently mutated in ovarian clear cell carcinoma. In this study, we evaluated the significance of p53 and BAF250a expression, as assessed by immunohistochemistry, in a group of 50 endometrial clear cell carcinomas. Seventeen of 50 cases (34%) were p53 positive; the remaining 33 cases had a p53 wild-type (p53-wt) immunophenotype. Of the 11 relapses/recurrences in the entire dataset, 73% were in the p53[+] group (p=0.008). On univariate analyses, the median overall survival for the p53-wt patients (83 mo) was longer than the p53[+] patients (63 mo) (p=0.07), and the median progression-free survival for the p53-wt group (88 mo) was significantly longer than the p53[+] group (56 mo) (p=0.01). On multivariate analyses, p53 expression was not associated with reduced overall or progression-free survival. Additionally, p53 status was not significantly associated with pathologic stage or morphologic patterns. Ten of the 50 cases (20%) showed a complete loss of BAF250a expression. There was no significant correlation between p53 and BAF250a expression. The p53+/BAF250a−, p53+/BAF250a+, p53-wt/BAF250a+, and p53-wt/BAF250a− composite immunophenotypes were identified in 8%, 26%, 54% and 12% of cases respectively, and neither loss of BAF250a expression nor composite p53/BAF250a expression patterns were associated with reduced overall or progression-free survival. In conclusion, a significant subset of CCC express p53, and these cases are apparently not definable by their morphologic features. p53 expression may be a negative prognostic factor in this histotype, and warrants additional studies. Loss of BAF250a expression has no prognostic significance in endometrial clear cell carcinomas.

Refining prognosis and identifying targetable pathways for high-risk endometrial cancer; a TransPORTEC initiative

“…Overlapping molecular features in clear cell cancers have been noted previously, including loss of ARID1a and p53 mutant-like expression. [35][36][37] This questions whether clear cell cancer are molecularly distinct or whether these cancers are morphological variants of serous and endometrioid cancers harboring the same spectrum of molecular alterations. The data presented here are not conclusive yet and a broader unbiased molecular analysis will be required to answer this question.…”

The emerging roles of ARID1A in tumor suppression

“…25,27,28,37 In endometrial cancer, no association between ARID1A loss and disease-specific survival was observed in three studies on endometrioid carcinoma, 34,35,88 or in one study on clear cell carcinoma. 37 In cervical cancer, ARID1A loss was a predictor of reduced overall survival in one study, 39 but not in another. 38 In bladder transitional cell carcinoma, Gui et al found no association between ARID1A mutation status and tumor grade or stage.…”

“…Figure 1 summarizes their mutation frequencies in reported human neoplastic diseases. In addition, studies applying immunohistochemistry have also identified frequent loss of ARID1A expression in several additional tumor types ( Table 1) including ovarian endocervical-type mucinous borderline tumor (33%), 29 cervical adenocarcinoma (24~31%), 38 endometrial clear cell carcinoma (21~26%), 33,[35][36][37] endometrial carcinosarcoma (14%), 33 and anaplastic thyroid carcinoma (14%). 33 Comparative genomic hybridization studies have also detected frequent heterozygous deletions involving ARID1A in pancreatic cancer (36~47%), 53,68 breast cancer (13~35%), 55,69 and clear cell renal cell carcinoma (16%).…”

The relationship between P53 and EGFR expression with development and progression of endometrial cancer

“…While in more than half in invasive muscle,p53 expression positive in 15 (40.5%) cases. On the other hand, results of [14] found that in lymph node invasion p53expression positive in 5 cases out of 10, while innon-invasive p53 expression was positive in 11 out of30 cases. Moreover, [20]explained thatin lymph node invasionp53 expression positive in 7 (46.7%),while in non-invasive p53 expression positive in 20 (18.2%) .…”

“…Results of [14]showed that 7 out of 27 cases had positive expression in the low stage (stage I and II) of endometrial cancer, while in thestage(III and IV )only 10cases out of the 23cases had p53-postive endometrial cancer .Moreover, [15] found in theendometriod adenocarcinomas, stage IB 5 (13.9%)out of 36 caseshad p53-postive , in stage IIIC 4 (80.0%)out of 5 cases had p53 positive. Whileserous papillary endometrial adenocarcinomas,stage IB showed 2(100.0%) had positive,in stage IC 5 (100.0%) cases had positive and, in stage IIIC 4 (80.0%) out of 5 cases had positive.…”