Correlation and Prognostic Significance of Mismatch Repair (MMR) Protein and ARID1A Gene Expression in Endometrial Carcinomas (ECs)
Ghassan Allo, Steve Kalloger, Aaron Pollett, Marcus Bernardini, Blaise Clarke. University of Toronto, Toronto, Canada; Toronto General Hospital, Toronto, Canada; Mount Sinai Hospital, Toronto, Canada; Princess Margaret Hospital, Toronto, Canada; University of British Columbia, Vancouver, Canada
Background: DNA MMR system plays a crucial role in DNA repair during its synthesis. ARID1A gene encodes a protein, BAF250a, which is a component of SWI/SNF chromatin remodelling complex, involved in multiple cellular functions including DNA repair. Defects in MMR genes have been reported in 15-20% of sporadic ECs. Mutations and loss of expression of ARID1A gene have been observed in ∼20-40% of ECs. In this study, we correlate MMR proteins loss with BAF250a negatibvity, and investigate their prognostic significance.
Design: A tissue microarray of 216 ECs were immunohistochemically stained for MMR markers (MLH1, MSH2, MSH6, and PMS2) and ARID1A gene product (BAF250a). The likelihood ratio (LR) and log rank test were used to correlate biomarkers expression and survival, respectively.
Results: Two hundred and eleven cases contained assessable tumour. Loss of any MMR proteins was observed in 69/211 (32.7%) ECs, with loss of MLH1 and PMS2 being the most common (table 1). BAF250a was negative in 60/211 (28.4%). ECs that retain MMR protein expression are more likely to be positive for BAF250a (100/194; 56.7%; LR, 33.6;p<0.0001). In univariate analysis, progression free survival (PFS) was worse in ECs with intact MMR proteins expression (Log rank, 5.7; p=0.0174), and in those positive for BAF250a (Log rank, 6.8; p= 0.0091). Moreover, ECs that show both BAF250a positivity and intact MMR expression have worse PFS than arid1- MMR lost EC (5Y PFS, 30% vs. 90%; log rank, 11.7; p=0.0084).
Conclusions: In univariate analysis, the retention of expression of MMR proteins and ARID1a gene product is associated with worse prognosis in endometrial carcinomas.
|Marker||number (%) of cases with loss|
|Any MMR||69/211 (32.7%)|