Dominant Negative PTEN Alterations in Endometrial Carcinoma Are Associated With Retained Immunohistochemical PTEN...

PTEN immunohistochemistry (IHC) is considered complimentary for assessment of PTEN abnormality in endometrial carcinoma (EC), since PTEN IHC staining pattern does not entirely correlate with the presence and absence of mutations on sequencing. A set of functionally defective PTEN variants with stable protein levels are known to act in a dominant-negative manner to suppress wild-type PTEN activity. Our objective was to evaluate PTEN IHC patterns in ECs with dominant-negative (DN) PTEN mutations. ECs with next-generation sequencing (NGS, using Oncomine Comprehensive Assay v3) over a 3-year period were enrolled. PTEN IHC was scored as loss, subclonal loss, reduced, and intact (the last 3 considered retained). Of 182 EC cases, 114 (62.6%) were identified to have PTEN mutation(s), the majority of endometrioid histotype (87.7%) from all EC molecular classes. Forty-seven cases (41.2%) harbored DN mutations which were of endometrioid (FIGO 1 [n=15, 31.9%], FIGO 2 [n=23, 48.9%], FIGO 3 [n=3, 6.4%]), dedifferentiated (n=2, 4%), carcinosarcoma (n=3, 6%), mixed endometrioid and clear cell carcinoma (n=1, 2%) histotype; with representatives from all molecular classes. PTEN IHC showed retained expression in 95.8% (45/47) of DN-mutated cases (intact staining in 36 [76.6%], reduced staining in 6 [12.5%], and subclonal loss in 3 [6.4%]) cases. Two cases showed loss of expression (4.2%). In the PTEN wild-type group, loss and subclonal loss of expression were seen in 12.5% and 9.4%, respectively. Our results indicate that DN PTEN mutations are common in EC, and are associated with retained IHC staining (intact, reduced, or subclonal loss). These results highlight that IHC and NGS are both required in capturing the full spectrum of PTEN-abnormal EC.