Phosphatase and Tensin Homolog Immunohistochemical Expression and Promoter Methylation Status in Endometrioid Endometrial Carcinoma and Its Precursor Lesions.

Abstract

Endometrioid endometrial carcinoma (EEC) is the most common invasive malignancy of the female genital tract. Despite advances in diagnosis and treatment, the incidence of EEC and mortality related to it have not decreased. Therefore, research is needed to explore the underlying molecular mechanisms of EEC and its precursors to reduce the mortality and societal burden associated with them. Phosphatase and tensin homolog (PTEN) is a tumor suppressor gene most commonly altered in endometrial carcinoma and its precursor lesions. Promoter methylation is a common mechanism for the inactivation of the PTEN tumor suppressor gene. This was a prospective nested case-control study involving women aged 35 to 70 years old whose endometrial biopsy and resected samples were obtained for histological diagnosis. Before enrolling a person in the study, signed informed consent was obtained from each individual. The ethics committee for the institute gave its approval to the study protocol. Immunohistochemistry (IHC) was used to measure PTEN expression was measured, and methylation-specific PCR (MSP) was used to determine PTEN promoter methylation status (Bisulfite conversion). A total of 95 samples were assessed histopathologically, along withPTEN expression and PTEN promoter methylation status. PTEN immunoreactivity was observed in 79% (15/19) of normal proliferative endometrium, and loss of PTEN expression was observed in 73% (27/37) of endometrial hyperplasia with or without atypia and 90% (35/39) of EEC. Methylation analysis showed that the PTEN promoter was completely unmethylated in all normal proliferative endometria and endometrial hyperplasia without atypia. In contrast, the promoter region was methylated in 50% of endometrial hyperplasia with atypia cases and 38.5% of EEC cases. The loss ofPTEN expression was significantly associated with EEC and precancerous lesions of the endometrium compared to normal proliferative endometria. Methylation analysis also revealed that the frequency of methylation is significant in EEC and endometrial hyperplasia with atypia. Integration of PTEN protein expression along with promoter methylation status elucidates the underlying carcinogenic mechanism. This may help with personalized therapy for EECs and triaging cases of potential precancerous lesions.