Expression of Extracellular Regulated Protein Kinase (ERK) & Promoter Methylation of RASSF1A In Endometrioid Endometrial Carcinoma and Its Precursor Lesions - A Nested Case Control Study and Review of Literature

ObjectiveEndometrial carcinoma (EC) is the most common invasive gynaecological cancer worldwide, majority being endometroid endometrial carcinoma (EEC). Mitogen-activated protein kinases (MAPKs) are important members of the intracellular signalling pathways that control cell proliferation and apoptosis, play an important role in EC. Promoter methylation of Ras association domain family 1 isoform A (RASSF1A) regulates, the key MAPK cascade, i.e. extracellular-regulated protein kinase (ERK). However, the role of ERK expression and its association with RASSF1A promoter methylation in EEC and its precursor lesions are currently less known.MethodsIt was a prospective nested case-control study involving women aged 35-70 years, whose endometrial biopsies were obtained for histological diagnosis. Signed informed consent was obtained before enrolling a woman in the study, and the approval to conduct the study was obtained from the institutional ethics committee. Immunohistochemistry (IHC) was done to measure the pERK1/2 expression, and methylation-specific PCR was done to determine RASSF1A promoter methylation status.ResultsPositive nuclear expression of pERK1/2 was observed in 63% of normal proliferative endometrium, while all precancerous (100%) and 97% cancerous lesions had positive expression. Significantly higher expression of pERK1/2 was observed in precancer and cancer cases as compared to normal controls. Methylation analysis showed that the RASSF1A promoter was methylated in 85% of EEC and 7% of controls, whereas all the precancer cases were unmethylated.ConclusionImmunohistolocalisation alone may not be practically of use in diagnostication or prognostication as 63% of controls also showed immunolocalisation of ERK. Since activation of pERK1/2 was also significantly associated with promoter methylation of RASSF1A in EEC, the integration of pERK1/2 immuno-expression and RASSFIA promoter methylation might offer a potential therapeutic target for EEC. This needs to be explored further.