Endometrial hyperplasia without atypia carries a low risk of progression to endometrial carcinoma (<5%), while complex atypical hyperplasia carries ~25% risk. Which molecular alteration is the earliest molecular event in the endometrioid (type I) carcinogenesis pathway?

• A PTEN tumour suppressor gene inactivation causing loss of PI3K pathway regulation ✓
• B TP53 mutation causing loss of G1/S checkpoint
• C CTNNB1 (beta-catenin) activating mutation
• D MLH1 promoter methylation causing microsatellite instability

Explanation

PTEN inactivation is the most common and earliest molecular event in endometrioid endometrial carcinogenesis (found in ~80% of type I endometrial carcinomas and even in normal-appearing eutopic endometrium of women at risk). PTEN is a phosphatase that antagonises PI3K; its loss leads to constitutive AKT/mTOR activation promoting cell survival and proliferation. In contrast, TP53 mutations are characteristic of high-grade serous (type II) endometrial carcinoma. MLH1 methylation is seen in ~20% of sporadic type I carcinomas as a later event causing MSI.

Reference: Robbins & Cotran Pathologic Basis of Disease, 10th ed.

High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP

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