The TCGA (The Cancer Genome Atlas) molecular classification of endometrial carcinoma identifies four subgroups. Which molecular subgroup has the BEST prognosis, characterized by ultramutated status due to DNA polymerase epsilon (POLE) exonuclease domain mutations?

• A MSI-H (microsatellite instability-high) group — hypermutated via mismatch repair deficiency
• B POLE-ultramutated group — highest mutation burden with paradoxically excellent prognosis despite high-grade histology ✓
• C NSMP (No Specific Molecular Profile) group with low copy number alterations — most common group
• D p53-abnormal (serous-like) group — worst prognosis with TP53 mutations and copy number high

Explanation

The TCGA/ProMisE molecular classification (2013, validated 2016) identifies four endometrial cancer groups: POLE-ultramutated (mutation in POLE exonuclease domain), MSI-H/hypermutated (MMR deficiency), NSMP (No Specific Molecular Profile, copy-number low), and p53-abnormal (copy-number high/serous-like). Despite often being high-grade (Grade 3 endometrioid or carcinosarcoma), POLE-ultramutated tumors have the best prognosis — 5-year disease-specific survival >90% — thought due to high neoantigen load driving strong immune surveillance with tumor-infiltrating lymphocytes. MSI-H (A) has intermediate prognosis. NSMP (C) has intermediate-good prognosis (most endometrioid Grade 1–2). p53-abnormal (D) has the worst prognosis, similar to uterine serous carcinoma.

Reference: Shaw's Textbook of Gynaecology, 17th ed.

High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP

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