According to the WHO 2020 classification of ovarian epithelial tumours, which molecular alteration specifically characterises the development pathway of high-grade serous carcinoma (HGSC) of the ovary, distinguishing it from low-grade serous carcinoma (LGSC)?

• A TP53 mutation with extensive chromosomal instability (CCNE1 amplification, BRCA1/2 mutations) ✓
• B KRAS/BRAF mutations with chromosomal stability
• C PTEN mutations with microsatellite instability
• D CTNNB1 (β-catenin) mutations with endometrioid differentiation

Explanation

HGSC is characterised by near-universal TP53 mutations (>96% of cases) and extensive chromosomal instability. BRCA1/2 germline mutations (homologous recombination deficiency) are present in ~20% of cases, and CCNE1 amplification occurs in a mutually exclusive subset. This 'chromosomally unstable' pathway (Type II pathway, Shih-Kurman model) drives rapid progression. In contrast, LGSC follows a Type I pathway with KRAS/BRAF or NRAS mutations, chromosomal stability, and indolent growth via a borderline tumour precursor. PTEN/β-catenin mutations are characteristic of endometrioid and clear-cell carcinoma (Type I).

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

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Written and medically reviewed by the StethoPrep medical team.