A 28-year-old woman presents to the gynaecology clinic with abnormal vaginal bleeding and postcoital spotting for 3 months. She is sexually active with a single partner for 5 years. On speculum examination, a friable, bleeding cervical lesion is noted. Pap smear shows atypical squamous cells of undetermined significance (ASCUS). HPV testing is positive for high-risk types (HPV-16 and HPV-18). Colposcopy with directed biopsy confirms cervical intraepithelial neoplasia grade 2 (CIN-2). Which viral protein is primarily responsible for the malignant transformation observed in this patient?

Explanation

## Mechanism of HPV-Mediated Cervical Malignancy **Key Point:** High-risk HPV types (16, 18, 31, 33, 45) express E6 and E7 oncoproteins that drive malignant transformation through inactivation of p53 and Rb tumour suppressors. ### E6 Oncoprotein Function - Binds to and degrades p53 (tumour suppressor) via ubiquitin-mediated proteasomal pathway - Prevents p53-induced apoptosis and cell cycle arrest - Allows accumulation of additional mutations ### E7 Oncoprotein Function - Binds to and inactivates retinoblastoma (Rb) protein - Disrupts G1/S cell cycle checkpoint - Promotes uncontrolled cell proliferation - Also inactivates p21 and p27 (CDK inhibitors) ### Progression Model in This Patient 1. HPV-16/18 infection → viral integration into host genome 2. Loss of E2 regulatory control → increased E6/E7 expression 3. p53 and Rb inactivation → CIN-1 → CIN-2 → CIN-3 → invasive carcinoma **High-Yield:** E6 and E7 are the critical oncoproteins; their presence in high-risk HPV types distinguishes them from low-risk types (6, 11) which produce non-transforming E6/E7 variants. **Clinical Pearl:** HPV-16 accounts for ~50% of cervical cancers; HPV-18 for ~20%. Together they account for ~70% of cervical cancer cases globally. ### Why This Patient Has CIN-2 - Persistent infection with high-risk HPV (not cleared by immune system) - E6/E7-mediated inactivation of tumour suppressors - Progression from normal epithelium → CIN-1 → CIN-2 (current state) - Risk of progression to CIN-3 and invasive cancer without intervention [cite:Robbins 10e Ch 7]