A 28-year-old woman presents to the gynaecology clinic with abnormal vaginal bleeding and postcoital bleeding for 3 months. She is sexually active with a single partner for the past 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 HPV-16. Colposcopy-directed cervical biopsy reveals cervical intraepithelial neoplasia grade 2 (CIN 2). Which HPV type is most likely responsible for this lesion, and what is the mechanism by which it promotes malignant transformation?

Question

Accepted Answer

C. HPV-16 inactivates p53 and Rb through E6 and E7 oncoproteins, leading to loss of cell cycle control and apoptosis resistance. ## HPV Oncogenesis Mechanism

**Key Point:** High-risk HPV types (16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66, 68) cause cervical cancer through inactivation of tumour suppressor proteins p53 and retinoblastoma (Rb).

### E6 and E7 Oncoproteins

HPV-16 (and other high-risk types) encode two critical viral oncoproteins:

1. **E6 oncoprotein**
   - Binds to and targets p53 for proteasomal degradation
   - Prevents p53-mediated apoptosis and cell cycle arrest
   - Allows accumulation of additional mutations

2. **E7 oncoprotein**
   - Binds to and inactivates Rb protein
   - Disrupts Rb–E2F interaction
   - Drives uncontrolled progression through G1/S checkpoint
   - Induces chromosomal instability

### Clinical Correlation

**High-Yield:** HPV-16 and HPV-18 account for ~70% of cervical cancers worldwide. HPV-16 is associated with more aggressive lesions and higher progression risk to invasive cancer compared to HPV-18.

**Clinical Pearl:** The presence of CIN 2 with high-risk HPV-16 in a young woman indicates significant malignant potential. Without treatment, ~30% of CIN 2 lesions progress to invasive cancer within 5 years.

### Comparison of HPV Types

| Feature | High-Risk HPV (16, 18) | Low-Risk HPV (6, 11) |
|---------|------------------------|----------------------|
| E6/E7 activity | Strong p53/Rb inactivation | Weak/absent |
| Integration | Frequent in cancers | Rare |
| Malignant potential | High (cervical, anal, oropharyngeal cancers) | Low (benign warts) |
| Mechanism | Tumour suppressor inactivation | Chronic inflammation |

**Mnemonic:** **HERB** — **H**igh-risk HPV types **E**xpress **R**b-inactivating **B**iological oncoproteins (E7 and E6).

[cite:Robbins 10e Ch 7]

Answer

A. HPV-31 produces viral DNA that directly damages host chromosomes, causing chromosomal instability

Answer

B. HPV-6 integrates into the host genome and produces capsid proteins that trigger chronic inflammation

Answer

D. HPV-11 upregulates telomerase activity through viral coat protein interactions with telomere-binding proteins

Explanation

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