Cancer: When Cell-cycle Control Fails

Multiple choice

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Short Answer Model Answers

SA1 (4 marks): Normal p53 function: p53 (encoded by TP53) is a tumour suppressor transcription factor, the cell's primary guardian against DNA damage. It detects DNA damage signals and responds by (1) halting the cell cycle at the G1/S checkpoint via p21 (which inhibits cyclin-dependent kinases) to allow repair before replication, or (2) if damage is irreparable, activating pro-apoptotic genes (e.g. BAX) to trigger programmed cell death [2]. When both TP53 alleles are mutated: the cell loses the ability to detect DNA damage and halt the cycle; cells with damaged DNA continue dividing, replicating damaged DNA and passing mutations to daughter cells; further mutations accumulate in other regulatory genes, and without p53-mediated apoptosis heavily mutated cells survive, progressively driving the cell toward malignancy [2].

SA2 (5 marks): PAHs (tobacco): (a) metabolically activated to reactive diol epoxides that form covalent adducts with guanine in DNA. (b) cause G→T transversions, mutating TP53 (e.g. codons 157, 248, 273) → non-functional p53 [1]. HPV: (a) E6 binds p53 and recruits E6AP ubiquitin ligase, degrading p53 post-translationally; E7 binds RB1, releasing E2F for continuous S-phase entry. (b) p53 and RB1 inactivated simultaneously [1.5]. Combined effect: p53 is disabled by BOTH a direct TP53 mutation (PAH) AND protein degradation (HPV E6), robust, near-total loss. With p53 gone and RB1 inactivated, PAH-induced DNA damage cannot be detected, repaired, or eliminated by apoptosis, while E7-released E2F drives cells into DNA synthesis copying unrepaired damage, a multiplicative increase in mutation accumulation and cancer risk [1.5]. p53 is the critical shared node whose loss enables both insults to produce maximal risk [1].

SA3 (6 marks): Mutations: UVB → thymine dimers → C→T mutations. The earliest driver is usually BRAF V600E (oncogene, ~50% of melanomas), a constitutively active kinase signalling continuous proliferation. This alone is insufficient, benign moles often carry BRAF V600E. Additional mutations accumulate: CDKN2A deletion (loses p16, the G1/S brake), PTEN loss (pro-survival PI3K signalling), TP53 mutation (loses apoptosis), plus adhesion/protease mutations for invasion [2]. Why multi-hit: each mutation gives a growth advantage but is individually insufficient, only accumulation of 4–8+ driver mutations across multiple checkpoints produces a malignant, invasive, metastatic cell. This explains why melanoma takes years to develop despite lifelong UV exposure and predominates in older individuals [2]. Why early detection is critical: before metastasis, melanoma is confined to the epidermis/superficial dermis and surgical excision with clear margins is curative (stage I ~98% 5-year survival). Once cells acquire the metastatic mutation set (detachment, invasion, intravasation, circulation survival, extravasation, secondary growth) and establish secondary tumours, treatment must address multiple sites; stage IV 5-year survival remains ~30–50% even with immunotherapy. Early detection intercepts the disease while it is still a localised, surgically addressable problem [2].