Cancer — Cell Cycle, Oncogenes, Tumour Suppressors and Metastasis

Multiple choice

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Activity 1 — Classify Oncogene or Tumour Suppressor

1. RAS mutation — oncogene, dominant. RAS is a proto-oncogene encoding a GTPase that normally cycles between active (GTP-bound) and inactive (GDP-bound) states, active only transiently when growth factors stimulate it. The mutation locks RAS in its GTP-bound active state (the GTPase activity that hydrolyses GTP→GDP is abolished). One mutant allele is sufficient (dominant) because the permanently active RAS signals for division continuously regardless of the other allele. The cell receives a constant growth signal even without growth factors. Gain-of-function, dominant.

2. BRCA1 — tumour suppressor, two-hit. BRCA1 encodes a protein involved in DNA double-strand break repair (homologous recombination). The inherited non-functional allele is the first hit (present in every cell since birth); the somatic mutation in the breast cell is the second hit, inactivating the remaining allele. With no functional BRCA1, double-strand breaks cannot be repaired accurately → mutations accumulate → cancer. Loss-of-function, recessive (both alleles must be inactivated).

3. HPV — biological carcinogen, dual tumour suppressor inactivation. E6 binds p53 and recruits a ubiquitin ligase that marks p53 for proteasomal degradation — the cell loses the G1/S checkpoint and apoptosis response. E7 binds and inactivates RB1, releasing the transcription factor E2F so cells continuously enter S phase. HPV is biological because it is a living organism promoting cancer via its proteins rather than direct chemical/physical DNA damage.

4. Retinoblastoma — two-hit hypothesis. Inherited form: every cell already has one inactivated RB1 allele (first hit inherited); cancer develops once any retinal cell acquires a second somatic mutation. With millions of retinal cells each needing only one more mutation, multiple bilateral tumours arise early. Sporadic form: both RB1 alleles start functional; cancer requires two independent somatic mutations in the same cell — a much rarer double event → single, unilateral, later-onset tumour.

Activity 2 — Clinical Scenarios

1. Metastatic bowel cancer — why surgery alone is not curative. Before the primary tumour was removed, cells had already completed the early steps of metastasis — acquiring mutations enabling detachment (E-cadherin loss, matrix metalloproteinase activity), intravasation, survival in circulation, and extravasation into liver and lung tissue. These cells were circulating or already established at secondary sites before surgery. Removing the primary tumour does not eliminate cells established elsewhere. Molecular requirements: (1) cell adhesion molecule loss (detachment); (2) ECM proteases (invasion); (3) anoikis resistance (survival without attachment); (4) immune evasion in circulation; (5) angiogenic factors (VEGF) for secondary tumour blood supply. Metastatic cancer needs systemic treatment (chemotherapy, immunotherapy, targeted therapy) addressing multiple sites, not just localised surgery.

2. BRCA1 — cause vs susceptibility. BRCA1 normally repairs DNA double-strand breaks via homologous recombination, maintaining genome stability. When lost, breaks are repaired by error-prone pathways → genomic instability → accelerated mutation accumulation. The inherited mutation does not directly cause cancer: every cell has one non-functional allele, but cancer only develops when a second somatic mutation inactivates the remaining allele in a breast/ovarian cell — most cells never acquire this. Risk rises dramatically because only one further hit is needed (instead of two independent hits in the same cell). Cause = necessary and sufficient; susceptibility = greatly increased probability but not certainty. BRCA1 mutation lowers the mutational barrier to tumour suppressor loss without being sufficient alone.

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].