HSC Exam Practice

Sample response. A proto-oncogene is a normal gene in every dividing cell that encodes a protein promoting cell division only in response to appropriate growth factor signals. A point mutation in the coding sequence can alter a single amino acid in the protein product — for example, changing glycine to valine at position 12 of the RAS protein — locking the protein in its active GTP-bound state regardless of whether growth factors are present. The resulting constitutively active protein continuously drives cell division without external signals; this gain-of-function mutation converts the proto-oncogene into an oncogene.

Marking notes. 1 mark — defines proto-oncogene as a normal growth-promoting gene (conditional on signals). 1 mark — explains the mechanism of conversion: point mutation → constitutively active protein (permanently switched on). 1 mark — states that the resulting oncogene drives continuous division without growth signals (or equivalent gain-of-function description).

Sample response. A benign tumour is a localised mass of abnormally dividing cells that does not invade surrounding tissue and does not metastasise; surgical removal is usually curative. A malignant tumour invades surrounding tissue and can spread via the bloodstream or lymphatic system to establish secondary tumours at distant sites, making it far harder to treat and rarely curable once metastasis has occurred.

Marking notes. 1 mark — correctly identifies that benign tumours do not invade or metastasise. 1 mark — correctly identifies that malignant tumours do invade surrounding tissue and are capable of metastasis. Both features required in the contrast; isolated statements about size or speed score 0 unless paired with invasion/metastasis.

Sample response. The three categories are: (1) Chemical — example: PAHs in tobacco smoke (or aflatoxin B1, benzene, nitrosamines). (2) Physical — example: UVB radiation from sunlight (or ionising radiation / X-rays, asbestos). (3) Biological — example: HPV strains 16/18 (or Hepatitis B/C virus, Helicobacter pylori, Epstein-Barr virus).

Marking notes. 1 mark per correctly named category paired with a valid named example from the lesson (max 3). A category name without a valid example, or a valid example without the correct category, scores 0 for that row.

Sample response. p53 is a tumour suppressor protein that monitors the G1/S checkpoint. When DNA damage is detected, p53 halts the cell cycle to allow repair; if damage is irreparable, p53 triggers apoptosis — programmed cell death — to eliminate the cell before it can replicate mutated DNA. When both copies of TP53 are lost (via the two-hit mechanism), cells with damaged DNA pass through the G1/S checkpoint unchecked, replicate their mutated DNA, pass mutations to daughter cells, and cannot be directed toward apoptosis. The accumulation of further mutations in these cells greatly increases the probability that the cell becomes malignant, which is why TP53 is mutated in approximately 50% of all cancers.

Marking notes. 1 mark — p53 detects DNA damage at G1/S and triggers arrest/repair or apoptosis. 1 mark — loss of both alleles removes the checkpoint; cells with DNA damage divide. 1 mark — consequence: mutations accumulate in daughter cells, increasing cancer risk (or: apoptosis is disabled so cells that should be eliminated survive).

Sample response. BRCA1 is a tumour suppressor gene involved in DNA double-strand break repair; because tumour suppressor mutations are recessive, both alleles must be inactivated for BRCA1 function to be lost. In the general population, two independent mutations must occur in the same cell — a rare double event — hence the 12% lifetime risk. People who inherit one non-functional BRCA1 allele already carry the first hit in every cell in their body. Only one additional somatic mutation (the second hit) in any breast epithelial cell is needed to eliminate BRCA1 function entirely. Because this second event is vastly more probable than two independent spontaneous mutations in the same cell, the effective lifetime risk rises to ~70%.

Marking notes. 1 mark — BRCA1 is a tumour suppressor; loss of function is recessive (both alleles must be inactivated). 1 mark — in the general population, two independent somatic hits are required — low probability → 12% risk. 1 mark — inherited carriers already have one non-functional allele (first hit) in every cell; only one additional somatic mutation (second hit) needed → dramatically elevated risk of ~70%.

Sample response. Step 1 — Local invasion: cancer cells acquire mutations in cell adhesion molecules (e.g. loss of E-cadherin) and secrete matrix metalloproteinases that digest the extracellular matrix and basement membrane, allowing cells to detach and invade surrounding tissue. Step 2 — Intravasation: cells penetrate the walls of nearby blood or lymphatic vessels and enter the circulation; this requires mutations enabling survival in a non-adherent state (anoikis resistance). Step 3 — Survival in circulation: most cells are destroyed by shear forces or immune cells; a small fraction survive, sometimes forming platelet clusters for protection. Step 4 — Extravasation: surviving cells arrest in small capillaries of distant organs and squeeze through vessel walls into surrounding tissue. Step 5 — Secondary tumour formation: cells proliferate and induce new blood vessel formation (angiogenesis) to establish a secondary tumour in the distant organ.

Marking notes. 1 mark per correctly named and briefly described step (steps 1, 2, 4, 5 must be named and described for full marks; step 3 not required for full marks but gives context). Accept any four steps named and correctly described. Naming without description, or description without naming, scores 0 for that step.

Sample response (a) — 2 marks. Melanoma incidence in Australian men increased consistently between 1985 and 2020 [1]. The rate rose from 25 per 100,000 in 1985 to 55 per 100,000 in 2020 — a more than doubling over 35 years [1].

Marking notes (a). 1 mark — identifies the trend as increasing/rising. 1 mark — quotes at least two specific data values (e.g. 25 in 1985 and 55 in 2020) or calculates the magnitude of change.

Sample response (b) — 2 marks. The proportion of melanomas carrying BRAF V600E has remained approximately constant at 50% even as overall incidence doubled. This suggests that BRAF V600E is not being introduced by a new carcinogen but is a pre-existing feature of melanoma biology — UV radiation (the primary physical carcinogen driving rising incidence) appears to promote melanoma through a pathway that activates BRAF V600E at a relatively fixed rate among melanoma cases [1]. Alternatively, BRAF V600E may arise from a non-UV mechanism (intermittent intense UV, as distinct from cumulative UV), and the rising incidence is driven by additional carcinogen exposures that trigger the other 3–7 required driver mutations in BRAF-mutant cell lineages, or by increased detection [1]. The key inference is that BRAF V600E alone does not determine overall incidence — it reflects a consistent fraction of cancer-initiating events, and additional factors drive the overall rise.

Marking notes (b). 1 mark — identifies that BRAF V600E proportion remains constant despite rising total incidence and correctly infers this means BRAF V600E is not a new/increasing risk but a consistent fraction. 1 mark — links to mechanism (UV promotes the other driver mutations needed for malignancy; BRAF V600E is likely an early event but alone insufficient; multi-hit model).

Sample response (c) — 3 marks. Vemurafenib (BRAF inhibitor) targets the constitutively active BRAF V600E protein directly, blocking the oncogene-driven proliferation signal in the ~50% of melanomas that carry this mutation [1]. However, cancer cells often carry additional driver mutations that provide alternative proliferation pathways not dependent on BRAF — so drug-resistant clones emerge as BRAF-independent cells are selected for (consistent with the multi-hit model: other mutations are already present). Pembrolizumab (PD-1 immune checkpoint inhibitor) works by a completely different mechanism — it removes the molecular “off” signal that metastatic melanoma cells use to suppress T-cell immune responses (a separate pathway from the BRAF oncogene) [1]. Combining both drugs attacks the tumour at two independent molecular points: the oncogene-driven proliferation signal AND the immune evasion mechanism — reducing the probability that any single clone can simultaneously resist both [1]. This is why combination therapy is now standard for metastatic BRAF-mutant melanoma in Australia.

Marking notes (c). 1 mark — explains vemurafenib mechanism (inhibits BRAF V600E protein → blocks oncogene-driven proliferation). 1 mark — explains pembrolizumab mechanism (immune checkpoint blockade → restores T-cell killing of melanoma; separate pathway from BRAF oncogene). 1 mark — justifies why combination is better (dual independent targets reduce probability of resistance; or: attacks both the oncogene growth pathway AND the tumour suppressor/immune evasion pathway simultaneously).

Sample response. The claim that cancer is fundamentally a disease of oncogene activation captures an important truth but is incomplete: cancer arises from the accumulation of mutations in both oncogenes (which provide excessive growth signals) AND tumour suppressor genes (which normally limit division and eliminate damaged cells). The multi-hit model explains why both are necessary.

Oncogenes arise from gain-of-function mutations in proto-oncogenes — normal genes encoding growth-signalling proteins. When mutated (e.g. RAS locked in GTP-bound active form, BRAF V600E, HER2 amplified), these proteins drive continuous cell division even without external growth factor signals. The mutation is dominant: one mutant allele is sufficient because the constitutively active protein is produced regardless of the normal allele. In this respect, cancer does involve oncogene activation, and oncogene-targeted drugs (vemurafenib for BRAF, trastuzumab for HER2) have produced real clinical benefits.

However, oncogene activation alone is insufficient for malignancy. Normal cells have multiple independent safeguards that detect oncogene-driven hyperproliferation and respond with apoptosis or growth arrest — most prominently via p53 (activated by the ARF/MDM2 pathway in response to oncogene-induced replicative stress). Cancer only becomes fully malignant when tumour suppressor genes are also inactivated. Tumour suppressor mutations are loss-of-function and recessive — both alleles must be inactivated (the two-hit model). Key examples: TP53 (mutated in ~50% of all cancers, removes G1/S checkpoint and apoptotic response), RB1 (removes the G1/S block on S-phase entry), BRCA1/2 (remove DNA repair capacity, accelerating mutation accumulation), APC (colorectal cancer), CDKN2A/p16 (melanoma). The biological necessity of losing BOTH oncogene control AND tumour suppressor function is illustrated by HPV-induced cervical cancer: HPV simultaneously activates oncogene-like signalling AND uses E6/E7 to destroy p53 and RB1 — because neither mechanism alone would produce cervical cancer.

The multi-hit model explains why cancer requires 4–8 driver mutations and predominantly affects older people: each mutation must arise independently in the same cell lineage, and each provides a selective growth advantage that enriches for that cell. This explains why cancer takes decades to develop and why exposure to carcinogens (which accelerate mutation rates) dramatically increases risk without guaranteeing cancer.

For cancer treatment, having multiple molecular targets has critical implications. Targeting a single oncogene (e.g. BRAF inhibition) often produces dramatic initial responses but is followed by relapse as cells that carry alternative driver mutations (from the multi-hit accumulation) survive and proliferate. This is why modern oncology favours combination approaches: BRAF + MEK inhibition blocks adjacent pathway steps; BRAF inhibitor + PD-1 checkpoint inhibitor combines oncogene targeting with immune re-activation. Each additional target reduces the probability that any single clone can simultaneously develop resistance to all treatments.

In conclusion, the claim that cancer is “fundamentally a disease of oncogene activation” underestimates the role of tumour suppressor loss, which is equally — often more — important. Cancer is fundamentally a disease of multiple accumulated mutations that both activate growth signals (oncogenes) AND remove the multiple independent brakes (tumour suppressors) that would normally prevent uncontrolled division and eliminate damaged cells.

Marking criteria.

• 1 mark — States an evaluative judgement that the claim is partially correct but incomplete/limited, and identifies what it correctly captures (oncogene activation does occur and is important).
• 1 mark — Correctly describes oncogene mechanism: gain-of-function, dominant, one mutant allele sufficient, constitutively active protein (not overproduced), with a named example (RAS, BRAF, HER2, MYC).
• 1 mark — Correctly describes tumour suppressor mechanism: loss-of-function, recessive, both alleles required (two-hit model), with a named example (p53/TP53, RB1, BRCA1, APC, CDKN2A); explains p53 or RB1 function specifically.
• 1 mark — Applies the multi-hit model: cancer requires 4–8 driver mutations; explains why multiple independent mutations in the same cell lineage are needed; links to ageing and carcinogen exposure as accelerators.
• 1 mark — Uses a named real-world example that integrates both oncogene and tumour suppressor pathways (HPV cervical cancer disabling p53 + RB1 while promoting proliferation; or melanoma BRAF V600E + CDKN2A loss; or any multi-mutation cancer correctly described).
• 1 mark — Assesses implications for cancer treatment: multiple molecular targets; mono-target therapy leads to resistance via tumour heterogeneity; combination approaches reduce resistance probability; specific drug examples welcomed.
• 1 mark — Reaches an explicit, integrative conclusion that both oncogenes and tumour suppressors are required for malignancy; cancer cannot be defined as purely an oncogene disease; reformulates the claim accurately using precise lesson terminology.