A patient inherits one mutant copy of RB1 in every cell of their body (familial retinoblastoma). Why do tumors develop earlier and more frequently than in patients who have two normal RB1 copies at birth?
AThe inherited mutant copy acts as a dominant oncogene, immediately driving proliferation in retinal cells
BHaving one mutant copy in every cell means only a single additional somatic mutation is needed to eliminate RB1 function, rather than two independent somatic events
CThe inherited mutant copy prevents DNA repair, accelerating all mutations throughout the genome
DHeterozygous loss of RB1 already reduces the brake on proliferation enough to cause tumors
This is the core of Knudson's two-hit hypothesis. Tumor suppressors require inactivation of BOTH copies before their protective function is lost (loss-of-function is recessive). In sporadic retinoblastoma, two independent somatic mutations must hit the same cell — a statistically rare double event. Inherited cases start with one hit already in every retinal cell at birth; only one additional somatic event is needed, making tumor formation far more likely and occurring earlier. Option D is wrong: heterozygous loss is typically insufficient because the remaining normal copy maintains function.
Question 2 Multiple Choice
An oncologist discovers that a cancer carries a point mutation in KRAS that locks its protein product in the GTP-bound (active) state. How many mutant copies of KRAS are needed to drive tumor growth?
ABoth copies must be mutated, since one normal copy would suppress the mutant signal
BOnly one mutant copy is sufficient, because the constitutively active protein overrides the normal regulatory system
CFour copies are required because KRAS has multiple isoforms
DNeither copy matters; KRAS mutations are always passenger mutations with no functional effect
Oncogenic mutations are dominant gain-of-function: one mutant copy is sufficient to drive excessive signaling because the activated protein (stuck in the 'on' state) floods the cell with growth signals regardless of what the second copy does. This is the gas pedal analogy — one stuck accelerator pushes the car forward even if the other pedal works normally. This distinguishes oncogenes fundamentally from tumor suppressors: oncogenes need ONE hit; tumor suppressors need TWO.
Question 3 True / False
Oncogene mutations are dominant because a single mutant copy can drive excessive proliferation even when the other copy of the gene is normal and functional.
TTrue
FFalse
Answer: True
This is the defining feature of oncogenes. The mutant protein product produces a gain of function — constitutive growth signaling, locked receptor activation, or unregulated transcription factor activity — that operates independently of the normal copy. One stuck accelerator is enough to keep the car moving. This contrasts sharply with tumor suppressors, where the remaining normal copy maintains function until it too is inactivated.
Question 4 True / False
A person who inherits one mutant copy of TP53 (as in Li-Fraumeni syndrome) has already lost p53 function in most their cells, so cancer development is inevitable from birth.
TTrue
FFalse
Answer: False
This is the key misconception about the two-hit model. Tumor suppressors require BOTH copies to be inactivated before protective function is lost — one normal allele is sufficient to maintain function. Li-Fraumeni syndrome patients have one normal TP53 copy in every cell, which continues to function. Cancer requires a second somatic mutation (the 'second hit') that eliminates that remaining copy in a particular cell. This is why Li-Fraumeni carriers face dramatically elevated cancer risk but do not develop cancer at birth — they are one somatic event away per cell, not zero.
Question 5 Short Answer
Why must both copies of a tumor suppressor gene be inactivated for cancer to result, while activation of only one copy of an oncogene is sufficient to drive tumor growth?
Think about your answer, then reveal below.
Model answer: Tumor suppressors have a loss-of-function mechanism: their normal role is to restrain proliferation, and one working copy is enough to maintain that brake. Only when both copies are inactivated is the restraint completely removed. Oncogenes have a gain-of-function mechanism: the mutant protein actively drives proliferation regardless of what the other copy does — one constitutively active accelerator overrides the system.
This mechanistic asymmetry explains why the two gene classes behave so differently in hereditary cancer syndromes. Tumor suppressor syndromes (BRCA1/2, RB1, APC, TP53) follow the two-hit pattern: one inherited hit plus one somatic hit. Oncogene-driven hereditary syndromes are rarer because a single germline oncogenic mutation would drive proliferation throughout development. The dominant/recessive distinction here is about the protein-level mechanism, not allele-level genetics in the traditional sense.