A 28-year-old woman presents with a diagnosis of invasive ductal carcinoma of the breast. Her mother died of osteosarcoma at age 19, and her maternal grandmother had gastric cancer at age 42. Genetic testing reveals a germline missense mutation in the TP53 gene located on the region marked **B** in the diagram. Which of the following best explains the molecular mechanism underlying the high cancer predisposition in this family?
A. The mutation causes complete loss of p53 protein expression, preventing any DNA-binding capacity and leading to uncontrolled cell proliferation
B. The mutation results in a hyperactive p53 that constitutively drives apoptosis, causing excessive cell death and genomic instability
C. The missense mutation produces a stable but transcriptionally inactive p53 protein that exerts dominant-negative effects over wild-type p53, impairing cell-cycle arrest, DNA repair, and apoptosis
D. The mutation impairs p53 phosphorylation by ATM kinase, preventing its activation in response to DNA damage
Explanation
Why option 1 is correct
The clinical anchor is that most TP53 mutations in Li-Fraumeni syndrome are missense mutations within the DNA-binding domain that produce a stable but transcriptionally inactive p53 protein. These mutant proteins exert dominant-negative effects over wild-type p53 (from the normal allele), effectively impairing the guardian-of-the-genome functions: cell-cycle arrest via p21/CDKN1A, DNA repair, senescence, and apoptosis via BAX, PUMA, and NOXA. This explains the extremely high penetrance (>70% in men, >90% in women) and lifetime cancer risk approaching 100%. The patient's presentation (early-onset breast cancer, family history of sarcoma and gastric cancer) is classic for Li-Fraumeni syndrome and reflects the broad tumor spectrum driven by this molecular mechanism. (Robbins 10e Ch 7; NCCN Genetic/Familial 2024)
Why each distractor is wrong
Option 2: While some TP53 mutations do cause loss of function, the anchor specifically emphasizes that most LFS mutations are missense with a stable protein — not complete loss of expression. Null mutations would not exert dominant-negative effects and are less common in classical LFS.
Option 3: A hyperactive, constitutively apoptotic p53 would cause excessive cell death and would not predispose to cancer; this is the opposite of the pathophysiology. LFS mutations lose function, not gain it in the apoptotic direction.
Option 4: While ATM phosphorylation is part of p53 activation, the anchor specifies that the defect in LFS is within the DNA-binding domain, not in upstream kinase recognition. This distractor confuses the site of mutation with the mechanism of p53 activation.
High-YieldNEET PG
Li-Fraumeni = germline TP53 missense mutation → stable but inactive p53 → dominant-negative effect → loss of guardian-of-genome functions → 100% lifetime cancer risk; core tumors = breast (early 30s), sarcoma, adrenocortical carcinoma, brain tumors, leukemia.
Robbins 10e Ch 7; NCCN Genetic/Familial 2024
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