A 52-year-old Indian man with a family history of early-onset colorectal cancer is found to have a germline TP53 mutation. Which feature best distinguishes his cancer predisposition syndrome from a patient with a germline APC mutation?

Question

Accepted Answer

A. TP53 mutations predispose to multiple cancer types across different organs (Li-Fraumani syndrome), whereas APC mutations specifically cause familial adenomatous polyposis with colorectal cancer as the predominant malignancy. ## TP53 vs. APC Germline Mutations: Syndrome Distinction

### Spectrum of Cancer Predisposition

| Feature | TP53 (Li-Fraumeni) | APC (FAP) |
|---------|-------------------|----------|
| **Associated cancers** | Breast, sarcoma, brain, adrenal, leukemia, pancreatic, gastric | Colorectal (nearly 100%), duodenal, gastric, pancreatic |
| **Organ specificity** | Multiple, diverse organs | Predominantly colorectal |
| **Polyp phenotype** | N/A (not a polyposis syndrome) | Hundreds to thousands of adenomatous polyps |
| **Age of onset** | Early (median 30–40 years) | Early (polyps by age 10–20) |
| **Inheritance pattern** | Autosomal dominant | Autosomal dominant |
| **Mechanism** | Loss of p53 (guardian of genome) → impaired apoptosis, cell cycle arrest | Loss of APC → uncontrolled Wnt signaling → adenoma initiation |

### Key Point

**High-Yield:** Li-Fraumeni syndrome (TP53) is a **multi-organ cancer predisposition** syndrome with diverse malignancies. Familial adenomatous polyposis (APC) is a **polyposis syndrome** with colorectal cancer as the dominant phenotype.

### Clinical Pearl

**Key Point:** Patients with Li-Fraumeni syndrome require surveillance for breast cancer (in women), sarcoma, brain tumors, and adrenal tumors. FAP patients require prophylactic colectomy (usually by age 20–30) to prevent colorectal cancer, which approaches 100% penetrance by age 40 without intervention.

### Mnemonic

**LFS = TP53 = Lots of cancers (diverse); FAP = APC = Adenomas Predominate in colon**

Answer

B. TP53 mutations are inherited in an autosomal recessive pattern, while APC mutations follow autosomal dominant inheritance

Answer

C. TP53 mutations cause loss of cell cycle checkpoint control, whereas APC mutations cause constitutive Wnt signaling activation

Answer

D. TP53 mutations result in increased apoptosis, whereas APC mutations result in decreased apoptosis

A 52-year-old Indian man with a family history of early-onset colorectal cancer is found to have a germline TP53 mutation. Which feature best distinguishes his cancer predisposition syndrome from a patient with a germline APC mutation?

Explanation

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