Which genetic alteration is the initiating event in the adenoma-carcinoma sequence of colorectal cancer?

Question

Accepted Answer

A. APC gene mutation. ## The Adenoma-Carcinoma Sequence

**Key Point:** The adenoma-carcinoma sequence is a well-established multi-step model of colorectal carcinogenesis, with APC mutation as the initiating event.

### Sequential Genetic Alterations

| Stage | Genetic Event | Morphology |
|-------|---------------|------------|
| Normal epithelium | — | Normal mucosa |
| Early adenoma | APC mutation | Small adenoma (<1 cm) |
| Intermediate adenoma | KRAS activation | Larger adenoma (1–2 cm) |
| Late adenoma | TP53 loss | Large adenoma (>2 cm) |
| Carcinoma | SMAD4 loss | Invasive cancer |

**High-Yield:** APC (Adenomatous Polyposis Coli) inactivation is the **first hit** in sporadic colorectal cancer and is present in ~80% of colorectal adenomas. Loss of APC function removes the "brake" on Wnt/β-catenin signalling, leading to uncontrolled cell proliferation and adenoma formation.

**Clinical Pearl:** Familial Adenomatous Polyposis (FAP) patients inherit a germline APC mutation and develop hundreds to thousands of adenomas by age 30–40, with near 100% risk of colorectal cancer if untreated.

**Mnemonic:** **A-K-P-S** = **A**PC → **K**RAS → **P**53 → **S**MAD4 (the order of genetic hits in the adenoma-carcinoma sequence).

### Why APC is the Initiator

1. Present in nearly all adenomas, even tiny ones
2. Sufficient alone to initiate adenoma formation (proven in APC knockout mouse models)
3. KRAS, TP53, and SMAD4 mutations occur later and drive progression to malignancy

[cite:Robbins 10e Ch 17]

Answer

B. KRAS gene mutation

Answer

C. TP53 gene mutation

Answer

D. SMAD4 gene mutation

Which genetic alteration is the initiating event in the adenoma-carcinoma sequence of colorectal cancer?

Explanation

The Adenoma-Carcinoma Sequence

Sequential Genetic Alterations

Why APC is the Initiator

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Stage	Genetic Event	Morphology
Normal epithelium	—	Normal mucosa
Early adenoma	APC mutation	Small adenoma (<1 cm)
Intermediate adenoma	KRAS activation	Larger adenoma (1–2 cm)
Late adenoma	TP53 loss	Large adenoma (>2 cm)
Carcinoma	SMAD4 loss	Invasive cancer