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Difficulty: EasyNeoplastic Processes

A 55-year-old man undergoes a screening colonoscopy, which reveals a 2-cm polyp in the descending colon. Biopsy shows a tubulovillous adenoma with high-grade dysplasia. The patient is scheduled for a polypectomy. The development of such lesions into invasive adenocarcinoma typically follows a well-characterized stepwise accumulation of genetic and epigenetic alterations.

Arrange the following molecular events in the typical chronological order of the classic adenoma-carcinoma sequence in colorectal cancer, from earliest (first) to latest (last).

  1. 1Biallelic loss of the APC tumor suppressor gene
  2. 2Activating mutation of the KRAS proto-oncogene
  3. 3Inactivation of the TP53 tumor suppressor gene

Answer

1. Biallelic loss of the APC tumor suppressor gene, 2. Activating mutation of the KRAS proto-oncogene, 3. Inactivation of the TP53 tumor suppressor gene
The correct chronological sequence of genetic alterations in the classic adenoma-carcinoma pathway is APC loss, followed by KRAS mutation, and finally TP53 inactivation. This stepwise progression correlates with the transition from normal epithelium to early adenoma, late adenoma, and eventually invasive adenocarcinoma.

Step-by-Step Solution

1
Identify the underlying biological pathway being tested based on the clinical scenario.
The scenario describes the progression of a colonic adenoma to adenocarcinoma, pointing to the classic adenoma-carcinoma sequence.
Recognizing the pathway is necessary to determine the specific genetic mutations involved.
2
Recall the first major genetic alteration in this pathway.
The initiating event is the loss of the APC tumor suppressor gene.
APC loss leads to decreased beta-catenin degradation, promoting the initial hyperproliferation of the normal epithelium into an early adenoma.
3
Determine the subsequent genetic alterations that drive progression and eventual malignancy.
KRAS mutation follows APC loss, leading to intermediate adenoma formation. Finally, TP53 inactivation occurs late, causing malignant transformation.
This specific stepwise accumulation of mutations (APC -> KRAS -> TP53) characterizes the transition from normal mucosa to invasive carcinoma.

Key Concept

The classic adenoma-carcinoma sequence in colorectal cancer involves a specific chronological accumulation of genetic mutations: APC loss (tumor initiation), KRAS mutation (adenoma progression), and TP53 inactivation (malignant transformation).
Estimated Time:45s
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Neoplastic Processes

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