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Difficulty: MediumNeoplastic Processes

A 22-year-old man presents to the gastroenterology clinic for evaluation of intermittent bright red blood per rectum over the past two months. He reports no abdominal pain, unexplained weight loss, or changes in stool caliber. His father died of metastatic colorectal cancer at age 38, and a paternal aunt underwent abdominal surgery for an unknown malignancy in her 30s. His temperature is 37.0°C (98.6°F), blood pressure is 118/76 mmHg, pulse is 72/min, and respirations are 14/min. Physical examination reveals a soft, non-tender abdomen without organomegaly. Digital rectal examination demonstrates normal sphincter tone with small amounts of bright red blood on the examining finger. Given his striking family history, a colonoscopy is performed and reveals over 150 small adenomatous polyps carpeting the entire colon and rectum. Biopsies of several polyps confirm tubular adenomas with low-grade dysplasia. Which of the following best describes the underlying foundational mechanism of this patient's condition and the most appropriate definitive management?

  1. A
    Defective DNA mismatch repair resulting in microsatellite instability; annual colonoscopy beginning at age 25
  2. B
    Activating point mutation in a proto-oncogene encoding a small GTPase; targeted therapy with an epidermal growth factor receptor inhibitor
  3. C
    Epigenetic hypermethylation of DNA mismatch repair gene promoters; segmental colectomy with rigorous endoscopic surveillance
  4. Loss-of-function mutation in a gene regulating degradation of beta-catenin; prophylactic proctocolectomyAnswer
  5. E
    Germline mutation in a tumor suppressor gene regulating the G1-to-S phase cell cycle transition; biannual fecal occult blood testing

Answer

The correct option identifies a loss-of-function mutation in a gene regulating degradation of beta-catenin, managed definitively with a prophylactic proctocolectomy.
The correct answer accurately identifies both the molecular pathogenesis of Familial Adenomatous Polyposis (FAP) and its standard definitive management. FAP is caused by a germline loss-of-function mutation in the APC (Adenomatous Polyposis Coli) gene. The APC protein is a critical component of the Wnt signaling pathway, where it normally binds to beta-catenin and marks it for ubiquitination and proteasomal degradation. Without a functional APC protein, beta-catenin accumulates in the cytoplasm, translocates to the nucleus, and continuously activates transcription factors (like TCF/LEF) that promote cellular proliferation. Because patients with FAP develop hundreds to thousands of adenomatous polyps, they carry a nearly 100% lifetime risk of colorectal cancer. Therefore, once widespread polyposis is identified, prophylactic proctocolectomy (often with an ileoanal pouch anastomosis) is indicated to prevent malignant transformation.

Step-by-Step Solution

1
Analyze the clinical presentation and endoscopic findings.
A 22-year-old with a strong early-onset family history and >150 colonic polyps is highly indicative of Familial Adenomatous Polyposis (FAP).
Recognizing the classic phenotype of FAP distinguishes it from other hereditary cancer syndromes like Lynch syndrome, which presents with far fewer polyps.
2
Identify the foundational molecular mechanism of the disease.
FAP is an autosomal dominant condition caused by a germline mutation in the APC tumor suppressor gene.
The normal APC protein complexes with beta-catenin and targets it for degradation. Loss of APC allows beta-catenin to accumulate, enter the nucleus, and drive cellular proliferation.
3
Determine the appropriate long-term definitive management.
Prophylactic proctocolectomy.
Patients with FAP have a nearly 100% lifetime risk of developing colorectal carcinoma, usually by age 40 to 50, making surgical removal of the colon and rectum the standard of care once polyposis is established.

Key Concept

The molecular pathogenesis and clinical management of Familial Adenomatous Polyposis (FAP).
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Topics

Neoplastic Processes

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