A physician-validated, board-style question from the Active Transport QBank. Try it, then check the reasoning for every option.
A 53-year-old man comes to the physician because of a 2-month history of multiple episodes of small amounts of blood in his stools. Examination shows pale conjunctivae. His hemoglobin concentration is 8.3 g/dL and mean corpuscular volume is 72μm3. Colonoscopy shows a 2.3-cm polypoid mass in the ascending colon. A photomicrograph of a biopsy specimen of the lesion is shown. Which of the following processes is most likely to be involved in the pathogenesis of this patient's condition?
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A
Underexpression of COX-2Incorrect. COX-2 is OVERexpressed in colorectal neoplasia (which is why aspirin chemoprotects); underexpression would be the opposite of what occurs.
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B
Increased phosphorylation of serine and threonineIncorrect. Increased serine/threonine phosphorylation is a generic kinase activity descriptor and is not the specific defining event in colorectal carcinogenesis.
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C
Impaired degradation of β-cateninCorrect. Loss of APC removes the destruction complex that ubiquitinates β-catenin, so β-catenin accumulates, translocates to the nucleus, and drives Wnt-target gene expression (MYC, cyclin D1) — the initiating event in the colorectal adenoma-carcinoma sequence.
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D
Abnormal transfer of phosphate to cellular proteinsIncorrect. 'Abnormal transfer of phosphate to cellular proteins' is too vague to define the specific colorectal pathogenesis (Wnt/β-catenin via APC loss).
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E
Methylation-induced silencing of a DNA mismatch repair geneIncorrect. Methylation of MLH1 underlies the microsatellite-instability pathway of colorectal carcinogenesis (typically right-sided, sporadic); the more common adenoma-carcinoma sequence here is driven by APC loss and β-catenin accumulation, not MMR silencing.
↑ Tap an answer to reveal the reasoning
Answer: C. An older patient with iron-deficiency anemia (low Hb, microcytic with MCV 72) from GI blood loss and a polypoid mass in the ASCENDING (right) colon has colon adenocarcinoma. Right-sided colon cancers classically present with occult bleeding and iron deficiency rather than obstruction (because the lumen is wider and stool is liquid). The pathogenesis of most sporadic colorectal cancers follows the adenoma–carcinoma sequence and the alternative serrated pathway.
The key molecular event in many colorectal cancers — and the only choice listed that fits — is IMPAIRED DEGRADATION OF β-CATENIN through loss of APC (a tumor suppressor in the Wnt/β-catenin pathway). Normally APC tags β-catenin for ubiquitin-mediated proteasomal degradation. With APC loss, β-catenin accumulates, translocates to the nucleus, and binds TCF/LEF transcription factors to drive expression of MYC, cyclin D1, and other proliferation genes. This is the initiating event in the classic FAP-associated adenoma-carcinoma sequence and in many sporadic adenomas.
COX-2 is OVERexpressed (not underexpressed) in colorectal neoplasia, which is why aspirin/NSAIDs are chemoprotective. 'Increased serine/threonine phosphorylation' and 'abnormal phosphate transfer' are vague descriptions of kinase activity not specific to colon carcinogenesis. APC/β-catenin is the pathognomonic mechanism on USMLE.
**Why each option:**
**A.** COX-2 is OVERexpressed in colorectal neoplasia (which is why aspirin chemoprotects); underexpression would be the opposite of what occurs.
**B.** Increased serine/threonine phosphorylation is a generic kinase activity descriptor and is not the specific defining event in colorectal carcinogenesis.
**C.** Loss of APC removes the destruction complex that ubiquitinates β-catenin, so β-catenin accumulates, translocates to the nucleus, and drives Wnt-target gene expression (MYC, cyclin D1) — the initiating event in the colorectal adenoma-carcinoma sequence.
**D.** 'Abnormal transfer of phosphate to cellular proteins' is too vague to define the specific colorectal pathogenesis (Wnt/β-catenin via APC loss).