A 68-year-old man presents with a 3-month history of fatigue and weight loss. Laboratory investigation reveals microcytic iron-deficiency anemia (Hb 8.2 g/dL, ferritin 8 ng/mL) without overt gastrointestinal bleeding. Colonoscopy reveals the structure marked **A** in the diagram—a large fungating polypoid mass in the cecum with friable surface and contact bleeding. Biopsy confirms moderately-differentiated adenocarcinoma. Which of the following best describes the most likely molecular pathogenesis underlying this right-sided cecal malignancy?

Explanation

## Why Chromosomal instability (CIN) pathway is right The fungating cecal mass marked **A** in a 68-year-old with iron-deficiency anemia and moderately-differentiated adenocarcinoma most likely arises via the adenoma-carcinoma sequence through chromosomal instability (CIN), which accounts for approximately 80% of sporadic colorectal cancers. This pathway progresses sequentially: APC loss (early adenoma formation) → KRAS activation (adenoma growth) → loss of 18q chromosome (SMAD4/DCC genes, adenoma progression) → p53 mutation (malignant transformation) → invasive cancer. This is the classic, well-established pathway described in the NCCN Colon Cancer Guidelines and AJCC 8th edition staging system, and it explains the gradual development of this moderately-differentiated adenocarcinoma over 10–15 years in an older adult. ## Why each distractor is wrong - **Microsatellite instability (MSI) pathway**: While MSI accounts for 15% of colorectal cancers and does show right-sided predilection with mucinous histology and BRAF mutations, the clinical presentation (moderately-differentiated adenocarcinoma, not mucinous) and the fact that MSI is less common (15% vs. 80% for CIN) make this less likely. MSI is associated with Lynch syndrome or sporadic MLH1 methylation, not the typical sporadic adenoma-carcinoma sequence. - **CpG island methylator phenotype (CIMP)**: CIMP is an alternative pathway (serrated polyp pathway) that accounts for a minority of colorectal cancers and is characterized by BRAF V600E mutations and serrated morphology. The histology here is moderately-differentiated adenocarcinoma, not serrated, making this pathway less likely. - **Familial adenomatous polyposis (FAP)**: FAP is a hereditary syndrome with germline APC mutations and early-onset polyposis (typically hundreds to thousands of polyps by age 20–30). This patient is 68 years old with a single cecal mass and no mention of familial history or polyposis, making FAP an unlikely diagnosis. FAP accounts for only ~1% of colorectal cancers. **High-Yield:** Elderly patient + iron-deficiency anemia without overt bleeding + right-sided cecal adenocarcinoma = CIN pathway (80% of sporadic CRC); MSI and CIMP are alternative pathways but less common and have distinct clinicopathologic features (mucinous, serrated, BRAF mutation). [cite: NCCN Colon Cancer Guidelines 2024; AJCC 8th edition; Fearon ER. Molecular genetics of colorectal cancer. Annu Rev Pathol. 2011;6:479-507.]