A 62-year-old woman from Delhi undergoes colonoscopy for iron-deficiency anaemia and is found to have a 3 cm polypoid lesion in the caecum. Histopathology shows invasive adenocarcinoma arising from a tubulo-villous adenoma with high-grade dysplasia. The tumour invades into the submucosa but does not breach the muscularis propria. Immunohistochemistry shows loss of MLH1 and PMS2 expression. Which molecular pathway is most likely implicated in the pathogenesis of this tumour?

Explanation

## Molecular Pathways in Colorectal Carcinoma **Key Point:** Loss of MLH1 and PMS2 expression indicates defective mismatch repair (MMR), which drives the microsatellite instability (MSI-H) pathway—a distinct molecular subtype of colorectal cancer with characteristic clinicopathological features. ### Three Major Molecular Pathways in CRC | Pathway | Genetic Alterations | MMR Status | MSI | Frequency | Clinical Features | |---------|-------------------|-----------|-----|-----------|-------------------| | **CIN (70%)** | APC → KRAS → TP53 | Intact | MSS | 70% | Distal colon, older age, sporadic | | **MMR-deficient (15%)** | MLH1/MSH2/MSH6/PMS2 loss | Defective | MSI-H | 15% | Right colon, younger age, Lynch syndrome, better prognosis | | **CIMP (15%)** | BRAF V600E, MLH1 methylation | Intact | MSI-L | 15% | Right colon, elderly, female, poor prognosis | ### MLH1 and PMS2 Loss = MMR Deficiency **High-Yield:** MLH1 and PMS2 are mismatch repair proteins: - **MLH1** (MutL homolog 1) — initiator protein for MMR complex - **PMS2** (postmeiotic segregation 2) — interacts with MLH1 to form MutLα complex - **Loss of both** → non-functional MMR → inability to correct DNA replication errors → **microsatellite instability (MSI-H)** ### Microsatellite Instability (MSI-H) Pathway 1. **Defective mismatch repair** → accumulation of mutations in microsatellite repeats 2. **Hypermutation phenotype** → hundreds to thousands of mutations per tumour 3. **Frameshift mutations** in genes with microsatellite repeats (e.g., BAX, IGFR2, TGFβRII) 4. **Right colon predilection** (caecum/ascending colon, as in this case) 5. **Better prognosis** than CIN pathway (Stage-for-stage) 6. **Better response to immunotherapy** (high tumour mutational burden, increased neoantigen load) **Clinical Pearl:** This patient's tumour in the caecum (right colon) with MLH1/PMS2 loss is classic for MMR-deficient CRC. Even though it is invasive (pT1), the MSI-H status confers a more favourable prognosis than a Stage-equivalent CIN tumour would have. **Mnemonic: MLH1/PMS2 Loss = MMR-deficient = MSI-H = Right colon = Better prognosis** ### Why Other Pathways Are Wrong **CIN Pathway (Option A):** - Driven by APC loss (early) → KRAS activation → TP53 mutation (late) - Presents with intact MMR and microsatellite stability (MSS) - More common (70% of CRC) but NOT indicated by MLH1/PMS2 loss - Associated with distal colon/rectum, older age **CIMP Pathway (Option C):** - Characterized by BRAF V600E mutation and MLH1 promoter methylation (not loss of protein expression) - Although this case has MLH1 loss, there is no mention of BRAF mutation or methylation - CIMP tumours are typically MSI-L or MSS, not MSI-H - Associated with poor prognosis and female gender **Serrated Pathway (Option D):** - Arises from serrated adenomas/polyps - Often involves KRAS mutation and BRAF mutation - MMR is typically intact (MSS) - MLH1/PMS2 loss would not be expected in pure serrated pathway [cite:Robbins 10e Ch 17; Harrison 21e Ch 131]