Colorectal Carcinoma MCQ — NEET PG Practice Question | NEETPGAI
Colorectal Carcinoma
hard
microscope Pathology
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?
A. Mismatch repair (MMR) deficiency pathway with microsatellite instability (MSI-H)
B. Chromosomal instability (CIN) pathway with APC and TP53 mutations
C. Serrated pathway with KRAS mutation and intact mismatch repair
D. CpG island methylator phenotype (CIMP) with BRAF V600E mutation
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
Table
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-YieldNEET PG
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)
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
Robbins 10e Ch 17; Harrison 21e Ch 131
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