A 62-year-old woman from Delhi presents with a 4-month history of progressive abdominal distension, early satiety, and weight loss of 8 kg. On examination, she has ascites and a firm, fixed mass palpable in the right lower abdomen. CT abdomen shows a caecal mass with peritoneal nodules and ascites. Colonoscopy reveals a fungating lesion in the caecum; biopsy confirms adenocarcinoma. Serum CEA is elevated at 12 ng/mL. Which of the following molecular alterations is most commonly associated with right-sided colorectal carcinomas like this one?

Explanation

## Molecular Pathology of Right-Sided Colorectal Carcinoma ### Right-Sided CRC: The Serrated Pathway **Key Point:** Right-sided (proximal) colorectal carcinomas most characteristically arise via the **serrated pathway**, defined by **BRAF V600E mutation**, **high microsatellite instability (MSI-H)**, and **MLH1 promoter methylation** (a CIMP-related epigenetic event). This is the hallmark molecular signature distinguishing right-sided from left-sided CRC. ### Comparison of Molecular Pathways by Tumour Location | Feature | Right-Sided (Proximal) CRC | Left-Sided (Distal) CRC | |---------|---------------------------|------------------------| | **Primary pathway** | Serrated pathway | Classical adenoma–carcinoma sequence | | **BRAF V600E** | Common (serrated pathway) | Rare | | **MSI-H** | More frequent (MLH1 methylation) | Less frequent | | **MLH1 methylation** | Characteristic (CIMP-high) | Rare | | **APC mutation** | Less frequent | Frequent (~80%) | | **TP53 mutation** | Less frequent early event | Frequent (50–70%) | | **KRAS mutation** | Can occur, but not the defining feature | Common in classical pathway | ### The Serrated Pathway: Step-by-Step **High-Yield:** Right-sided CRCs frequently arise from sessile serrated lesions (SSLs) via: 1. **BRAF V600E mutation** → initiates serrated polyp formation 2. **CIMP-high** (CpG island methylator phenotype) → epigenetic silencing of **MLH1** promoter 3. **MLH1 silencing** → mismatch repair (MMR) deficiency → **MSI-H** 4. Progression to invasive adenocarcinoma This is the dominant molecular signature of sporadic right-sided CRC and is well-established in Robbins Pathology and Harrison's Principles of Internal Medicine. ### Why Option B (BRAF V600E + MSI-H + MLH1 methylation) is Correct **Clinical Pearl:** The combination of BRAF V600E mutation + MSI-H + MLH1 promoter methylation is the **most characteristic** molecular profile of right-sided (proximal/caecal) sporadic colorectal carcinoma. This profile: - Distinguishes sporadic MSI-H CRC (BRAF mutant) from Lynch syndrome (BRAF wild-type, germline MMR mutation) - Is strongly associated with proximal colon location - Has distinct prognostic and therapeutic implications ### Why Other Options Are Incorrect - **Option A (APC mutation + chromosomal instability + aneuploidy):** This is the classical adenoma–carcinoma sequence, predominantly seen in **left-sided** CRC. APC mutations are the initiating event in ~80% of left-sided tumours but are less frequent in right-sided serrated pathway tumours. - **Option C (TP53 mutation + MSI-H + MMR deficiency):** TP53 mutations are a hallmark of the **chromosomal instability (CIN) pathway** in left-sided CRC. While TP53 loss can occur in advanced right-sided tumours, it is not the defining molecular feature. MSI-H in right-sided CRC is driven by MLH1 methylation, not TP53 mutation. - **Option D (KRAS mutation + MSS + CIMP):** KRAS mutations do occur in right-sided CRC, but the defining serrated pathway signature is BRAF V600E (not KRAS) with MSI-H (not MSS). KRAS-mutant, MSS, CIMP-high is a less specific and less dominant profile for right-sided CRC compared to the BRAF V600E + MSI-H + MLH1 methylation combination. ### Prognostic and Therapeutic Implications **Key Point:** BRAF V600E–mutant, MSI-H right-sided CRCs: - Are resistant to EGFR inhibitors (cetuximab, panitumumab) - MSI-H status predicts benefit from immune checkpoint inhibitors (pembrolizumab) - BRAF V600E can be targeted with BRAF + MEK inhibitor combinations (encorafenib + binimetinib) - Sporadic MSI-H (BRAF mutant) must be distinguished from Lynch syndrome (BRAF wild-type) for genetic counselling [cite: Robbins & Kumar Basic Pathology 10e, Ch 17; Harrison's Principles of Internal Medicine 21e, Ch 297; WHO Classification of Tumours of the Digestive System 5e]