A 58-year-old man undergoes colectomy for a caecal adenocarcinoma that is mucinous and poorly differentiated, with prominent tumour-infiltrating lymphocytes. Immunohistochemistry shows loss of nuclear MLH1 staining in tumour cells but preserved staining in stromal cells, and testing shows no germline MLH1 mutation. The most likely explanation is:

• A Somatic mutation of KRAS activating MAP kinase signalling
• B Loss of APC causing accumulation of beta-catenin
• C Promoter hypermethylation silencing MLH1 transcription ✓
• D Amplification of HER2 in the tumour cells

Explanation

Loss of MLH1 protein with intact stromal staining indicates acquired silencing rather than germline deletion. Sporadic microsatellite unstable colorectal cancers usually arise through CpG island methylator phenotype driven hypermethylation of the MLH1 promoter, mimicking Lynch syndrome histologically. KRAS and APC alterations belong to the conventional adenoma-carcinoma pathway and do not abolish mismatch repair protein expression, and HER2 amplification is characteristic of gastric and breast cancers.

Reference: Robbins and Cotran Pathologic Basis of Disease, 10th ed.

High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP

Written and medically reviewed by the StethoPrep medical team.