Lynch syndrome (hereditary non-polyposis colorectal cancer, HNPCC) is caused by germline mutations in mismatch repair (MMR) genes. The molecular hallmark detectable in tumour tissue is:

• A Loss of heterozygosity (LOH) at chromosome 5q (APC gene)
• B CpG island methylator phenotype (CIMP) from IDH mutation
• C Microsatellite instability (MSI-High) due to error accumulation at simple repetitive sequences ✓
• D KRAS mutation at codon 12 as the earliest tumourigenic event

Explanation

Microsatellite instability (MSI) is the genomic fingerprint of MMR deficiency. When MLH1, MSH2, MSH6, or PMS2 are non-functional, DNA polymerase slippage errors at short tandem repeat sequences (microsatellites) are not corrected, causing length variation at these loci. MSI-H (high) tumours are associated with Lynch syndrome, carry a better prognosis, and are specifically responsive to immune checkpoint inhibitors (anti-PD-1) due to high mutational burden generating neoantigens. APC LOH characterises the adenoma-carcinoma sequence in sporadic/FAP colon cancer.

Reference: Harper's Illustrated Biochemistry, 32nd ed.

High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP

Written and medically reviewed by the StethoPrep medical team.