Lynch syndrome (hereditary non-polyposis colorectal cancer, HNPCC) results from germline mutations in mismatch repair (MMR) genes such as MLH1, MSH2, MSH6, or PMS2. The biochemical hallmark of MMR deficiency in tumor tissue is:

• A Loss of heterozygosity at multiple chromosomal loci
• B Increased chromosomal translocations involving immunoglobulin loci
• C Hypermethylation of CpG islands at tumor suppressor gene promoters
• D Microsatellite instability (MSI) due to failure to correct replication slippage errors at repetitive sequences ✓

Explanation

Mismatch repair proteins (MutS homologs recognize mismatches; MutL homologs coordinate excision and resynthesis) correct base-base mismatches and insertion-deletion loops arising from replication slippage at microsatellite sequences. When MMR is deficient, slippage errors at microsatellites accumulate, causing microsatellite instability (MSI-H). MSI testing and MMR immunohistochemistry are the primary screening tools for Lynch syndrome. MSI-H tumors also respond better to immune checkpoint inhibitors (pembrolizumab) due to their high mutational burden.

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

High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP

Written and medically reviewed by the StethoPrep medical team.