Which gene set is most commonly associated with Lynch syndrome?

• A. BRCA1, BRCA2, PALB2
• B. APC, MUTYH, MUTYH-associated polyposis
• C. MLH1, MSH2, MSH6, PMS2, EPCAM
• D. TP53, CHEK2

Answer: (C)

Lynch syndrome is caused by inherited defects in DNA mismatch repair genes, which leads to microsatellite instability and greatly increased risk for colorectal cancer and other cancers. The genes classically involved are MLH1, MSH2, MSH6, and PMS2, with deletions in EPCAM that disrupt MSH2 expression also contributing to the syndrome. This set is the best answer because it directly represents the mismatch repair pathway whose loss drives Lynch-associated tumorigenesis. The other gene groups are linked to different hereditary cancer syndromes: BRCA1/2 and PALB2 with hereditary breast and ovarian cancer; APC and MUTYH with polyposis conditions; and TP53 and CHEK2 with Li-Fraumeni or other cancer predispositions.