Colonoscopy screening outcomes in Lynch syndrome and differential colorectal cancer paths among MLH1/MSH2 carriers.

MLH1, MSH2

Constitutional pathogenic variants in MLH1 or MSH2 (mismatch repair genes)

Using the Familial Gastrointestinal Cancer Registry of the Zane Cohen Centre (Mount Sinai, Toronto), the authors jointly modelled colonoscopy visits, adenoma counts and colorectal cancer (CRC) occurrence in carriers of a pathogenic MLH1 or MSH2 variant. In MSH2 carriers, more frequent colonoscopies detecting more adenomas effectively reduced CRC risk; MLH1 carriers did not experience the same benefit. After 10 years, among individuals with adenomas, CRC risk was higher in MLH1 than in MSH2 carriers: 7.9% (95% CI 3.9-15.8) vs 4.0% (1.6-9.6) in males and 4.2% (2.2-8.2) vs 1.6% (0.7-3.5) in females. The authors link the inverse adenoma-CRC relationship in MSH2 carriers to the adenoma-carcinoma sequence and suggest alternative carcinogenic pathways, requiring further study, in MLH1 carriers.

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

The result is in line with the already discussed hypothesis of colorectal cancers bypassing the adenoma-carcinoma sequence in MLH1 carriers, and questions the use of uniform colonoscopy intervals across MMR genes. Major limitation: the abstract reports neither the number of carriers nor the number of events, confidence intervals are wide and the registry is single-centre. Multicentre replication is needed before tailoring surveillance intervals by gene.

Analysis by Dr Thibaut Benquey