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Colorectal cancer cases with de novo germ-line mutations in MLH1, MSH2, and MSH6 from the Colon Cancer Family Registry.

3538 Background: Lynch syndrome is caused by a germ-line mutation in a DNA mismatch repair (MMR) gene. Carriers are at high risks of colorectal (CRC), endometrial and some other cancers. To date, there have been only a few reports on single cases with de novo mutations in MLH1 or MSH2. We now report a case series of de novo mutations in MMR genes from the Colon Cancer Family Registry.


METHODS
Screening for germ-line MLH1, MSH2, MSH6 and PMS2 mutations was performed for: all incident CRC cases recruited from cancer registries (population-based probands) displaying microsatellite instability (MSI) or positive immunohistochemistry (IHC); and the earliest-onset CRC cases in multiple-case families recruited from clinics (clinic-based probands) regardless of MSI or IHC status. Mutation testing was performed by denaturing high pressure liquid chromatography, followed by confirmatory DNA sequencing. All relatives of probands with a deleterious mutation who donated a blood sample underwent testing for the mutation identified in the proband. For this study, a de novo mutation was defined as a mutation in a proband that was not detected in the parents, siblings, spouse, and children.


RESULTS
Of 261 probands with MMR gene mutations for whom it was possible to classify the de novo status, six (2.3%; 95%CI 0.9-5.0%) were de novo and 255 (92.7%; 95%CI 95.0-99.1%) were not de novo. Of the de novo mutation carriers, three were in the 202 clinic-based probands (1.5%; 95%CI 0.3-4.5%) and three were in the 59 population-based probands (5.1%; 95%CI 1.2-14.5%). Two were in MLH1, three in MSH2, and one in MSH6 (details in table).


CONCLUSIONS
De novo mutations are rare causes of Lynch syndrome with prevalence in MMR gene mutation carriers of between 1 in 100 and 1 in 20. [Table: see text].