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

Abstract

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. Summary of de novo MMR mutation carriers. Case Gene Exon Mutation description Age at CRC (year) TNM stage Source Family history of CRC (age) 1 MLH1 1-19 deletion 27 T3N1M0 Population Father (48) 2 MLH1 13 c.1459C>T p.Arg487X 36 T3N0M0 Clinic No 3 MSH2 8 deletion 32 T3N0M0 Population Uncle (41) 4 MSH2 5 c.942+3A>T p. Val265_Gln314del 49 T3N1M9 Clinic Son (43) 5 MSH2 6 c.1034G>A p.Trp345X 31 T3N0M9 Clinic Uncle (unknown) 6 MSH6 4 c.1422_1423delGCinsAT p.Gln475X 31 T3N0M9 Population No