A proven de novo germline mutation in HNPCC

Hereditary non-polyposis colon cancer (HNPCC) is a heterogeneous group of t umour predisposition syndromes caused by germline mutations in at least fou r different mismatch repair genes. HNPCC patients are prone to the developm ent of carcinomas of the intestinal tract and other specific sites. Identif ication of presumptive HNPCC patients is primarily based on a positive fami ly history of colorectal cancer in at least two generations. In the course of mutation screening of the MLH1 and MSH2 genes in patients manifesting a carcinoma of the HNPCC tumour spectrum before the age of 45 years, we ident ified a germline MSH2 344delA frameshift mutation in a male proband. This i ndex patient, at the age of 25 years, initially developed a large rectal ad enoma that was removed by polypectomy. Ten years later he was operated on f or an invasive right sided colon carcinoma in the caecum (International Uni on Against Cancer (UICC) stage III). The mother and father, aged 61 and 66 years, respectively, were healthy and had no family history of colorectal c ancer. Subsequent molecular analyses excluded the germinal MSH2 344delA alt eration identified in their son and at the same time paternity was confirme d with a set of informative polymorphic markers. Thus, the genetic alterati on identified in our patient definitely represented a de novo germline muta tion in one of the major HNPCC genes. This case report of a patient with co lorectal cancer at a relatively young age with no family history is intende d to encourage mutation screening of the MSH2 and MLH1 genes in similar cas es to find out whether this group of patients contains an increased proport ion of de novo mutations in mismatch repair genes.