Clinical consequences of molecular diagnosis in families with mismatch repair gene germline mutations

Hereditary nonpolyposis colorectal cancer (HNPCC), clinically defined by th e Amsterdam criteria, is associated with mismatch repair gene germline muta tions. This study was performed to evaluate the efficiency of combined clin ical and molecular diagnostics in identifying carriers of a mutated gene in families meeting criteria of the Bethesda guidelines and to examine the in fluence of molecular diagnosis on clinical decision-making in carriers and noncarriers. Seventy-two patients meeting criteria of the Bethesda guidelin es were tested for microsatellite instabilities (MSI). MSI-H tumors were fo und in 38 (52.8%) index patients. Complete sequencing of hMLH1 and hMSH2 in 38 MSI-H patients and of hMSH6 in one of these patients revealed 15 pathog enic germline mutations, including three novel mutations, and three novel u nclassified germline variants. Twelve of the 15 pathogenic mutations were f ound in patients fulfilling the Amsterdam I/II criteria. Surgical and genet ic counseling was offered to the affected families; as a result of molecula r diagnosis in the 15 families, 26 index patients and affected carriers and 8 asymptomatic carriers of a mutated mismatch repair gene were included in the surveillance program, and 26 noncarriers were excluded from this progr am. Although germline mutations are detected in only 20.8% of patients fulf illing criteria of the Bethesda guidelines, family history and MSI-H tumor classification are both strong indicators for germline mutations in hMSH2, hMLH1, and hMSH6 genes, resulting in a 51.9% mutation detection rate. Ident ification of individual mutation status allows clear-cut decisions on wheth er or not inclusion in surveillance programs is indicated.