Germline hMSH2 and differential somatic mutations in patients with Turcot's syndrome

Turcot's syndrome is characterized clinically by the occurrence of primary brain tumor and colorectal tumor and has in previous reports been shown to be associated with germline mutations in the genes APC, hMLH I, and hPMS2. Here we describe three patients with Turcot's syndrome, each having colorec tal adenocarcinoma and malignant glioma. All the colorectal and brain tumor s from these patients showed replication errors in most of the microsatelli te loci investigated. Search for underlying germline mutations in the nucle otide mismatch repair genes revealed three different hMSH2 mutations. AII c olorectal tumors showed a frameshift in the A(10) tract in the coding seque nce of the transforming growth factor beta type II receptor (TGFBRII) gene, but no such change was detected in any of the brain tumors. Frameshift mut ation in the BAX gene was found in one colon carcinoma and mutations in ins ulin-like growth factor type II receptor (IGFIIR) gene in one glioma. Our d ata have broadened the possible mutation spectrum of patients with Turcot's syndrome. The difference in the mutation spectrum of TGFBRII, BAX, and IGF IIR between brain and colorectal tumors in these individuals suggests that the mutator phenotype may target different pathogenic pathways in the oncog enic process of the two organs. (C) 1999 Wiley-Liss, Inc.