Turcot's syndrome is characterized clinically by the concurrence of a primary brain tumor and multiple colorectal adenomas. We attempted to define the syndrome at the molecular level. Fourteen families with Turcot's syndrome identified in two registries and the family originally described by Turcot and colleagues were studied. Germ-line mutations in the adenomatous polyposis coli (APC) gene characteristic of familial adenomatous polyposis were evaluated, as well as DNA replication errors and germ-line mutations in nucleotide mismatch-repair genes characteristic of hereditary nonpolyposis colorectal cancer. In addition, a formal risk analysis for brain tumors in familial adenomatous polyposis was performed with a registry data base. Genetic abnormalities were identified in 13 of the 14 registry families. Germ-line APC mutations were detected in 10. The predominant brain tumor in these 10 families was medulloblastoma (11 of 14 patients, or 79 percent), and the relative risk of cerebellar medulloblastoma in patients with familial adenomatous polyposis was 92 times that in the general population (95 percent confidence interval, 29 to 269; P<0.001). In contrast, the type of brain tumor in the other four families was glioblastoma multiforme. The glioblastomas and colorectal tumors in three of these families and in the original family studied by Turcot had replication errors characteristic of hereditary nonpolyposis colorectal cancer. In addition, germ-line mutations in the mismatch-repair gene hMLH1 or hPMS2 were found in two families. The association between brain tumors and multiple colorectal adenomas can result from two distinct types of germ-line defects: mutation of the APC gene or mutation of a mismatch-repair gene. Molecular diagnosis may contribute to the appropriate care of affected patients.
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