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Germline and Somatic Mutations in an Oncogene: RET Mutations in Inherited Medullary Thyroid Carcinoma¹

Kolling Institute of Medical Research [D. J. M., S. D. A., D. L. L., A. G. C., R. P., A-L. R., B. G. R.] and Department of Endocrinology [D. L. L., B. G. R.], Royal North Shore Hospital, St Leonards, N.S.W. 2065, Australia; University of Sydney, Sydney, N.S.W., Australia [D. J. M., D. L. L., A. G. C., B. G. R.]; Department of Medicine, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts [C. E.]; Cancer Research Campaign Human Cancer Genetics Research Group, University of Cambridge, Addenbrooke's Hospital, Box 238, Cambridge CB2 2QQ, England [C. E., C. H., B. A. J. P.]; and Departments of Paediatrics and Pathology, Queen's University, Kingston, Ontario, K7L 3N6 Canada [L. M. M.]

Inherited cancer syndromes predispose an individual to the development of specific tumors. Somatic and germline mutations in the same tumor suppressor gene, as described in Knudson's two-mutation model, are well recognized. Inherited mutations in the RET proto-oncogene, which encodes a receptor tyrosine kinase, predispose individuals to the multiple endocrine neoplasia type 2 (MEN 2) cancer syndromes. The major component tumor of these syndromes is medullary thyroid carcinoma (MTC). To date, somatic mutations in RET have not been identified in tumors from individuals with MEN 2, although they have been well documented in sporadic MEN 2-related tumors. We have identified, among 16 MEN 2 cases with well-defined RET germline mutations, a somatic missense mutation at codon 918 of RET in 3 of 15 MTCs and in a sample with hyperplastic C-cells (the presumed precursor to hereditary MTC). We suggest that the presence of a somatic mutation, in addition to the preexisting germline mutation in hereditary MTCs, may contribute to tumorigenesis in vivo.

¹ This work has been supported by a number of grants and scholarships: Mary Jo Reeve Fellowship (to D. L. L.); National Health and Medical Research Council biomedical scholarship (to A. G. C.); core and program grants from the Cancer Research Campaign (CRC), CRC Dana-Farber Cancer Institute Fellowship, Lawrence and Susan Marx Investigatorship in Cancer Genetics in the Division of Cancer Epidemiology and Control, Dana-Farber Cancer Institute, and Young Scientist Award from the Markey Charitable Trust (to C. E.); Medical Research Council of Canada (to L. M. M.); and the CRC Gibb Life Fellowship (to B. A. J. P.).

² To whom requests for reprints should be addressed, at Kolling Institute of Medical Research, Royal North Shore Hospital, St. Leonards, N.S.W. 2065, Australia. Phone: +61 2 9926 7267; Fax: +61 2 9926 8523.

Received 12/13/95. Accepted 1/31/96.

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