GERM-LINE MUTATIONS OF THE RET PROTOONCOGENE IN MULTIPLE ENDOCRINE NEOPLASIA TYPE-2A

MULTIPLE endocrine neoplasia type 2A (MEN 2A) is a dominantly inherite d cancer syndrome that affects tissues derived from neural ectoderm. I t is characterized by medullary thyroid carcinoma (MTC) and phaeochrom ocytoma1. The MEN2A gene has recently been localized by a combination of genetic and physical mapping techniques to a 480-kilobase region in chromosome 10q11.2 (refs 2,3). The DNA segment encompasses the RET pr oto-oncogene, a receptor tyrosine kinase gene expressed in MTC and pha eochromocytoma and at lower levels in normal human thyroid4. This sugg ested RET as a candidate for the MEN2A gene. We have identified missen se mutations of the RET proto-oncogene in 20 of 23 apparently distinct MEN 2A families, but not in 23 normal controls. Further, 19 of these 20 mutations affect the same conserved cysteine residue at the boundar y of the RET extracellular and transmembrane domains.