SOMATIC MUTATIONS OF THE RET PROTOONCOGENE ARE NOT REQUIRED FOR TUMOR-DEVELOPMENT IN MULTIPLE ENDOCRINE NEOPLASIA TYPE-2 (MEN-2) GENE CARRIERS

Germ line mutations in one allele of the RET proto-oncogene predispose to the multiple endocrine neoplasia type 2 (MEN 2) syndromes, To inve stigate whether these inherited mutations alone can cause the developm ent of tumors in vivo (oncogene model) or whether somatic mutations in the homologous RET allele are required for tumorigenesis (tumor suppr essor gene model), we analyzed the entire coding region of both allele s of the RET gene in two MEN 2A and two MEN 2B tumors by reverse trans cription-PCR and direct sequencing, No tumor-specific mutations could be detected in either allele of the RET gene in these tumors, Unlike t he molecular mechanism in other hereditary tumor syndromes, somatic mu tations in the homologous allele are apparently not required in MEN 2 tumorigenesis, Thus, RET genes with MEN 2-specific germ line mutations act as dominantly transforming oncogenes in vivo.