MOLECULAR SCREENING FOR RET PROTOONCOGENE MUTATIONS IN A GERMAN MEN2APEDIGREE

Multiple endocrine neoplasia type 2A (MEN2A), a dominantly inherited c ancer syndrome, is defined by the presence of medullary thyroid carcin oma (MTC), pheochromocytoma (pheo), and primary hyperparathyroidism (p -HPT). Along with multiple endocrine neoplasia type 2B (MEN2B) and fam iliar medullary thyroid carcinoma (FMTC), it is associated with germli ne mutations of the RET proto-oncogene localized in 10q11.2. In FMTC a nd MEN2A, point mutations result in the substitution of one of five Cy s residues in the extracellular domain of RET. In a larger pedigree fr om Saarland, several individuals were observed with C-cell thyroid car cinoma. We screened 16 members of this extended family by single-stran d conformation polymorphism analysis (SSCP), polymerase chain reaction (PCR), followed by restriction enzyme analysis, and by sequencing the mutated regions. In 7 family members, all of whom had been earlier op erated on because of MTC, a DNA transition from T to C was observed, c ausing an amino acid substitution Cys(634)Arg. Nine members of the kin dred did not carry the mutation and may be excluded from yearly bioche mical testing. One of these persons seems to have been unnecessarily o perated on owing to a borderline pentagastrin test.