CLINICAL-VALUE OF DIRECT DNA ANALYSIS OF THE RET PROTOONCOGENE IN FAMILIES WITH MULTIPLE ENDOCRINE NEOPLASIA TYPE 2A

Background. The multiple endocrine neoplasia type 2A gene is the RET p roto-oncogene located on the long arm of chromosome 10, and many mutat ions within this gene have been reported. Methods. Peripheral blood DN A was analyzed from 95 members of twelve families with multiple endocr ine neoplasia type 2A and known mutations in codon 634 (of exon 11) of the RET proto-oncogene. This region was amplified by the polymerase c hain reaction, followed by digestion with Cfo I, which detects restric tion sites created by the most common TGC->CCC mutation and by a TGC-> TGG mutation or with Rsa I, which detects a restriction site created b y a TGC->TAC mutation. Results. Diagnoses were confirmed in 39 patient s; 15 of 56 at-risk persons were gene carriers and 41 were noncarriers . The noncarriers included seven persons who had previously undergone thyroidectomies for suspected C-cell hyperplasia but were negative for the RET mutation present in affected members of their families. Concl usions. Identification of the specific gene alterations within familie s permits direct DNA diagnosis of at-risk family members. The 41 nonca rriers will not require further testing nor need to be concerned about transmitting multiple endocrine neoplasia type 2A to their descendant s. The normal DNA findings in seven of these persons emphasize the imp ortance of DNA studies in patients with C-cell hyperplasia but no medu llary thyroid cancer at operation.