UPDATE ON THE PROFILE OF MULTIPLE ENDOCRINE NEOPLASIA TYPE 2A RET MUTATIONS - PRACTICAL ISSUES AND IMPLICATIONS FOR GENETIC TESTING

BACKGROUND, The RET protooncogene is responsible for the inherited can cer syn dromes multiple endocrine neoplasia type 2a (MEN 2a) and famil ial medullary thyroid carcinoma (FMTC). Identification of predisposing germline RET mutations has allowed a DNA-based approach to diagnosis. Despite known mutational occurrences in RET exons 10, 11, 13, and 14, the majority of national diagnostic laboratories, with rare exception , continue to limit genetic analysis for MEN 2a and FMTC to RET exons 10 and 11. This study was undertaken to examine the genotype pattern o f germline MEN 2a/FMTC RET mutations in an ethnically diverse North Am erican population and assess the sensitivity of a more comprehensive t esting approach to mutation detection that encompassed RET exons 10, 1 1, 13, and 14. METHODS, The study group was comprised of 414 unselecte d consecutive patients at risk for hereditary MTC referred to a single laboratory. Genetic analysis used genomic DNA and a polymerase chain reaction-based denaturing gradient gel electrophoresis strategy for mu tation detection in exons 10, 11, 13, and 14. RESULTS. Thirty-five dis tinct MEN 2a or FMTC kindreds were identified. Thirteen different miss ense germline mutations were detected in 29 of the 35 families at RET codons 609, 618, 620, and 634 within exons 10 (31.4%) and 11 (51.4%). Of the 18 families with an exon 11 mutation, 12 (66.7%) harbored the m ost common TGC-->CGC missense change at codon 634. Four families (11.4 %) harbored a codon 804 mutation in exon 14. Two of the codon 804 muta tions uncovered were novel (GTG-->ATG and GTG-->CTG) and occurred in t hree of the four families. Germline mutations were not observed in exo n 13. A RET sequence abnormality remained undetected in two families w ith established multigenerational MTC. Hirschsprung's disease cosegreg ated in five families with MEN 2a. CONCLUSIONS. The sensitivity of gen etic screening for MEN 2a offered by diagnostic laboratories that limi t RET analysis to exons 10 and 11 is 82.8%. Genetic testing that inclu des RET exon 14 results in a more complete and accurate analysis with a sensitivity approaching 95%. The authors recommend that clinicians c onfirm the comprehensiveness of a laboratory's genetic screening appro ach for MEN 2a to ensure thoroughness of sample analysis. (C) 1997 Ame rican Cancer Society.