High prevalence of the C634Y mutation in the RET proto-oncogene in MEN 2A families in Spain

The RET proto-oncogene encodes a receptor tyrosine kinase expressed in neur al crest derived tissues. Germline mutations in the RET proto-oncogene are responsible for three different: dominantly inherited cancer syndromes: mul tiple endocrine neoplasia type 2A (MEN 2A), type 2B (MEN 2B), and familial medullary thyroid carcinoma (FMTC). MTC can also occur sporadically. Molecu lar characterisation of the RET proto-oncogene has been performed by PCR-SS CP analysis, direct DNA sequencing, and restriction enzyme analysis in 49 u nrelated, Spanish, MEN 2 families: 30 MEN 2A families, six FMTC families, a nd 13 families classified as "other". Germline missense mutations in one of six cysteine codons (609, 611, 618, and 620 in exon 10, and codons 630 and 634 in exon ii), which encode part of the extracellular cysteine rich doma in of RET, have been detected in the majority of these families: 100% of ME N 2A families, 67% of FMTC families, and 54% of families classified as "oth er". No RET mutations in exons 10, 11, 13, 14, 15, or 16 were detected in t he remaining families. The most frequent RET mutation in MEN 2A Spanish fam ilies is C634Y, occurring in 73% of cases. Haplotype analysis does not excl ude the possibility of founder effects in Spanish MEN 2A families with the C634Y mutation.