HIRSCHSPRUNG-DISEASE IN MEN 2A - INCREASED SPECTRUM OF RET EXON-10 GENOTYPES AND STRONG GENOTYPE-PHENOTYPE CORRELATION

The RET proto-oncogene encodes a transmembrane receptor with tyrosine kinase activity, Germline mutations in RET are responsible for a numbe r of inherited diseases, These include the dominantly inherited cancer syndromes multiple endocrine neoplasia types 2A and 2B (MEN 2A and ME N 2B) and familial medullary thyroid carcinoma (FMTC), as well as some cases of familial Hirschsprung disease (HSCR1), RET mutations in HSCR 1 have been shown to cause a loss of RET function,, while the cancer s yndromes result in RET oncogenic activation, Occasionally MEN 2A or FM TC occurs in association with HSCR1, albeit with low penetrance, An in itial report linked HSCR1 in MEN 2A solely to the C618R and C620R RET mutations. In this study we have analyzed 44 families with MEN 2A, HSC R1 co-segregated with MEN 2A in seven (16%) of the 44 families, The pr edisposing RET mutation in all seven families had been previously repo rted in MEN 2A or FMTC and occurred in exon 10 at codons 609, 618 or 6 20, resulting in C609Y, C618S, C620R or C620W substitution. MEN 2A fam ilies with RET exon 10 Cys mutations had a substantially greater risk of developing HSCR1 than those with the more common RET exon 11 Cys634 or exon 14 c804 mutations (P = 0.0005), These findings suggest that e xpression of HSCR1 in MEN 2A may be peculiar to RET exon 10 Cys mutati ons, However, HSCR1 in MEN 2A is not exclusive to C618R or C620R RET m utations and can occur with other exon 10 Cys amino acid substitutions , The strong correlation between disease phenotype and position of the MEN 2A RET mutation suggests that oncogenic activation of RET alone i s insufficient to account for co-expression of the diseases.