Modification of multiple endocrine neoplasia 2A phenotype by cell membrane proximity of RET mutations in exon 10

Rearranged during transfection (RET) germ-line mutations in exon 10 are peculiar because they produce both gain-of-function multiple endocrine neoplasia 2A and loss-of-function Hirschsprung's disease phenotypes. Drawing on 38 medullary thyroid cancer patients harboring germ-line mutations in codon 620 (n=8), 618 (n=19), 611 (n=10), and 609 (n=1), this study aimed to test the hypothesis that closer proximity of RET germ-line mutations in exon 10 to the cell membrane may translate into earlier or more advanced disease. The closer mutations in codon 620, 618, and 611 were located to the transmembrane domain (codons 657-636) of the RET receptor, the greater were mean primary tumor diameters (23.5, 18.7, and 7.5 mm, P=0.020), the frequency of lymph node metastasis (75, 68, and 30%, P=0.11) and pheochromocytoma (38, 16, and 0%, P=0.11). Periods of observation were broadly comparable for these groups (mean age 33.4-39.3 years; P=0.71). When mutations in adjoining codons were collapsed (codons 620/618 vs 611/609), the differences in mean primary tumor diameter (20.1 vs 7.4 mm, P=0.005) and lymph node metastasis (70 vs 36%; P=0.07) were accentuated. Compared with 80 carriers of exon 11 mutations (codon 634, n=78; codon 630, n=2), the 38 carriers of exon 10 mutations, which are rarer and confer a weaker transforming activity in vitro than exon 11 mutations, required significantly more time to develop fewer tumors. Although limited in numbers, these data suggested that membrane proximity is an important determinant of tumor development in carriers of RET mutations in exon 10.