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

Abstract

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 germline mutations in codon 620 (nZ8), 618 (nZ19), 611 (nZ10), and 609 (nZ1), 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, PZ0.020), the frequency of lymph node metastasis (75, 68, and 30%, PZ0.11) and pheochromocytoma (38, 16, and 0%, PZ0.11). Periods of observation were broadly comparable for these groups (mean age 33.4-39.3 years; PZ0.71). 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, PZ0.005) and lymph node metastasis (70 vs 36%; PZ0.07) were accentuated. Compared with 80 carriers of exon 11 mutations (codon 634, nZ78; codon 630, nZ2), 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.

Familial associations in medullary thyroid carcinoma with Hirschsprung disease: the role of the RET-C620 “Janus” genetic variation

“…extracellular, transmembrane, and intracellular regions), which seem to have specific roles [23]. For instance, the less common Codons C620, C618, and C611 within exon 10 confer a weaker transforming activity in vitro than exon 11 (C634) mutations, and recent studies have shown that the closer mutations are to the transmembrane domain (codons 657-636), the higher their importance in terms of tumor risk [24]. Less is known of the actual mechanisms, whereby extracellular domain mutations (eg, C620S) may result in C-cell proliferation [25].…”

Advances in risk-oriented surgery for multiple endocrine neoplasia type 2

“…1), there are further, though clinically more subtle codon-specific differences: earlier progression to MTC when the mutation lodges in the extracellular cysteine-rich domain, especially in close proximity to the cell membrane (Machens et al 2009a), as compared to a position in one of the intracellular tyrosine kinase domains (Rich et al 2014). The thyroid gland is more expendable than the adrenal or parathyroid glands, rendering pre-emptive thyroidectomy a more viable strategy than bilateral total adrenalectomy or 4-gland parathyroidectomy.…”

Molecular epidemiology of multiple endocrine neoplasia 2: implications for RET screening in the new millenium

“…Although the intensity of C-cell stimulation is genetically encoded and more predictable, the acquisition of somatic mutations by a single C-cell is difficult to anticipate as these 'second hits' follow stochastic principles subject to the law of chance. The stronger is the transforming activity of a RET mutation in vitro, the faster is the development of MTC (10). For extracellular RET mutations, the transforming activity is the weaker (codon 609/611!618/620!630/634) the farther these mutations are positioned away from the cell membrane (10,11).…”

“…The stronger is the transforming activity of a RET mutation in vitro, the faster is the development of MTC (10). For extracellular RET mutations, the transforming activity is the weaker (codon 609/611!618/620!630/634) the farther these mutations are positioned away from the cell membrane (10,11). Because the transition from C-cell hyperplasia to node-negative and ultimately nodepositive MTC takes time, the above histopathological stages are separated by time intervals (5,6).…”