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This Article Accepted manuscript (PDF) All Versions of this Article: ERC-08-0096v1 16/1/171    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Machens, A. Articles by Dralle, H. Search for Related Content PubMed PubMed Citation Articles by Machens, A. Articles by Dralle, H.

A Machens, Dpt. of General, Visceral and Vascular Surgery, Martin Luther University Halle-Wittenberg, Halle (Saale), D-06097, Germany
S Hauptmann, Dpt. of Pathology, Martin Luther University Halle-Wittenberg, Halle (Saale), Germany
H Dralle, Dpt. of General, Visceral and Vascular Surgery, Martin Luther University Halle-Wittenberg, Halle (Saale), Germany

Correspondence: Andreas Machens, Email: AndreasMachens{at}aol.com

Abstract

REarranged during Transfection (RET) germline mutations in exon 10 are peculiar because they produce both gain-of-function MEN (multiple endocrine neoplasia) 2A and loss-of-function HSCR (Hirschsprung`s disease) phenotypes. Drawing on 38 medullary thyroid cancer patients harboring germline 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 germline 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 mm, 18.7 mm, 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 to 39.3 years; P=0.71). When mutations in adjoining codons were collapsed (codons 620/618 versus 611/609), the differences in mean primary tumor diameter (20.1 mm versus 7.4 mm, P=0.005) and lymph node metastasis (70% versus 36%; P=0.07) were accentuated. Compared with 80 carriers of exon 11 mutations (codon 634, n=78; codon 630, n=2), the 36 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.