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Clinical presentations and RET protooncogene mutations in seven multiple endocrine neoplasia type 2 kindreds
Author(s) -
Blank Robert D.,
Sklar Charles A.,
Dimich Alexandra B.,
LaQuaglia Michael P.,
Brennan Murray F.
Publication year - 1996
Publication title -
cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.052
H-Index - 304
eISSN - 1097-0142
pISSN - 0008-543X
DOI - 10.1002/(sici)1097-0142(19961101)78:9<1996::aid-cncr22>3.0.co;2-s
Subject(s) - medicine , mutation , multiple endocrine neoplasia type 2 , germline , genetics , germline mutation , disease , megacolon , exon , gene , biology
BACKGROUND Multiple endocrine neoplasia type 2 (MEN 2) is a group of related autosomal dominant cancer syndromes caused by mutations in the RET protooncogene. A subset of familial Hirschsprung's disease, aganglionic megacolon, is also caused by mutations in this gene. METHODS The authors performed mutation analysis of exons 10, 11, 13, and 16 of the RET gene in six established MEN 2 kindreds and in six patients with apparent sporadic disease, in order to correlate their genotypes and phenotypes. RESULTS One of these kindreds carried both Hirschsprung's disease and MEN 2A in conjunction with a cysteine‐to‐arginine substitution of codon 620 of the RET gene. One patient with apparently sporadic disease was found to have a germline M918T mutation. Patients with confirmed familial disease all carried pathologic germline mutations of RET. CONCLUSIONS Several lines of evidence support a gain of function mechanism for tumorigenesis in the MEN 2 syndromes but a loss of function mechanism for aganglionosis in Hirschsprung's disease. The authors propose that a multihit mechanism can reconcile the apparent paradox of a single mutation that gives rise to both gain and loss of function disorders in a single patient. Cancer 1996;78:1996‐2003.