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Low frequency of germline mutations in the RET proto‐oncogene in patients with apparently sporadic medullary thyroid carcinoma
Author(s) -
Eng Charls,
Mulligan Lois M.,
Smith Darrin P.,
Healey Catherine S.,
Frilling Andrea,
Raue Friedhelm,
Neumann Hartmut P.H.,
Ponder Margaret A.,
Ponder Bruce A.J.
Publication year - 1995
Publication title -
clinical endocrinology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.055
H-Index - 147
eISSN - 1365-2265
pISSN - 0300-0664
DOI - 10.1111/j.1365-2265.1995.tb01903.x
Subject(s) - germline mutation , germline , ret proto oncogene , thyroid carcinoma , mutation , multiple endocrine neoplasia type 2 , medicine , multiple endocrine neoplasia , polymerase chain reaction , thyroid , genetics , cancer research , biology , pathology , gene
Summary BACKGROUND AND OBJECTIVES Medullary thyroid carcinoma (MTC) occurs both sporadically and In the autosomal domlnantly inherited multiple endocrine neoplasia (MEN) type 2 syndromes. The distinction between true sporadic MTC and a new mutation familial case is important for future clinical managment of both the patient and family. The susceptibility gene for MEN 2 is the RET proto‐oncogene. Systematic analysis for germ‐line mutations of the RET proto‐oncogene was performed in a series of 67 patients with apparently sporadic MTC to determine whether they were true sporadic cases or unsuspected de novo MEN 2 cases. DESIGN AND PATIENTS Sixty‐seven unselected patients with sporadic MTC were randomly ascertained from clinic patients from four centres. The diagnosis of MTC was confirmed by hlstopathology. Germline DNA was extracted from peripheral blood leucocytes or from paraffin‐embedded tissue and subsequently used for polymerase chain reaction amplification. MEASUREMENTS Polymerase chain reaction based RET mutation analysis was performed by direct double‐stranded cycle sequencing of axons 10, 11, 13 and 16, within which the majority of MEN2 mutations have been shown to occur. RESULTS In this series, there was one proven case of germline mutation In RET codon 620, which previously has been shown to be responsible for MEN 2, thus Indicating heritable disease. No germline mutation in codon 918, typical of MEN 2B, was found. CONCLUSIONS A figure of 1.5% germline mutations In 67 apparently sporadic MTC Is lower than the incidence of familial disease reported in previous series Involving clinical and biochemical screening. The presence of a germline mutation in the RET proto‐oncogene in a patient with MTC indicates heritable disease. The absence of germline RET exon 10,11,13 or 16 mutation appears to rule out MEN 2A to a high probability, although the presence of a familial form of MTC other than classical MEN 2A cannot be excluded conclusively.