RET genetic screening in patients with medullary thyroid cancer and their relatives: experience with 807 individuals at one center.
BACKGROUND
Germline RET gene mutations are causative of multiple endocrine neoplasia (MEN) 2 and may be identified by genetic screening. Three different syndromes are distinguished: MEN 2A, when medullary thyroid carcinoma (MTC) is associated with pheochromocytoma and/or parathyroid adenomas; MEN 2B, when accompanied by a marfanoid habitus and/or pheochromocytoma; and familial medullary thyroid carcinoma (FMTC), when only MTC is present.


METHODS
During the last 13 yr, we performed RET genetic screening in 807 subjects: 481 with apparently sporadic MTC, 37 with clinical evidence of MEN 2, and 289 relatives. Genomic DNA was extracted from the blood of all subjects, and exons 10, 11, 13, 14, 15, and 16 were analyzed by direct sequencing after PCR.


RESULTS
We unexpectedly discovered a germline RET mutation in 35 of 481 (7.3%) apparently sporadic MTC patients. A germline RET mutation was also found in 36 of 37 patients with clinical evidence of hereditary MTC. The distribution of RET mutations in cysteine and noncysteine encoding codons was significantly different in the two groups of patients, with the prevalence of RET mutations in noncysteine codons being higher in MTC that presented as apparently sporadic (P < 0.0001). A total of 34 FMTCs (75.5% of all FMTC) arrived with apparent sporadic MTC, with no familial history of other MTC cases. According to genetic screening and clinical data, our 72 families were classified as follows: 45 FMTC (62.5%), 22 MEN 2A (30.5%), and five MEN 2B (7%).


CONCLUSIONS
In this large series of MTC, hereditary forms, mainly FMTC, were clinically unsuspected in 7.3% of apparently sporadic cases. As a consequence, the prevalence of FMTC in our series is higher than that previously reported (60 vs. 10%). In these cases, RET mutations were more prevalently located in noncysteine codons. Data derived from our series helped elucidate the role of RET genetic screening for the identification of all forms of MEN 2, and especially for FMTC, which are frequently clinically misdiagnosed as nonheritable, sporadic cases.
Elisei
Rossella
R
Department of Endocrinology, University of Pisa, Via Paradisa 2, 56100 Pisa, Italy. relisei@endoc.med.unipi.it
Romei
Cristina
C
Cosci
Barbara
B
Agate
Laura
L
Bottici
Valeria
V
Molinaro
Eleonora
E
Sculli
Mariangela
M
Miccoli
Paolo
P
Basolo
Fulvio
F
Grasso
Lucia
L
Pacini
Furio
F
Pinchera
Aldo
A
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018276:Carcinoma, Medullary / Q000235:genetics*; D003062:Codon; D005091:Exons / Q000235:genetics; D005260:Female; D005820:Genetic Testing; D005838:Genotype; D018095:Germ-Line Mutation; D006801:Humans; D008297:Male; D008875:Middle Aged; D018813:Multiple Endocrine Neoplasia Type 2a / Q000235:genetics; D009154:Mutation / Q000502:physiology; D010641:Phenotype; D051096:Proto-Oncogene Proteins c-ret / Q000235:genetics*; D013964:Thyroid Neoplasms / Q000235:genetics*
D003062:Codon; D051096:Proto-Oncogene Proteins c-ret