Premium
A novel de novo germ‐line V292M mutation in the extracellular region of RET in a patient with phaeochromocytoma and medullary thyroid carcinoma: functional characterization
Author(s) -
Castellone Maria D.,
Verrienti Antonella,
Magendra Rao Deva,
Sponziello Marialuisa,
Fabbro Dora,
Muthu Magesh,
Durante Cosimo,
Maranghi Marianna,
Damante Giuseppe,
Pizzolitto Stefano,
Costante Giuseppe,
Russo Diego,
Santoro Massimo,
Filetti Sebastiano
Publication year - 2010
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.1365-2265.2009.03757.x
Subject(s) - multiple endocrine neoplasia type 2 , thyroid carcinoma , mutation , medullary thyroid cancer , multiple endocrine neoplasia , proto oncogene proteins c ret , cancer research , pheochromocytoma , biology , germline mutation , medicine , endocrinology , genetics , thyroid , gene , receptor , neurotrophic factors , glial cell line derived neurotrophic factor
Summary Context In multiple endocrine neoplasia (MEN), re arranged during t ransfection ( RET ), gene testing has been extensively exploited to characterize tumour aggressiveness and optimize the diagnostic and clinical management. Objective To report the underlying genetic alterations in an unusual case of MEN type 2 (MEN‐2A). Design and patient Occult medullary thyroid carcinoma (MTC) was diagnosed in a 44‐year‐old man who had presented with unilateral phaeochromcytoma. DNA extracted from the blood and tumour tissues was analysed for mutations in RET . The transforming potential and mitogenic properties of the identified RET mutation were investigated. Results The patient carried a novel heterozygous germ‐line RET mutation in exon 5 (Val292Met, GTG>ATG) (V292M/ RET ) with no evidence of additional somatic alterations. The mutation maps to the third cadherin‐like domain of RET, which is usually not included in RET screening. Interestingly, MTC with concomitant phaeochromcytoma has never been associated with a RET mutation involving the extracellular cadherin‐like domain. V292M/ RET was absent in the only two relatives examined. In vitro assays indicate that the mutant has low‐grade transforming potential. Conclusions Complete characterization and classification of all novel RET mutations are essential for extending genetic analysis in clinical practice. Our findings suggest that: (i) in all MEN‐2 patients negative for RET hot‐spot mutations, testing should be extended to all coding regions of the gene and (ii) the newly identified V292M/ RET mutation is characterized by relatively weak in vitro transforming ability.