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

作者：Castellone Maria D; Verrienti Antonella; Rao Deva Magendra; Sponziello Marialuisa; Fabbro Dora; Muthu Magesh; Durante Cosimo; Maranghi Marianna; Damante Giuseppe; Pizzolitto Stefano; Costante Giuseppe; Russo Diego; Santoro Massimo; Filetti Sebastiano^*

来源：Clinical Endocrinology, 2010, 73(4): 529-534.

DOI：10.1111/j.1365-2265.2009.03757.x

P>Context
In multiple endocrine neoplasia (MEN), rearranged during transfection (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.

• 出版日期2010-10