ECE2009 Clinical Highlights Hot topics: Clinical (5 abstracts)
ESE Young Investigator Award
Daniela Cordella 3 , Marina Muzza 1, , Johny Bombled 4 , Brigitte Bressac-de Paillerets 4 , Paolo Beck-Peccoz 1, , Martin Schlumberger 5 , Luca Persani 1, & Laura Fugazzola 1,
1Department of Medical Sciences, University of Milan, Milan, Italy; 2Endocrine and Diabetological Unit, Fondazione Policlinico IRCCS, Milan, Italy; 3Laboratory of Experimental Endocrinology, Istituto Auxologico Italiano IRCCS, Milan, Italy; 4Service de Génétique, Laboratoire Génomes et Cancer, FRE2938 CNRS2, Institut Gustave Roussy, Villejuif, France; 5Department of Nuclear Medicine and Endocrine Oncology, Institut de Cancérologie Gustave-Roussy and University Paris-Sud 11, Villejuif, France.
Germline activating mutations of the RET proto-oncogene are associated with inherited medullary thyroid cancer (MTC) and can be also detected in about 10% of apparently sporadic MTC cases. In the present study, 4 novel RET mutations, located in the extracellular domain (A510V, E511K and C531R) and in the intracellular juxtamembrane region (L666N), all identified by the genetic screening on sporadic MTC cases, are firstly reported and functionally characterized. RET Plasmids carrying Ret9-WT (the short isoform of protoRet gene) and RET mutants, obtained by site-direct mutagenesis, were transiently transfected in HEK cells. Ret9-C634R (the protoRet gene containing a MEN2A causing mutation) was used as positive control. The tyrosine phosphorylation level was evaluated by immunoprecipitation and Western blot analyses. The extracellular variants A510V, E511K and C531R were found to harbour an autophosphorylation higher than Ret9-WT, but significantly lower than Ret9-C634R. Differently, the L666N variant, located 8 residues downstream the transmembrane domain displayed a high kinase activity, similar to that observed with the Ret9-C634R mutant and consistent with a strong transforming activity.
In conclusion, functional analyses on four novel germline RET mutations are reported. Consistent with previous data on a complex mutation, the L666N variant is associated with a high constitutive activation indicating that alterations in the juxtamembrane region can strongly activate RET in a ligand independent manner and be associated with a phenotype of intermediate-high severity. Therefore, we advocate strict follow-up since early age for carriers of mutations in this novel ‘hot’ region. Finally, present data confirm the need to routinely perform the genetic screening for RET in apparently sporadic MTC and to extend the molecular analyses to regions other than the cysteine residues and other classical hot spots.
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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