title: 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.
abstract: BACKGROUND
  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).
  
  
  METHODS
  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.
authors.affiliation: Istituto di Endocrinologia ed Oncologia Sperimentale G Salvatore, CNR, Dipartimento di Biologia e Patologia Cellulare e Molecolare, L Califano, Universita' Federico II, Napoli, Italy.
authors.forename: Maria D
authors.initials: MD
authors.lastname: Castellone
authors.forename: Antonella
authors.initials: A
authors.lastname: Verrienti
authors.forename: Deva
authors.initials: D
authors.lastname: Magendra Rao
authors.forename: Marialuisa
authors.initials: M
authors.lastname: Sponziello
authors.forename: Dora
authors.initials: D
authors.lastname: Fabbro
authors.forename: Magesh
authors.initials: M
authors.lastname: Muthu
authors.forename: Cosimo
authors.initials: C
authors.lastname: Durante
authors.forename: Marianna
authors.initials: M
authors.lastname: Maranghi
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Damante
authors.forename: Stefano
authors.initials: S
authors.lastname: Pizzolitto
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Costante
authors.forename: Diego
authors.initials: D
authors.lastname: Russo
authors.forename: Massimo
authors.initials: M
authors.lastname: Santoro
authors.forename: Sebastiano
authors.initials: S
authors.lastname: Filetti
mesh_terms: D000310:Adrenal Gland Neoplasms / Q000235:genetics*; D000328:Adult; D000818:Animals; D018278:Carcinoma, Neuroendocrine; D018095:Germ-Line Mutation; D006801:Humans; D008297:Male; D051379:Mice; D018813:Multiple Endocrine Neoplasia Type 2a / Q000235:genetics*; D041681:NIH 3T3 Cells; D010673:Pheochromocytoma / Q000235:genetics*; D051096:Proto-Oncogene Proteins c-ret / Q000235:genetics* / Q000502:physiology*; D013964:Thyroid Neoplasms / Q000235:genetics
chemical_list: D051096:Proto-Oncogene Proteins c-ret; C099282:RET protein, human