RESUMEN
BACKGROUND: A novel Cys-Ser Ret germline point mutation in a 58-year-old woman with bilateral medullary thyroid carcinoma (MTC) prompted us to perform genetic analysis of the family and evaluate the biological consequences of such a mutation. METHODS: Ret analysis by direct sequencing was performed in five family members. The biological activity and biochemical properties of the Ret- Cys515Ser mutant were analyzed in NIH-3T3 cells. RESULTS: The proband's son, age 35, had the Ret- Cys515Ser mutation and the L769 CTT/CTG exon 13 polymorphic variant, which was also found in his father. Clinical evaluation of the son also revealed bilateral multifocal microscopic MTC and papillary thyroid carcinoma (PTC). In vitro and in vivo analysis indicated ligand-independent activation of the Ret-Cys515Ser mutant due to aberrant disulfide homodimerization, increased mitogenic activity, and ability to induce anchorage-independent growth in NIH-3T3 cells in comparison to wild-type Ret, suggesting a possible role of Cys515Ser in tumor development. CONCLUSIONS: The Cys515Ser mutation adds to cysteine substitution groups that have been described in association with MTC. Our data also highlight the importance of performing a complete genetic analysis in patients who present with MTC.
Asunto(s)
Carcinoma Medular/genética , Exones/genética , Mutación de Línea Germinal/genética , Mutación Puntual/genética , Proteínas Proto-Oncogénicas c-ret/genética , Neoplasias de la Tiroides/genética , Carcinoma Medular/cirugía , Femenino , Predisposición Genética a la Enfermedad , Humanos , Persona de Mediana Edad , Linaje , Neoplasias de la Tiroides/cirugía , TiroidectomíaRESUMEN
Although most thyroid cancers may be cured by surgery and 131I therapy, approximately 10-20% of patients die from advanced differentiated and anaplastic tumors that are unresponsive to conventional treatments. Thus, alternative approaches such as gene therapy are of interest, especially using targeted therapeutic gene delivery. Several strategies have been designed specifically for thyroid cancer and some have proven to be feasible in preclinical studies. In particular, it is suggested that combined gene therapy approaches, as well as multimodality therapeutic regimens, including gene therapy and conventional treatments, should be pursued to achieve clinically significant results. The recent discovery of new markers of thyroid cancer should improve the efficacy of gene therapy.
RESUMEN
This study represents the first report of gene therapy for anaplastic thyroid carcinoma, one of the most aggressive solid tumors in humans. Two patients with end-stage anaplastic thyroid carcinoma were treated by direct intratumor injection of retroviral vector producer cells followed by ganciclovir. The retroviral vector carried the human IL-2 gene and the suicide gene thymidine kinase of herpes simplex virus type 1. Treatment was safe and associated with only mild adverse events. Transduction of tumor cells and production of T helper type 1 cytokines was demonstrated in tumor biopsies. Gene therapy led also to a marked increase in T helper type 1 cytokine expression in peripheral blood mononuclear cells. Radiological evaluation of injected tumor masses demonstrated local tumor necrosis.