Identification of genetic markers predictive of paclitaxel-induced peripheral neuropathy

• Autores: María Valvanera Apellániz Ruiz
• Directores de la Tesis: Mercedes Robledo Batanero (dir. tes.), Cristina Rodríguez (dir. tes.)
• Lectura: En la Universidad Autónoma de Madrid ( España ) en 2016
• Idioma: inglés
• Tribunal Calificador de la Tesis: Montserrat Baiget Bastús (presid.), Fátima Al-Shahrour (secret.), Ana Isabel Gonzalez (voc.), Teresa Sevilla Mantecón (voc.), A. Redondo Sánchez (voc.)
• Programa de doctorado: Programa Oficial de Doctorado en Bioquímica, Biología Molecular, Biomedicina y Biotecnología (Biociencias Moleculares)
• Materias:
  • Química
    • Bioquímica
      • Quimioterapia
      • Biología molecular
  • Ciencias de la vida
    • Biología humana
      • Genética humana
    • Biología vegetal (botánica)
  • Sociología
    • Problemas sociales
      • Enfermedad
• Enlaces
  • Tesis en acceso abierto en: Biblos-e Archivo
• Resumen

  • Paclitaxel, an antimitotic agent widely used for the treatment of solid tumors, has the neuropathy as its dose limiting toxicity. In the majority of the patients the neuropathy resolves after finishing the treatment; however, in severe cases the nerves can be irreversibly damaged affecting permanently patients’ quality of life. In addition, dose reductions and treatment suspensions due to neuropathy are common, and may lead to sub-optimal disease treatment and increased likelihood of relapse. The genetic background has been suggested to explain a substantial proportion of the inter-individual variability observed in paclitaxel toxicities. Thus, the main goal of this Thesis was to identify genetic markers associated with paclitaxel-induced peripheral neuropathy. First, we evaluated the role of previously proposed genetic markers. And second, we performed whole exome and targeted next generation sequencing to discover new genetic variants associated with the neuropathy.

    With regard to the previously proposed genetic variants, we confirmed the association of the common polymorphisms rs7349683 in EPHA5, rs301927 in EPHA6 and rs209709 in EPHA8 with an increased risk of peripheral neuropathy. Concerning CYP2C8*3, we only found a tendency towards being a neuropathy risk factor.

    Applying whole exome sequencing to patients with severe neuropathy, we identified CYP3A4 defective variants associated with increased risk of severe neuropathy and higher probability of treatment modifications due to this adverse effect. Furthermore, targeted sequencing of candidate genes led us to discover that low frequency coding variants in EPHA5, EPHA6 and EPHA8 contributed to the susceptibility to paclitaxel-induced neuropathy.

    To sum up, this Thesis supports a role for CYP3A4 and EPHAs genetic variants in the development of paclitaxel-induced neuropathy. It also recognizes the use of next generation sequencing techniques as novel approaches to detect low-frequency variants associated with drug adverse events. Moreover, the involvement of EphA receptors in neuronal repair function suggests they could also be risk markers for other neurotoxic drugs. The genetic markers identified in this Thesis may help to personalize paclitaxel treatment by identifying, beforehand, those patients with an increased neuropathy risk and that may benefit from alternative drugs and from an extensive follow-up along the therapy.