Sequence variations of mitochondrial DNA and individual sensitivity to the ototoxic effect of cisplatin

Anticancer Res. Mar-Apr 2003;23(2B):1249-55.

Abstract

Background: Since mutations in the mitochondrial genome are associated with hearing loss, we analyzed whether sequence variations of mtDNA are associated with individual sensitivity to cisplatin-induced ototoxicity.

Materials and methods: The mtDNA of 20 patients with and 19 patients without hearing impairment under therapeutic doses of cisplatin was sequenced for mutations and characterized for haplotype by restriction analysis.

Results: Neither the A7445G mutation, nor the 7472insC insertion or the A1555G mutation were identified in any of the patients. Nucleotide variations in the variable D-loop region did not correlate with cisplatin-induced hearing loss. However, these patients clustered more frequently (5 out of 20) in the rare European haplogroup J, than those with normal hearing after therapy (1 out of 19).

Conclusion: The linkage of cisplatin-induced hearing impairment to the mitochondrial haplogroup J, which is also associated with the mitochondrially-mediated Leber's Hereditary Optic Neuropathy, might act as a predisponsing genetic background for biochemical differences in mitochondria.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Antineoplastic Agents / adverse effects*
  • Bone Neoplasms / drug therapy
  • Brain Neoplasms / drug therapy
  • Child
  • Child, Preschool
  • Cisplatin / adverse effects*
  • DNA Mutational Analysis
  • DNA, Mitochondrial / genetics*
  • Dose-Response Relationship, Drug
  • Genetic Linkage
  • Genetic Predisposition to Disease
  • Germinoma / drug therapy
  • Hair Cells, Auditory, Outer / drug effects
  • Haplotypes / genetics
  • Hearing Loss, Sensorineural / chemically induced*
  • Hearing Loss, Sensorineural / genetics
  • Humans
  • Medulloblastoma / drug therapy
  • Mutagenesis, Insertional
  • Mutation, Missense
  • Neuroblastoma / drug therapy
  • Optic Atrophy, Hereditary, Leber / genetics
  • Osteosarcoma / drug therapy
  • Phenotype
  • Phylogeny
  • Point Mutation
  • Polymorphism, Genetic
  • Sequence Deletion

Substances

  • Antineoplastic Agents
  • DNA, Mitochondrial
  • Cisplatin