JMIR Publications

ABSTRACT

Background:

Survival rates after childhood cancer now reach nearly 80% in developed countries. However, the treatment leading to this improved survival can cause serious adverse effects that have life-long negative impacts on survivor’s quality of life. Hearing impairment is a common adverse effect in children treated with cisplatin-based chemotherapy or cranial radiotherapy. Ototoxicity can extend from high-tone hearing impairment to involvement of speech frequencies. Hearing impairment can impede speech and language, and neurocognitive development. Although treatment related risk factors for hearing loss following childhood cancer treatment have been identified, the individual variability in toxicity of adverse effects after similar treatment between childhood cancer patients suggests a role for genetic susceptibility. Currently, twelve candidate gene approach studies have been performed to identify polymorphisms predisposing to platinum-induced ototoxicity in children being treated for cancer. However, most studies were underpowered, lacked replication, and results were inconsistent.

Objective:

We describe the design of PCL work packages (WP) 4b and 5 addressing the genetic susceptibility of platinum-induced ototoxicity.

Methods:

As a part of the PanCareLIFE study within the framework of the PanCare consortium, we address genetic susceptibility of treatment-induced ototoxicity during and after childhood cancer treatment in a large European cohort.

Results:

This study includes 1124 survivors treated with cisplatin, carboplatin or cranial radiotherapy for childhood cancer, resulting in the largest clinical European cohort assembled for this late-effect to date. Nested within the larger cohort is a homogenous, unique, well-defined cohort of 598 cisplatin-treated childhood cancer patients, not confounded by cranial radiotherapy.

Conclusions:

The PanCareLIFE initiative provides, for the first time, a unique opportunity to both confirm already identified determinants for hearing impairment during childhood cancer using a candidate gene approach and to set up the first international genome-wide association study of cisplatin-induced direct ototoxicity in childhood cancer patients to identify novel allelic variants. Results will be validated in an independent replication cohort. Genetic factors, identified as part of this pan-European project PanCareLIFE, may contribute to more accurate prediction models that can be incorporated in future clinical trials of platinum-based therapies for cancer, and may help with the development of prevention strategies.