Genetic Susceptibility to Ototoxicity in Pediatric Germ Cell Tumor Survivors
Lay Summary: Survival rates are high for germ cell tumors (GCTs) due to the effectiveness of platinum-based chemotherapy; however, we don’t know much about how treatment for GCT affects the health of survivors because they have not been included in previous childhood cancer survivor studies. Data from men with testicular GCT and from other childhood cancer survivors suggest that considerable late effects of cancer treatment are likely to exist, including second cancers, hearing loss, heart disease and infertility. Hearing loss (ototoxicity) is the most frequent late effect in the years immediately after treatment. Cisplatin-related hearing loss typically affects both ears and is irreversible. When this occurs in children during the prime years of language development, it can have a serious impact on educational outcomes, social functioning and quality of life. Known risk factors for hearing loss after chemotherapy include high doses of chemotherapy and young age a treatment; however, there is a lot of variation in prevalence even after accounting for these factors. There is some evidence to suggest that genetic variation may also be important in determining which children have hearing loss, but there isn’t enough evidence to resolve this issue yet. Importantly, none of the studies conducted to date have included a large number of GCT survivors. Since treatment dose and duration varies across types of childhood cancer, it is important to study late effects in a uniform group of childhood cancer survivors. In our proposal, we will investigate the importance of genetic variation on platinum-induced hearing loss in a large cohort of GCT survivors with confirmation of findings in other childhood cancer survivors.
We have recently completed a large study of GCT designed to evaluate risk factors (the GaMETES study), and additional data collection in these individuals will provide a unique opportunity to evaluate late effects of treatment in pediatric GCT. In the GaMETES study, we collected DNA samples and questionnaire data from 867 GCT cases. In our proposed project, we will follow up with these cases using both questionnaires and medical record information to find out who developed hearing loss. These data will be combined with data from an ongoing clinical trial of GCT that includes detailed treatment data, collection of DNA, and information regarding hearing loss. We will then use genotyping data to find out whether certain individuals are more likely to develop hearing loss based on their genetic background. We have access to data from other studies of childhood cancer and adult testicular GCT that we will use to confirm any genetic associations that we discover in the GCT studies. This will help us determine whether there are common genetic variants that influence hearing loss across tumor types. This information could be useful for identifying individuals who are more likely to develop hearing loss and would benefit the most from additional follow up or chemoprevention.