Approximately 1 in 3 Americans will be diagnosed with cancer in their lifetime (IOM, 2006). Within VA last year alone, an estimated 10,421 patients received platinum-based chemotherapy with cisplatin [2,443], carboplatin [5,621], or oxaliplatin [2357] (VA Cancer Registry, 2018). These are common treatments for myriad cancers (Rybak, 2007; Miaskowski et al., 2018; Sogaard et al., 2013) and are known to cause lasting damage to the ear [ototoxic]. The reported incidence of sensorineural hearing loss (SNHL) and tinnitus arising from these treatments varies considerably. Pre-treatment knowledge of the genetic indicators of ototoxicity could improve the accuracy of ototoxicity risk estimates, and prompt intervention to potentially prevent SNHL, tinnitus, and the related psychosocial impacts for these patients. This is important because these auditory problems are grossly underdiagnosed and undertreated (Chou et al., 2011; Cunningham & Tucci, 2017). However, it remains unclear why some patients retain their pre-treatment auditory function despite high cumulative drug dosing (Rybak ,2007; Obermair et al., 1998), thus suggesting genetic susceptibility (Tserga et al., 2019). The objective of this proposed research is to test for genetic associations of 3 candidate genes: ACYP2, (Xu et al., 2015), TPMT (Ross et al., 2009), and TRPV1 (Jian et al., 2019) with well-characterized ototoxicity. We will incorporate locally developed, behavioral and non-behavioral auditory tests and risk factor models to provide proof of principle and sample size calculations for replication and a genome wide association study (GWAS) in a multi-site context.
The specific aims are to gather preliminary evidence of: (1) Associations of candidate genes with SNHL and tinnitus in patients found to be vulnerable or resilient to ototoxicity from cancer treatment; and (2) Associations of candidate genes with outer hair cell and synaptic/neural integrity following cancer treatment. We will obtain blood and genetic samples from approximately 150 participants in Dr. Konrad-Martin?s new and completed projects on ototoxicity. By recruiting from these samples, we leverage a rich data set that will provide the comprehensive, audiometric and physiological, auditory phenotyping necessary to conduct this study. In Year 1, we will focus on recruiting and obtaining blood draws from participants, obtaining data on their cancer treatment using the electronic medical record (EMR) at the VA and at Oregon Health & Science University, extracting genomic DNA, and developing tags for the single nucleotide polymorphisms (SNPs) associated with each candidate gene. These data will be used in Aim 1 to verify if a set of candidate genes potentiates platinum-drug-induced SNHL or tinnitus in clinical models of cisplatin-, carboplatin- and oxaliplatin- ototoxicity. Pre-clinical models demonstrate that carboplatin and oxaliplatin induce cochlear synaptic/neural dysfunction without the same degree of outer hair cell death seen with cisplatin.
In Aim 2, the data obtained in Aim 1 will be used to evaluate whether individual SNPs are associated with ototoxic changes in auditory physiologic function. We will assess the influence of these genetic variants on distortion product otoacoustic emission, DPOAE-based estimates of outer hair cell dysfunction; and on DPOAE-adjusted auditory brainstem response, ABR, following Bramhall et al. (2018), as well as on wideband acoustic reflex, WIAR-based estimates of synaptic/neural degeneration (Feeney et al., 2017). For each Aim, a patient?s vulnerability or resilience to ototoxicity will be assessed in relation to the drug type (cisplatin, carboplatin, oxaliplatin), the drug regimen (e.g., radiotherapy, aminoglycoside antibiotics) and patient risk factors (e.g., pre-treatment auditory function, age). This research will provide preliminary evidence relating genetic variants thought to influence auditory dysfunction from platinum-based chemotherapies, and the perceptual deficits that develop, for common chemotherapies known to induce a wide range of sensorineural injury. Our long-term goal is to develop a genetic screen that can assist with pre-treatment counseling, patient-provider decision making regarding treatment modification, and can guide audiological service utilization to maximize quality of life in this vulnerable population.
Platinum-based chemotherapy is a mainstay treatment for many common cancers and a frequent cause of hearing loss and tinnitus among cancer survivors. Within VA last year alone, an estimated 10,421 patients received chemotherapy with a platinum-based drug. The most ototoxic of these, cisplatin and carboplatin, cause substantial hearing loss in 40-80% of patients treated with these drugs; however, it is unknown why large numbers of patients retain their pre-treatment hearing despite high cumulative drug dosing. The objective of this pilot research is to provide proof of principle and development of sample size calculations for an expanded study to identify genetic variants associating with hearing loss and tinnitus from cancer treatment. The approach leverages our sensitive ototoxicity assessments and risk factor model to investigate candidate genes whose products regulate drug uptake or metabolism. Identifying genetic factors that influence ototoxicity risk may permit fine tuning of the treatment plan, and development of otoprotective or ototherapeutic interventions.
