Genetic Associations with Hearing Loss from Cancer Treatment

大约三分之一的美国人在一生中会被诊断出患有癌症（IOM，2006）。最后VA内 仅一年，估计有10，421例患者接受了含顺铂的铂类化疗[2，443]， 卡铂[5，621]或奥沙利铂[2357]（VA癌症登记，2018）。这些都是常见的治疗方法 癌症（Rybak，2007; Miaskowski等，2018; Sogaard等人，2013年），并已知会造成持久的损害 耳毒性（otototoxic）。感音神经性听力损失（SNHL）和耳鸣的报告发病率由这些 治疗方法差别很大。治疗前对耳毒性遗传指标的了解可以提高 耳毒性风险评估的准确性，以及及时干预以潜在地预防SNHL、耳鸣和 对这些患者的心理影响。这很重要，因为这些听觉问题是严重的， 诊断不足和治疗不足（Chou等人，2011; Cunningham & Tucci，2017）。但尚不清楚 为什么有些患者在高累积药物剂量下仍能保持治疗前的听觉功能（Rybak，2007; Obermair等人，1998），从而表明遗传易感性（Tserga等人，2019年）。 这项研究的目的是检测3个候选基因的遗传关联：ACYP 2，（Xu 例如，2015）、TPMT（Ross等人，2009）和TRPV 1（Jian等人，2019），具有良好的耳毒性特征。我们将 结合当地开发的行为和非行为听觉测试以及风险因素模型， 复制和全基因组关联研究（GWAS）的原理证明和样本量计算， 多站点上下文。具体目的是收集以下方面的初步证据：（1）候选基因的关联 SNHL和耳鸣的患者被发现对癌症治疗的耳毒性敏感或有弹性;以及 (2)癌症治疗后候选基因与外毛细胞和突触/神经完整性的关联。 我们将从大约150名参与者那里获得血液和基因样本， 并完成了耳毒性方面的项目。通过从这些样本中招募，我们利用丰富的数据集， 提供全面的，听力和生理，听觉表型进行必要的， study.在第一年，我们将专注于招募和获取参与者的血样，获取他们的数据， 在VA和俄勒冈州健康与科学中心使用电子病历（EMR）进行癌症治疗 提取基因组DNA，并开发单核苷酸多态性（SNP）标签 与每个候选基因相关。这些数据将用于目标1，以验证是否有一组候选基因 在顺铂、卡铂和奥沙利铂的临床模型中增强铂类药物诱导的SNHL或耳鸣， 耳毒性临床前模型表明，卡铂和奥沙利铂诱导耳蜗突触/神经突触 没有与顺铂相同程度的外毛细胞死亡。在目标2中， 目的1将用于评估个体SNPs是否与听觉系统中的耳毒性改变相关。 生理功能我们将评估这些遗传变异对畸变产物耳声的影响 外毛细胞功能障碍的基于DPOAE的估计;以及DPOAE调整的听觉脑干 根据Bramhall等人（2018）以及宽带声反射，基于WIAR的估计， 突触/神经变性（Feeney等人，2017年）。对于每一个目标，患者的脆弱性或弹性， 耳毒性将根据药物类型（顺铂、卡铂、奥沙利铂），药物方案（例如， 放疗，氨基糖苷类抗生素）和患者风险因素（例如，治疗前听觉功能、年龄）。 这项研究将提供初步的证据， 以铂为基础的化疗的功能障碍，以及发展的感知缺陷，对于常见的 已知会引起广泛的感觉神经损伤的化疗。我们的长期目标是开发一种基因 可以帮助治疗前咨询、患者-提供者关于治疗的决策的屏幕 修改，并可以指导听力服务的利用，以最大限度地提高生活质量，在这个弱势群体。

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.