Genetic Associations with Hearing Loss from Cancer Treatment

大约三分之一的美国人会在他们的一生中被诊断出癌症(IOM，2006)。在退伍军人事务部内 仅去年一年，估计有10,421名患者接受了以铂为基础的顺铂化疗[2,443]， 卡铂[5,621]，或奥沙利铂[2357](退伍军人事务部癌症登记，2018年)。这些是治疗无数疾病的常用方法 癌症(Rybak，2007；Miaskowski等人，2018；Sogaard等人，2013)，众所周知会造成持久的损害 对耳朵[耳毒性]。由这些因素引起的感音神经性听力损失(SNHL)和耳鸣的发生率 治疗方法差别很大。对耳毒性遗传指标的前处理知识可以提高 耳毒性风险评估的准确性，并及时进行干预，以潜在地预防SNHL、耳鸣和 对这些患者的相关心理社会影响。这一点很重要，因为这些听觉问题 诊断不足和治疗不足(Chou等人，2011年；Cunningham&Tucci，2017)。然而，目前仍不清楚 为什么尽管累积用药剂量很高，一些患者仍能保持治疗前的听觉功能(Rybak，2007； Obermair等人，1998年)，从而表明遗传易感性(Tserga等人，2019年)。 这项拟议的研究的目的是测试3个候选基因的遗传关联：ACYP2，(XU TPMT(Ross等人，2009年)和TRPV1(Jian等人，2019年)具有良好的耳毒性特征。我们会 纳入当地开发的行为和非行为听觉测试和风险因素模型，以提供 复制和全基因组关联研究的原理证明和样本量计算 多站点环境。具体目的是收集以下的初步证据：(1)候选基因的关联性 对癌症治疗的耳毒性敏感或有抵抗力的患者出现SNHL和耳鸣；以及 (2)癌症治疗后候选基因与外毛细胞和突触/神经完整性的关系。 我们将从康拉德-马丁博士新研究的大约150名参与者身上获取血液和基因样本 并完成了有关耳毒性的项目。通过从这些样本中招聘，我们利用丰富的数据集 提供进行这项工作所需的全面、测听和生理、听觉表型 学习。在第一年，我们将专注于招募和获取参与者的血液，获得他们的数据 退伍军人管理局和俄勒冈健康与科学公司使用电子病历(EMR)治疗癌症 大学，提取基因组DNA，开发单核苷酸多态(SNPs)标签 与每个候选基因相关联。这些数据将在目标1中用于验证一组候选基因 在顺铂、卡铂和奥沙利铂的临床模型中增强铂药物诱导的SNHL或耳鸣 耳毒性。临床前模型显示卡铂和奥沙利铂可诱导耳蜗神经突触 功能障碍，没有顺铂所见的相同程度的外毛细胞死亡。在目标2中，在中获得的数据 目标1将用于评估单个SNPs是否与听觉中的耳毒性变化相关 生理功能。我们将评估这些遗传变异对失真耳声产物的影响 发射，基于DPOAE的外毛细胞功能障碍的估计；以及DPOAE调整的听性脑干 回应，ABR，跟随BramHall等人。(2018)，以及宽带声反射，基于WAR的估计 突触/神经变性(Feeney等人，2017年)。对于每个目标，患者对 将根据药物类型(顺铂、卡铂、奥沙利铂)、药物方案(例如， 放射治疗、氨基糖苷类抗生素)和患者危险因素(如治疗前的听功能、年龄)。 这项研究将提供与被认为影响听觉的遗传变异有关的初步证据 以铂为基础的化疗所致的功能障碍，以及发展为常见的知觉缺陷 已知的化疗会引起大范围的感觉神经损伤。我们的长期目标是开发出一种基因 可以帮助进行治疗前咨询、患者提供者关于治疗的决策的屏幕 改进，并可以指导听力学服务的利用，以最大限度地提高这一弱势群体的生活质量。

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.