Population-Specific Genetic Determinants of Susceptibility to Chemotherapies

描述（由申请人提供）：基于个体独特基因组成的个体化药物治疗范例在血液学/肿瘤学领域尤其可取，因为该领域的治疗指数通常很窄，化疗药物毒性的后果可能危及生命。如果临床医生能够更好地预测哪些人遭受化疗相关毒性的风险最大，这将极大地影响癌症患者的整体护理。对于癌症药物，毒性的发展在所有接受治疗的个体中并不是普遍可预测的。有证据表明，个体之间和种群之间的遗传差异可能解释了这种异质性的重要部分。例如，与其他人群相比，亚洲人铂类化疗相关毒性的发生率明显更高。这一观察结果表明，亚洲人特有的基因多态性或在亚洲人中较高的比例可能解释了这种差异。如果能够在人群和个体中发现“铂毒性易感性多态性”，基于基因型预测铂毒性风险可能成为可能。假设：生殖系遗传多态性是铂化疗相关毒性的关键决定因素。我们开发了一个实验模型，利用来自不同种族背景的健康个体的ebv转化的b淋巴母细胞样细胞系（LCLs），通过无偏倚的全基因组方法阐明了化疗相关毒性易感性的遗传决定因素。在本研究中，我们将该模型应用于发现控制顺铂和卡铂两种铂化疗毒性敏感性的种系单核苷酸多态性（snp）。我们将首先确定与亚洲人LCLs体外细胞毒性相关的snp，因为亚洲人代表了“富集毒性表型”人群。然后，利用在亚洲人身上发现的snp，结合来自高加索人和非洲人的基因型信息，我们将确定“跨人群”存在的snp，这些snp可以预测任何个体的铂毒性易感性，而不考虑种族。“跨群体”snp将在我们的第二个目标中进行验证，该目标建立一项临床试验，招募顺铂治疗的患者，以确定临床前衍生的“顺铂毒性”snp是否可预测地与顺铂相关肾毒性的发展相关。该试验还将通过对患者样本的二次全基因组关联分析来鉴定额外的、新颖的“顺铂肾毒性”snp。这些信息可能会导致癌症患者更明智地使用化疗，可能会使化疗的选择和/或剂量基于个人产生副作用的风险，平衡潜在的益处。在人口规模上，这项工作的结果有可能减少化疗可能带来的重大疾病负担。对于实习生来说，该提案代表了在基本药物遗传学发现和临床试验设计方面的全面学习经验。

DESCRIPTION (provided by applicant): The paradigm of individualized drug therapy based on an individual's unique genetic make-up is especially desirable in the field of hematology/oncology, where the therapeutic index is often narrow, and the consequences of chemotherapy drug toxicity can be life-threatening. If clinicians could better predict which individuals are at the greatest risk of suffering chemotherapy-related toxicities, this could greatly impact the overall care of cancer patients. For cancer drugs, development of toxicities is not universally predictable among all individuals being treated. Evidence suggests that genetic differences between individuals, and between populations, might explain a significant portion of this heterogeneity. For example, Asians have significantly higher rates of platinum chemotherapy-related toxicities compared to other populations. This observation suggests that genetic polymorphisms unique to, or present at higher rates in, Asians might explain this difference. If one could identify "platinum toxicity susceptibility polymorphisms" in populations and individuals, prediction of platinum toxicity risk based on genotype might be possible. Hypothesis: Germline genetic polymorphisms are critical determinants of platinum chemotherapy-related toxicity. We have developed an experimental model employing EBV-transformed B-lymphoblastoid cell lines (LCLs) from healthy individuals of different ethnic backgrounds that permits elucidation of genetic determinants of chemotherapy-related toxicity susceptibility via an unbiased genome-wide approach. In this proposal, we apply this model toward discovery of germline single nucleotide polymorphisms (SNPs) governing toxicity susceptibility to two platinum chemotherapies, cisplatin and carboplatin. We will first identify SNPs which associate with in vitro cytotoxicity in LCLs from Asian individuals, since Asians represent an "enriched toxicity phenotype" population. Then, using SNPs identified in Asians, in conjunction with genotype information from Caucasians and Africans, we will identify SNPs existing "across-populations" which may predict platinum toxicity susceptibility in any individual, regardless of ethnicity. "Cross population" SNPs will then be subjected to validation in our second aim, which establishes a clinical trial enrolling cisplatin-treated patients to determine whether the pre-clinically derived "cisplatin toxicity" SNPs predictably associate with development of cisplatin-related nephrotoxicity. The trial will also permit identification of additional, novel, "cisplatin nephrotoxicity" SNPs through a secondary genome-wide association analysis of patient samples. This information could lead to more judicious use of chemotherapy in cancer patients, potentially allowing chemotherapies to be chosen and/or dosed based on an individual's personal risk of developing side- effects, balanced against the potential benefits. On a population scale, results of this work have the potential to reduce the significant burden of illness that can be conferred by chemotherapy. For the trainee, the proposal represents a comprehensive learning experience in both basic pharmacogenetic discovery and clinical trial design.