Incorporation of microRNA expression in pharmacogenetic prediction models

描述（由申请人提供）：大多数化疗药物同时影响肿瘤和正常细胞，对许多患者无效，并表现出严重的毒性；因此，开发预测模型，在治疗前识别有不良反应和/或对化疗药物无反应风险的患者是至关重要的。本提案的目的是采取协调一致的翻译努力来阐明种族间化疗敏感性差异的潜在原因。在本提案中，我们将重点关注两类细胞毒性药物：铂化药物（顺铂和卡铂）和抗代谢药物（卡培他滨和Ara-C），它们在体外的细胞敏感性上存在显著的种族差异。我们的假设是，与欧洲人后裔相比，非洲人后裔个体的microRNA （miRNA）表达差异至少在一定程度上导致了这两个群体对化疗诱导的细胞毒性敏感性的差异。我们的长期目标是建立一个无偏倚的全基因组模型，以识别生殖系遗传变异，mRNA或miRNA表达，包括那些在服务不足的人群中，预测化疗不良反应和无反应的风险。我们的假设是存在一组与miRNA表达相关的种系药物遗传多态性，这些多态性影响化疗诱导的细胞毒性，并且这些多态性表现出种族间的差异。我们的具体目标是：1)量化HapMap淋巴母细胞样细胞系（LCLs）中全基因组miRNA的表达，并鉴定与miRNA表达和化疗诱导的细胞毒性相关的snp；2)鉴定与化疗敏感性显著相关的mRNA和miRNA表达特征，比较不同民族人群中miRNA表达的化疗敏感性特征；3)在其他lcl中重复我们的发现。公共卫生相关性：本提案旨在更好地了解遗传变异如何影响个体对化疗的敏感性。长期目标是利用患者的基因组成来识别那些有化疗相关毒性风险的患者，以减少他们发生不良事件的机会。

DESCRIPTION (provided by applicant): Most chemotherapeutic drugs affect both tumor and normal cells, are ineffective in a number of patients, and exhibit serious toxicity; hence developing predictive models that identify patients at risk for adverse reactions and/or non-response to chemotherapeutic agents prior to treatment is essential. An objective of this proposal is to take a concerted translational effort to elucidate the underlying cause for the inter-ethnic differences in sensitivity to chemotherapy. In this proposal, we will focus on two classes of cytotoxic agents: platinating agents (cisplatin and carboplatin) and antimetabolites (capecitabine and Ara-C), of which significant inter-ethnic differences in cellular sensitivity have been observed in vitro. Our hypothesis is that there are microRNA (miRNA) expression differences in individuals of African descent compared to individuals of European descent that contribute, at least in part, to the difference in sensitivity to chemotherapy-induced cytotoxicity in these two populations. Our long-term goal is to develop an unbiased genome-wide model to identify germline genetic variants, mRNA or miRNA expression including those in an underserved population, that predict risk for adverse reactions and non-response to chemotherapy. Our hypothesis is that there is a set of germline pharmacogenetic polymorphisms associated with the expression of miRNA that affect chemotherapy-induced cytotoxicity and these polymorphisms exhibit interethnic differences. Our specific aims are 1) To quantify genome-wide miRNA expression in HapMap lymphoblastoid cell lines (LCLs) and to identify SNPs associated with miRNA expression and chemotherapy-induced cytotoxicity; 2) To identify mRNA and miRNA expression signatures that significantly correlate with chemotherapy sensitivity and to compare the miRNA expression chemotherapeutic sensitivity signatures in different ethnic populations; 3) To replicate our findings in additional LCLs. PUBLIC HEALTH RELEVANCE: This proposal is intended to better understand how genetic variation contributes to individual sensitivity to chemotherapy. The long term goal is to identify patients, using their genetic make up, that are at risk for toxicities associated with chemotherapy with the intent to reduce their chances of an adverse event.