Synergizing genome sequencing with advances in patient reprted outcomes (PRO)

描述(由申请人提供)：总体目标：确定与患者报告结果(PRO)相关的基因和途径或机制，这是症状科学的一个重要领域：化疗引起的周围神经病变(CIPN)。背景：CIPN是癌症治疗中最重要的未减轻的毒性。随着存活人数的增加，CIPN的发病率继续上升。每年新增病例40万例，每年增加23亿美元的医疗成本。我们和其他人的研究表明，CIPN的易感性与几个基因的单核苷酸变异(SNV)有关，这表明CIPN是一个复杂的遗传特征。初步数据：由ADVICAL PRO进行的CIPN表型分析提供了相当于将患者数量增加5.1倍的统计能力。在一项完整的考试测序(WES)研究中，我们发现CIPN与常见的SNV和遗传性神经疾病共有的基因中罕见的有害突变有关。通过检查范围的分析，我们确定髓鞘形成途径是通过遗传变异与CIPN相关联的分子机制。假设：罕见和常见的遗传变异是CIPN PRO的遗传基础。统计能力方面的考虑将指导这一方法。WES有在小队列中成功实施的记录，如NHLBI急性肺损伤WES(n=88)和NHLBI慢性铜绿假单胞菌感染WES(n=91)。我们关于CIPN的首个WES研究也很小，n=119，但通过优先考虑生物信息假说和测试每个基因/途径，提供了具有研究范围意义的结果。该提案旨在通过更大的队列进一步提高疗效；它还将我们的研究扩展到另一类导致CIPN的化疗药物。目的：1.在奥沙利铂试验N08CB中，用WES检测180例极端CIPN前表型患者的罕见编码突变和常见SNV；检测HN基因罕见突变或常见SNV与CIPN的相关性；确定与奥沙利铂-CIPN相关的分子机制/途径。这一目标将把我们紫杉醇WES研究(初步数据)中的方法应用于一种新的药物类别(白金)。目的2.检测CIPN候选基因调控(非编码区)的基因组变异增加是否与前表型相关。这一目标将把一种新的方法--全基因组测序(WGS)应用于我们以前用WES分析的患者。目的3.分析与外周神经系统(PNS)生物学无关的生活质量相关候选基因：前脑和免疫系统机制。目的4.通过对新设计的CIPN定制基因表型(紫杉醇400例，奥沙利铂400例)在两个独立队列中的测序，验证AIMS 1和AIMS 2的关键结果。对FOA 13-264的响应性：该提案通过使用WES和WGS作为新兴技术来预测患者对CIPN症状的个人易感性，以基于序列PRO的创新方法来量化FOA。由具有编码和调节功能的稀有和常见的生殖系遗传变异组成的各种信息将被整合。

DESCRIPTION (provided by applicant): Overall Goal: To identify genes and pathways or mechanisms associated with patient reported outcomes (PRO) in an important area of symptom science: chemotherapy induced peripheral neuropathy (CIPN). Background: CIPN is the most important unmitigated toxicity of cancer treatments. As survivorship ranks grow, CIPN incidence continues to rise. 400,000 new cases occur yearly adding annual healthcare costs of $2.3 billion. Studies by us and others have associated CIPN susceptibility with single nucleotide variants (SNV) in several genes suggesting that CIPN is a complex genetic trait. Preliminary Data: CIPN phenotyping by adverse PRO provided statistical power equivalent to increasing the patient number (compared with prior designs) 5.1-fold. In a whole exam sequencing (WES) study we found that CIPN was associated with common SNV and rare deleterious mutations in genes shared with hereditary neuropathies. Through an exam-wide analysis, we identified the myelination pathway as a molecular mechanism linked to CIPN through genetic variants. Hypothesis: Rare and common genetic variants contribute to the hereditary basis of CIPN PRO. Statistical power considerations guide the Approach. WES has a record of successful implementation in small cohorts such as the NHLBI acute lung injury WES (n=88) and the NHLBI chronic P. aeruginosa infection WES (n=91). Our inaugural WES study on CIPN was also small, n=119, yet provided results with study-wide significance by prioritizing biologically informed hypotheses and by testing per-gene/pathway. The proposal aims to increase power further by larger cohorts; it also extends our studies to another class of chemotherapy drugs causing CIPN. Aim 1. Determine rare coding mutations and common SNV by WES in 180 patients with extreme CIPN PRO phenotypes in the oxaliplatin trial N08CB; test HN genes for an association with CIPN due to rare mutations or common SNV; identify molecular mechanisms/pathways genetically associated with oxaliplatin-CIPN. This aim will apply the methods from our paclitaxel WES study (preliminary data) to a new drug class (platinum's). Aim 2. Test if increased genomic variation in regulatory (non-coding) regions of CIPN candidate genes is associated with the PRO phenotype. This aim will apply a new method, whole genome sequencing (WGS), to patients previously analyzed by us with WES. Aim 3. Analyze candidate genes nominated because of a role for QOL unrelated to peripheral nervous system (PNS) biology: forebrain- and immune system mechanisms. Aim 4. Validate key results from Aims 1 and 2 by sequencing a newly designed CIPN custom gene panel in two independent cohorts with serial CIPN phenotyping (n=400 paclitaxel, n=400 oxaliplatin). Responsiveness to FOA 13-264: The proposal responds to the FOA by using WES and WGS as emerging technologies to predict individual susceptibility of patients to CIPN symptoms, which will be quantified with innovative methods based on serial PRO. Diverse information consisting of rare and common germ line genetic variants with coding and regulatory functions will be integrated.