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

描述（由申请人提供）：总体目标：在症状科学的一个重要领域：化疗诱导的周围神经病变（CIPN）中，确定与患者报告结局（PRO）相关的基因和途径或机制。背景：CIPN是癌症治疗中最重要的未缓解毒性。随着生存率的增长，CIPN的发病率继续上升。每年有40万例新病例，每年增加23亿美元的医疗费用。我们和其他人的研究已经将CIPN易感性与几个基因中的单核苷酸变异（SNV）相关联，表明CIPN是一种复杂的遗传性状。初步数据：通过不良PRO进行的CIPN表型分析提供的统计功效相当于将患者数量增加5.1倍（与先前设计相比）。在一项全基因测序（WES）研究中，我们发现CIPN与遗传性神经病共有的常见SNV和罕见有害基因突变相关。通过一个考试范围内的分析，我们确定了髓鞘形成途径作为一个分子机制，通过遗传变异与CIPN。假设：罕见和常见的遗传变异有助于CIPN PRO的遗传基础。统计功效考虑因素指导该方法。WES在小型队列中有成功实施的记录，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）。我们对CIPN的首次WES研究也很小，n=119，但通过优先考虑生物学信息假设和测试每个基因/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增加功效;它还将我们的研究扩展到另一类引起CIPN的化疗药物。目标1。在奥沙利铂试验N 08 CB中，在180例具有极端CIPN PRO表型的患者中通过WES确定罕见编码突变和常见SNV;检测HN基因与罕见突变或常见SNV导致的CIPN的相关性;确定与奥沙利铂-CIPN相关的分子机制/遗传途径。这一目标将应用我们的紫杉醇WES研究（初步数据）的方法到一个新的药物类别（铂）。目标二。测试CIPN候选基因的调控（非编码）区的基因组变异增加是否与PRO表型相关。这一目标将应用一种新的方法，全基因组测序（WGS），对我们以前用WES分析的患者进行分析。目标3。分析候选基因提名，因为一个角色的生活质量无关的外周神经系统（PNS）生物学：前脑和免疫系统机制。目标4。通过在具有连续CIPN表型分型的两个独立群组中对新设计的CIPN定制基因组进行测序（n=400紫杉醇，n=400奥沙利铂），获得来自目的1和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症状的个体易感性，从而对FOA做出响应，该技术将使用基于序列PRO的创新方法进行量化。将整合由具有编码和调控功能的罕见和常见生殖系遗传变异组成的各种信息。

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.