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Genetics of Common Cancers: Discovery to Implementation

常见癌症的遗传学：发现到实施

基本信息

批准号：
10676955
负责人：
Rosalie Griffin
金额：
$ 10.23万
依托单位：
MAYO CLINIC ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-10 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10676955
关键词：
Academy Address Adoption Area Automobile Driving Award BRAF gene BRCA1 gene BRCA2 gene Clinic Clinical Clinical Data Collection Communication Complex Data Disease Disparity Documentation Early Diagnosis Engineering Epidermal Growth Factor Receptor Evidence based practice Exhibits Family Family health status Feasibility Studies Genetic Genetic Heterogeneity Genetic Services Genomic medicine Genomics Goals Health Heritability Heterogeneity Individual Investigation Malignant Neoplasms Malignant neoplasm of lung Maps Medicine Methods Modeling Molecular Molecular Profiling Multiple Myeloma Mutation Oncogenes Outcome Patients Phase Phenotype Population Positioning Attribute Postdoctoral Fellow Preparation Preventive care Primary Care Prognosis Publications Recommendation Recording of previous events Reporting Research Research Personnel Research Project Grants Research Technics Risk Risk Assessment Screening for cancer Signal Transduction Solid Somatic Mutation Subgroup Training Translating Variant Work bridge program cancer care cancer genetics cancer genomics cancer prevention cancer risk cancer therapy career clinical implementation clinical practice combat evidence based guidelines experience gene discovery genetic information genetic pedigree genetic testing genome sciences genome wide association study high risk high risk population implementation science implementation study improved individualized medicine melanoma model organism novel personalized care post-doctoral training pre-doctoral primary care provider primary care setting rare variant risk variant screening screening guidelines segregation skills translational genomics treatment response tumor tumor heterogeneity user centered design

项目摘要

My ultimate goal is to become an independent cancer researcher with a program that bridges genetic discovery and implementation science for common and complex cancers. My predoctoral training in genomic discovery and my postdoctoral direction in implementation science will build solid ‘research pillars’ to support my independent research program bridging translational genomic science. My F99 training will provide expertise in genomic discovery by tackling critical barriers that exist for common and complex cancers, including: germline genetic and tumor heterogeneity, and mapping functional variants for genomewide association studies (GWAS) loci. Cancers are phenotypically complex, with multiple germline risk variants and tumors that exhibit different molecular profiles. These heterogeneities complicate studies attempting to identify factors influencing risk, prognosis, and response to therapies or other clinical outcomes. GWASs have identified many significant, common, low-risk loci, but the functional variants driving GWAS signals are largely unmapped. Further, the vast majority of heritability is unexplained, and rare variants are largely undiscovered. In my recent first-author publication, I propose a novel method to address germline genetic heterogeneity in high-risk pedigree studies. I applied this method to myeloma to discover the first, segregating risk variants for the disease (Waller et al, PLoS Genetics, 2018). I have subsequently expanded the approach to identify overlapping evidence from multiple pedigrees, uncovering additional regions likely to harbor rare-risk variants (Waller et al, in preparation). I have also investigated strategies to utilize family-based data to map functional variants at GWAS loci (Waller et al, in preparation). During the F99 phase, I will complete my graduate work in discovery with novel methods to improve molecular characterization of myeloma tumors, another strategy to combat heterogeneity. My F99 training will also prepare me for my postdoctoral direction in implementation science by tackling barriers to the use of family- health history (FHx) in primary care. Genetic discoveries are rapidly advancing, but personalizing clinical screenings and implementing complex, patient-specific risk assessments is challenging in today’s overwhelmed primary care settings. FHx is still the most valuable piece of information a clinician and patient have to identify potential health risks and personalize care. However, FHx remains largely underutilized in routine cancer prevention due to low collection and low adoption of evidence-based guidelines. In my F99, I will investigate the impact of FHx documentation workflows on compliance with cancer screening guidelines. For my postdoctoral work (K00 phase), I will identify research and training experiences to build expertise in implementation science for genomic medicine. Specifically, one research project I could pursue is a feasibility study of implementing proven risk communication approaches in the primary care setting. My background in genomic discovery for common cancers will allow me to bring an understanding of genomics to my implementation science work, and will uniquely position me to bring more complex findings to the clinic when the field is ready.

我的最终目标是成为一名独立的癌症研究人员，以及针对常见和复杂癌症的实施科学。我在基因组发现方面的博士前训练我在实施科学的博士后方向将建立坚实的“研究支柱”，以支持我的独立的研究计划，连接翻译基因组科学。我的F99培训将提供以下方面的专业知识通过解决常见和复杂癌症存在的关键障碍进行基因组发现，包括：遗传和肿瘤异质性，以及全基因组关联研究（GWAS）的功能变异作图的位点癌症是表型复杂的，具有多种生殖系风险变体，并且肿瘤表现出不同的分子图谱这些异质性使试图确定影响风险的因素的研究复杂化，预后和对治疗或其他临床结果的反应。GWAS已经确定了许多重要的，常见的，低风险的基因座，但驱动GWAS信号的功能变异在很大程度上是未映射的。此外，广大大多数遗传性是无法解释的，罕见的变异在很大程度上未被发现。在我最近的第一作者发表，我提出了一种新的方法来解决生殖系遗传异质性的高风险谱系研究。我我将该方法应用于骨髓瘤以发现该疾病的第一个分离风险变体（Waller等人，PLoS Genetics，2018）。随后，我扩大了方法，以确定重叠的证据，从多个家系，发现可能含有罕见风险变异的其他区域（Waller et al，in preparation）。我有还研究了利用基于家族的数据来定位GWAS基因座处的功能变体的策略（Waller等人，in 制备）。在F99阶段，我将完成我的研究生发现工作，用新的方法来改进骨髓瘤肿瘤的分子特征，另一种对抗异质性的策略。我的F99训练将我也准备我的博士后方向在实施科学通过解决障碍，使用家庭- 健康史（FHx）在初级保健。基因发现正在迅速发展，但个性化的临床筛查和实施复杂的，患者特定的风险评估是具有挑战性的，在今天的不堪重负初级保健机构。FHx仍然是临床医生和患者必须识别的最有价值的信息潜在的健康风险和个性化护理。然而，FHx在常规癌症中的利用率仍然很低由于收集和采用循证指南的程度低，预防工作受到影响。在我的F99中，我将调查 FHx文档工作流程对癌症筛查指南依从性的影响。为了我的博士后工作（K 00阶段），我将确定研究和培训经验，以建立实施科学的专业知识基因组医学具体来说，我可以从事的一个研究项目是实施的可行性研究。在初级保健环境中行之有效的风险沟通方法。我的基因组发现背景常见的癌症会让我把对基因组学的理解带到我的实施科学中，工作，并将独特的位置，我带来更复杂的发现，临床时，该领域准备就绪。