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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：
10474629
负责人：
Rosalie Griffin
金额：
$ 9.98万
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/10474629
关键词：
Academy Address Adoption Animal Model Area Automobile Driving Award BRAF gene BRCA1 gene BRCA2 gene Clinic Clinical Clinical Data Collection Communication Complex Data Disease Documentation Early Diagnosis Epidermal Growth Factor Receptor Evidence based practice Exhibits Family Family health status Feasibility Studies Genetic Genetic Heterogeneity Genetic Models 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 Preparation Preventive care Primary Health Care Prognosis Publications Recommendation Recording of previous events Reporting Research Research Design Research Personnel Research Project Grants Research Technics Research Training Risk Risk Assessment Screening for cancer Signal Transduction Solid Somatic Mutation Subgroup Training Translating Variant Work base bridge program cancer care cancer genetics cancer genomics cancer prevention cancer risk cancer therapy care providers career clinical implementation clinical practice combat engineering design evidence based guidelines experience gene discovery genetic information genetic pedigree genetic testing genome sciences genome wide association study high risk implementation science implementation study improved individualized medicine melanoma novel personalized care post-doctoral training pre-doctoral primary care setting rare variant risk variant screening screening guidelines 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员，并开展一个连接基因发现的项目以及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培训我在实施科学方面的博士后方向将建立坚实的“研究支柱”来支持我连接转化基因组科学的独立研究计划。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来发现基因组，包括：遗传和肿瘤异质性，以及绘制全基因组关联研究 (GWAS) 的功能变异基因座。癌症表型复杂，具有多种种系风险变异和表现出不同的肿瘤分子概况。这些异质性使试图确定影响风险因素的研究变得复杂，预后以及对治疗或其他临床结果的反应。 GWAS 已经确定了许多重要的、常见的低风险位点，但驱动 GWAS 信号的功能变异在很大程度上尚未定位。此外，广阔的大多数遗传性是无法解释的，罕见的变异基本上未被发现。在我最近的第一作者中在这篇文章中，我提出了一种解决高风险谱系研究中种系遗传异质性的新方法。我将这种方法应用于骨髓瘤，发现了第一个分离该疾病的风险变异（Waller 等人，PLoS 遗传学，2018）。随后，我扩展了该方法，以识别多个重叠证据谱系，发现可能含有罕见风险变异的其他区域（Waller 等人，正在准备中）。我有还研究了利用基于家族的数据来绘制 GWAS 位点功能变异的策略（Waller 等人，in 准备）。在F99阶段，我将完成我的研究生工作，用新颖的方法来改进发现骨髓瘤肿瘤的分子特征，这是对抗异质性的另一种策略。我的 F99 训练将还通过解决使用家庭的障碍，为我在实施科学方面的博士后方向做好准备初级保健中的健康史（FHx）。基因发现正在迅速推进，但个性化临床在当今不堪重负的情况下，筛查和实施复杂的、针对患者的风险评估具有挑战性初级保健机构。 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 在常规癌症中仍未得到充分利用由于循证指南的收集和采用较少而导致预防。在我的 F99 中，我将调查 FHx 文档工作流程对遵守癌症筛查指南的影响。对于我的博士后工作（K00 阶段），我将确定研究和培训经验，以建立实施科学方面的专业知识用于基因组医学。具体来说，我可以开展的一个研究项目是实施的可行性研究初级保健环境中经过验证的风险沟通方法。我的基因组发现背景常见癌症将使我能够将基因组学的理解带入我的实施科学中工作，并且将使我处于独特的地位，以便在该领域准备就绪时将更复杂的发现带到诊所。