Genetics of Common Cancers: Discovery to Implementation

我的最终目标是成为一名独立的癌症研究人员，拥有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训练 我在实现科学方面的博士后方向将建立坚实的“研究支柱”来支持我的 连接翻译基因组科学的独立研究计划。我的F99培训将在以下方面提供专业知识 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：生殖系 遗传和肿瘤的异质性，以及全基因组关联研究的功能变异图谱(GWAS) 精神错乱。癌症的表型很复杂，有多种生殖系风险变异，肿瘤表现不同 分子图谱。这些异质性使试图确定影响风险的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、低风险的基因座，但驱动Gwas信号的功能变异在很大程度上尚未被定位。此外，广大的 大多数遗传性是无法解释的，罕见的变异很大程度上是未被发现的。在我最近的第一作者中 发表后，我提出了一种新的方法来解决高危家系研究中的种系遗传异质性问题。我 将这种方法应用于骨髓瘤，发现了该疾病的第一个分离风险变异(Waller等人，PLoS 遗传学，2018年)。我随后扩展了这种方法，以从多个 家谱，发现可能存在罕见风险变异的其他区域(Waller等人，正在准备中)。我有过 还研究了利用基于家族的数据来定位Gwas基因座功能变异的策略(Waller等人，在 准备)。在F99阶段，我将完成我在发现方面的毕业工作，用新的方法来改进 骨髓瘤肿瘤的分子特征，对抗异质性的另一种策略。我的F99训练将会 通过克服使用家庭的障碍，为我在实施科学方面的博士后方向做好准备- 初级保健的健康史(FHx)。基因发现进展迅速，但使临床个性化 在当今不堪重负的情况下，筛选和实施复杂的、针对患者的风险评估是具有挑战性的 初级保健设置。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在常规癌症中仍然很大程度上没有得到充分利用 由于收集较少和采用循证指南较少而导致的预防。在我的F99中，我将调查 FHx文件工作流程对遵守癌症筛查指南的影响。为了我的博士后 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 用于基因医学。具体地说，我可以从事的一个研究项目是实施 初级保健环境中经过验证的风险沟通方法。我在基因组发现方面的背景 常见的癌症将使我将对基因组学的理解带入我的实施科学 工作，并将独特地定位我带来更复杂的发现，当现场准备好了临床。

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.