(PQ3) Integrative biomarkers of cancer progression and therapeutic response from germline and somatic clinical sequencing

项目摘要/摘要 在过去的十年里，肿瘤学已经成为临床基因组学应用于 疾病的诊断和治疗。用于临床评估的高通量技术的可用性， 再加上对促进肿瘤生长和进展的基因组异常的新兴知识 肿瘤，使癌症医学发生了革命性的变化。2014年，我们发起了一项预期的临床测序计划，以 检测341个(现为468个)肿瘤相关基因，并与来自非霍奇金淋巴瘤患者的正常标本配对。 晚期癌症，这一队列现在超过了25,000人。我们已经使用这些数据来识别和报告体细胞 突变以便于登记到基因组匹配的临床试验和致病种系等位基因以揭示 家族性癌症易感性。然而，我们缺乏对生殖系在多大程度上 突变促进体细胞突变并与之相互作用，从而影响癌症的进展和对治疗的反应。 整合生殖系和体细胞分析以进一步告知预后仍是一个变革性的机会 和治疗决定。此外，可以利用体细胞突变模式和特征来发现 具有生物学和临床意义的新的生殖系等位基因。在这里，我们建议建立在我们独特的 预期的临床测序计划，以获得生殖系和体细胞变化的全面图像 相互作用，影响癌症的发生、发展和治疗反应。建立在广泛的初步基础上 数据，我们将通过3个具体目标来实现这一目标：(1)建立生殖系风险等位基因的流行率和 肿瘤间体细胞突变的相关模式；(2)建立完整的种系-体细胞临床 肿瘤进展的生物标志物和对DNA修复剂的反应；(3)发现新的候选致病因子 具有生物学意义和临床意义的等位基因。在这笔赠款的时间范围内，我们将对肿瘤正常进行排序 来自70,000名正在积极治疗的患者的配对，提供了一个前所未有的机会来识别和 严格评估种系-体细胞相互作用及其与临床实践的相关性。我们将利用 通过我们现有的临床测序计划收集的丰富的基因组和临床数据集，以识别 致病种系变异、肿瘤特异性合子变化和体细胞突变的共生模式 在所有实体肿瘤类型中。通过将临床注释、家族史和结果数据与变更相结合 在每个患者中确定，我们将确定新的功能等位基因和临床上有意义的疾病生物标记物- 具体结果和治疗反应。我们在这里学到的经验教训将有助于新的临床指南和 癌症患者的诊断方法，并建立发现和临床验证的最佳实践 生殖系和体细胞遗传学交汇处的预测和预测生物标记物。

PROJECT SUMMARY/ABSTRACT Over the last decade, oncology has served as a paragon for the application of clinical genomics towards the diagnosis and treatment of disease. The availability of high-throughput technologies for clinical assessment, coupled with emerging knowledge of the genomic aberrations that promote the growth and progression of tumors, has revolutionized cancer medicine. In 2014, we initiated a prospective clinical sequencing initiative to examine 341 (now 468) cancer associated genes in tumor and matched normal specimens from patients with advanced cancer, a cohort which now exceeds 25,000. We have used these data to identify and report somatic mutations to facilitate enrollment to genomically matched clinical trials and pathogenic germline alleles to reveal familial cancer susceptibility. Yet, we lack a fundamental understanding regarding the extent to which germline alterations promote and interact with somatic mutations to affect cancer progression and response to therapy. There remains a transformative opportunity to integrate germline and somatic analysis to further inform prognosis and treatment decisions. Moreover, somatic mutational patterns and signatures can be harnessed to discover novel germline alleles of biological and clinical significance. Here, we propose to build upon our unique prospective clinical sequencing initiative to gain a comprehensive picture of how germline and somatic alterations interact to influence cancer initiation, progression and therapeutic response. Building upon extensive Preliminary Data, we will pursue this goal through 3 specific aims: (1) establish the prevalence of germline risk alleles and associated patterns of somatic mutations across cancers; (2) establish integrated germline-somatic clinical biomarkers of tumor progression and response to DNA repair agents; (3) discover novel candidate pathogenic alleles of biological and clinical significance. Within the timeframe of this grant, we will sequence tumor-normal pairs from >70,000 patients under active treatment, providing an unprecedented opportunity to identify and rigorously evaluate germline-somatic interactions and their relevance to clinical practice. We will leverage the rich genomic and clinical data set collected through our existing clinical sequencing initiative to identify pathogenic germline variants, tumor-specific zygosity changes, and co-occurring patterns of somatic mutations in all solid tumor types. By integrating clinical annotations, family history and outcome data with the alterations identified in each patient, we will identify novel functional alleles and clinically significant biomarkers of disease- specific outcomes and therapeutic response. The lessons we learn here will facilitate new clinical guidelines and diagnostic approaches for cancer patients and establish best practices for discovering and clinically validating prognostic and predictive biomarkers at the intersection of germline and somatic genetics.