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

项目总结/摘要 在过去的十年中，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， 再加上新出现的基因组畸变的知识，促进生长和进展， 彻底改变了癌症医学。2014年，我们启动了一项前瞻性临床测序计划， 检测了341个（现在是468个）肿瘤和匹配的正常标本中的癌症相关基因， 晚期癌症，这个群体现在超过25，000人。我们已经使用这些数据来识别和报告体细胞 突变，以促进招募到基因组匹配的临床试验和致病性种系等位基因，以揭示 家族性癌症易感性然而，我们对生殖细胞在多大程度上 改变促进体细胞突变并与体细胞突变相互作用，以影响癌症进展和对治疗的反应。 仍然有一个变革的机会，整合生殖系和体细胞分析，以进一步告知预后 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 前瞻性临床测序计划，以全面了解生殖系和体细胞改变 相互作用以影响癌症的发生、发展和治疗反应。建立在广泛的初步 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患病率， 癌症间体细胞突变的相关模式;（2）建立整合的生殖系-体细胞临床 肿瘤进展和对DNA修复剂的反应的生物标志物;（3）发现新的候选致病性 具有生物学和临床意义的等位基因。在此资助的时间范围内，我们将测序肿瘤正常 来自70，000多名积极治疗的患者，提供了前所未有的机会， 严格评估生殖细胞-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， 致病性生殖系变异、肿瘤特异性接合性改变和体细胞突变的共现模式 所有实体瘤类型。通过整合临床注释、家族史和结果数据， 在每个患者中识别，我们将识别新的功能等位基因和临床上重要的疾病生物标志物- 具体结果和治疗反应。我们在这里学到的经验教训将促进新的临床指南， 癌症患者的诊断方法，并建立发现和临床验证的最佳实践 在生殖系和体细胞遗传学的交叉点的预后和预测生物标志物。

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.