GENOMIC HARBINGERS OF BRAIN METASTASIS IN NON SMALL CELL LUNG CANCER

描述(申请人提供)：尽管系统治疗取得了进步，脑转移仍然是非小细胞肺癌(NSCLC)患者死亡的一个重要原因。近50%的非小细胞肺癌患者在病程中会发生脑转移。尽管许多与实体瘤转移相关的生物学途径和过程已经被定义，但这些进展仍然没有导致用于预测原发非小细胞肺癌转移行为的强有力的生物标记物。我们假设原代NSCLC肿瘤细胞亚群通过基因组和表观基因组改变的多步骤过程进化，从而导致转移细胞表型。虽然最终的功能结果可能是相同的，但患者之间甚至同一患者的肿瘤细胞之间发生的确切变化可能是非常不同的，从而解释了为什么单基因生物标记物或相关基因表达特征在所有情况下都不能充分预测。在这项计划中，我们计划利用‘下一代’测序(NGS)技术同时进行外显子组和RNA测序，对患者匹配的原发非小细胞肺癌和脑转移瘤细胞群体的基因组进行全面而重点的比较分析。精心挑选的大约75名腺癌患者将被用作发现集，其中将包括配对的原发肿瘤和脑转移病例，以及配对的原发肿瘤和晚期淋巴转移病例，以供比较。我们将确定基因组和基因表达的变化，这些变化在转移性肿瘤细胞群中丰富，并在患者中复发。我们不是专注于单个基因，而是识别已知有助于转移表型的途径的关键基因组调节因子中的协同和互补变化。对于在第一个目标中发现的基因组和基因表达变化，我们将构建一个基于风险的模型，该模型将在一个独立的回溯性队列中进行验证，该模型将使用有针对性的深度测序，该队列来自300名来自有或没有最终发生脑转移的患者的原发NSCLC腺癌。这项建议将利用相对较大和精细化的患者队列来研究NSCLC(脑转移)的特定和临床相关的表型，并将应用一种创新的、基于生物学的风险模型方法来确定一组更强大的生物标记物来预测NSCLC患者的脑转移行为。这种预测器的可用将允许对非小细胞肺癌患者进行更个性化的治疗，并最终降低与治疗和疾病进展相关的发病率和死亡率。

DESCRIPTION (provided by applicant): Despite advances in systemic therapy, brain metastases remain a significant cause of mortality in non-small cell lung cancer (NSCLC) patients. Nearly 50% of patients with NSCLC will develop brain metastases during the course of their disease. Although many of the biological pathways and processes associated with solid tumor metastasis have been defined, these advances have still not led to robust biomarkers for predicting metastatic behavior in primary NSCLC. We hypothesize that subpopulations of primary NSCLC tumor cells evolve through a multistep process of genomic and epigenomic alterations that result in a metastatic cell phenotype. While the end functional consequence may be the same, the exact alterations that occur between patients and perhaps even between tumor cells in the same patient are likely to be highly varied, thus explaining why single gene biomarkers or correlative gene expression signatures are not sufficiently predictive in all cases. In this proposal, we plan to leverage 'next generation' sequencing (NGS) technologies for simultaneous exome and RNA sequencing to perform a comprehensive yet focused comparative analysis of the genomes of patient-matched primary NSCLC and brain metastatic tumor cell populations. A judiciously selected population of approximately 75 patients with adenocarcinoma will be used for a discovery set and will include paired primary tumor and brain metastasis cases as well as paired primary tumor and late stage lymph node metastasis cases for comparative purposes. We will identify both genomic and gene expression alterations that are enriched in metastatic tumor cell populations and recurrent across patients. Rather than focusing on individual genes, we will identify both synergistic and complementary alterations in key genomic regulators of pathways known to contribute to the metastatic phenotype. For those genomic and gene expression alterations identified in this first aim, we will construct a risk-based model that will be validated using targeted, 'deep' sequencing in an independent, retrospective cohort of 300 primary NSCLC adenocarcinomas from patients with and without the eventual development of brain metastases. This proposal will utilize both a relatively large and refined cohort of patients to study a specific and clinically relevant phenotype in NSCLC (brain metastasis) and will apply an innovative, biologically based risk model approach to identify a more robust set of biomarkers to predict brain metastatic behavior in NSCLC patients. The availability of such a predictor will allow for more personalized therapies for NSCLC patients and ultimately reduce the morbidity and mortality associated with treatment and disease progression.