Cell-of-Origin Footprints of Passenger Mutations in Human Lung Cancer

项目概要/摘要 癌症起源的正常细胞（COO）是我们对癌症的基本概念的基础 发展首席运营官是造血系统癌症护理标准的核心， 预后和指导治疗。然而，COO未被纳入治疗肺结核的临床范例中。 腺癌是一种上皮癌，是全世界癌症死亡的主要原因之一。主要 这是因为我们仍然不知道大多数肺腺癌的COO，或者COO是否不同， 从病人到病人。解决这一问题的一个主要科学障碍是对 肺细胞类型和一般的上皮类型。第二个障碍是发生在肺移植期间的血统不忠。 癌症进展，当我们从形态学上分析肿瘤时， 转录。因此，该领域必须依赖于基因工程小鼠模型， 其在完全概括人肺的基因型和临床特征的能力方面仍然有限 腺癌我们和该领域其他人最近的工作表明， 乘客突变可以提供患者特异性COO信号。然而，这一假设尚未得到检验 严格地用于肺癌或其他恶性肿瘤。在这项研究中，我们调查乘客突变如何 肺癌的发病机制特别是非编码表面活性蛋白基因（SPG） 插入和缺失，我们最近的研究（Cell 2017）和初步数据确定为 肺腺癌中最常见的突变事件（30-40%的患者）。在这项研究中，我们假设 这种神秘但非常普遍的突变模式是肺泡II型（AT 2）的体细胞遗传“纹身”， SPG突变型肺腺癌的细胞起源。我们将通过肿瘤的深度剖析来研究这一点， 使用靶向和单细胞测序的邻近组织。此外，我们将研究SPG突变体是否 肺腺癌与不同的进化轨迹有关，就其突变而言， 转录和组织学状态。最后，我们将在初步研究的基础上， 肺癌中体细胞单核苷酸变异（SNVs）的基因组分布与细胞类型之间的联系 从良性肺的单细胞RNA测序获得的特异性基因表达谱。这些初步 数据表明，一些肺腺癌可能具有近端（俱乐部或基底细胞）而不是远端（AT 2 细胞）起源。我们将在初步研究结果的基础上，生成和分析健康肺部的更高深度的图谱 并将细胞类型特异性转录和开放染色质谱的模式与基因组 体细胞SNV的分布。这项工作将提供一些第一个直接证据来绘制人类肺部 腺癌到特定COO。此外，我们建立了乘客之间的严格联系， 肺癌中的突变模式和COO可能对其他癌症中的COO研究具有更广泛的适用性。 流行且致命的人类上皮癌。

Project summary / abstract The normal cell of origin (COO) from which a cancer arises is fundamental to our basic notions of cancer development. COOs are central to the standard of care for hematopoietic cancers, where they inform prognosis and guide therapy. However, COOs are not incorporated into the clinical paradigms for treating lung adenocarcinomas, an epithelial cancer that is among the leading causes of cancer death worldwide. The major reason for this is that we still don’t know the COO for most lung adenocarcinomas or whether the COO varies from patient to patient. One major scientific obstacle to addressing this question is the limited understanding of lung cell types, and epithelial types in general. A second obstacle is lineage infidelity that occurs during lung cancer progression, which can obscure the COO when one analyzes tumors morphologically or transcriptionally. As a result, the field has been required to rely on genetically engineered mouse models, which are still limited in their ability to fully recapitulate genotypes and clinical features of human lung adenocarcinomas. Recent work by us and others in the field has shown that genome-wide patterns of passenger mutations can provide a patient-specific COO signal. However, this hypothesis has not been tested rigorously for lung cancer or for other malignancies. In this study, we investigate how passenger mutation patterns inform COOs in lung cancer. In particular, we focus on noncoding surfactant protein gene (SPG) insertions and deletions, which our recent study (Cell 2017) and preliminary data establishes as one of the most common mutational events in lung adenocarcinoma (30-40% of patients). In this study, we hypothesize that this mysterious but highly prevalent mutational pattern is a somatic genetic “tattoo” of alveolar type II (AT2) cell origin in SPG mutant lung adenocarcinomas. We will investigate this through deep profiling of tumor adjacent tissue using targeted and single cell sequencing. In addition, we will investigate whether SPG mutant lung adenocarcinomas are associated with distinct evolutionary trajectories, with respect to their mutational, transcriptional, and histological state. Finally, we will build on our preliminary studies that establish compelling links between genome distributions of somatic single nucleotide variants (SNVs) in lung cancer and cell-type specific gene expression profiles obtained from single-cell RNA sequencing of benign lung. These preliminary data indicate that some lung adenocarcinomas may have proximal (club or basal cell) rather than distal (AT2 cell) origins. We will build on our initial findings, to generate and analyze higher depth atlases of healthy lung and correlate the patterns of cell type specific transcriptional and open chromatin profiles with genomic distributions of somatic SNVs. This work will provide some of the first direct evidence to map human lung adenocarcinoma to specific COOs. Furthermore, our establishment of rigorous links between passenger mutational patterns and COO in lung cancer may have broader applicability to the study of COOs in other prevalent and deadly human epithelial cancers.