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

人类肺癌中乘客突变的细胞起源足迹

• 批准号: 10299387
• 负责人: Marcin Imielinski
• 金额: $ 55.6万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-23 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10299387
• 关键词: ATAC-seq; Address; Affect; Alleles; Alveolar; Atlases; Basal Cell; Benign; Cancer Biology; Cancer Etiology; Carcinoma; Cells; Cessation of life; Chromatin; Classification; Clinical; DNA sequencing; Data; Development; Disease model; Disseminated Malignant Neoplasm; Distal; Epigenetic Process; Epithelial; Event; Gene Expression; Gene Proteins; Genetic; Genetic Transcription; Genetically Engineered Mouse; Genome; Genomics; Genotype; Goblet Cells; Gold; Hematologic Neoplasms; Hematopoietic Neoplasms; Histologic; Histology; Human; Individual; Knowledge; Link; Lung; Lung Adenocarcinoma; Malignant Neoplasms; Malignant neoplasm of lung; Maps; Mediating; Modeling; Morphology; Mutation; Neuroendocrine Cell; Normal Cell; Outcome; Patients; Pattern; Pharmaceutical Preparations; Prognosis; Research; STK11 gene; Sampling; Signal Transduction; Single Nucleotide Polymorphism; Somatic Mutation; Stress; Study models; Tattooing; Testing; Therapeutic; Tissues; Tumor Biology; Untranslated RNA; Woman; Work; alveolar type II cell; base; benign state; blood treatment; cancer cell; cancer subtypes; cancer type; cell type; clinically significant; cohort; driver mutation; genome sequencing; genome-wide; insertion/deletion mutation; insight; lung cancer cell; mouse model; mutant; mutational status; never smoker; novel; novel strategies; response; single cell sequencing; single-cell RNA sequencing; standard of care; surfactant; targeted sequencing; tumor; tumor progression; whole genome

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.

项目摘要/摘要 产生癌症的正常起源细胞(COO)是我们对癌症的基本概念的基础 发展。COO是血液病癌症护理标准的核心，它们在哪里提供信息 预后及指导治疗。然而，慢性阻塞性肺疾病并未纳入治疗肺部疾病的临床范例。 腺癌是一种上皮性癌症，是全球癌症死亡的主要原因之一。少校 原因是我们仍然不知道大多数肺腺癌的COO，也不知道COO是否变化 从一个病人到另一个病人。解决这个问题的一个主要科学障碍是对 肺细胞类型，以及一般的上皮类型。第二个障碍是发生在肺部的血统不忠。 癌症进展，当人们分析肿瘤的形态或 从转录上讲。因此，该领域被要求依赖于转基因小鼠模型， 它们在全面概括人类肺的基因类型和临床特征方面的能力仍然有限 腺癌。我们和该领域的其他人最近的工作表明，全基因组模式 乘客突变可以提供患者特有的COO信号。然而，这一假设尚未得到检验。 严格适用于肺癌或其他恶性肿瘤。在这项研究中，我们调查了乘客突变是如何 模式为肺癌的首席运营官提供了信息。特别是，我们关注非编码表面活性物质蛋白基因(Spg)。 插入和删除，这是我们最近的研究(Cell 2017)和初步数据建立的 肺腺癌最常见的突变事件(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(AT2)的体细胞遗传“纹身” SPG突变肺腺癌的细胞起源。我们将通过对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，我们将调查SPG突变是否 肺腺癌与不同的进化轨迹有关，就其突变而言， 转录和组织状态。最后，我们将在初步研究的基础上，建立令人信服的 肺癌中体细胞单核苷酸变异(SNV)基因组分布与细胞类型的关系 良性肺单细胞核糖核酸测序获得的特异性基因表达谱。这些初步的 数据表明，一些肺腺癌可能位于近端(棒状细胞或基底细胞)，而不是远端(AT2 细胞)起源。我们将以我们的初步发现为基础，生成和分析更深层次的健康肺部图谱。 并将细胞类型特异性转录和开放染色质图谱与基因组相关联 体细胞SNV的分布。这项工作将为绘制人类肺图提供第一批直接证据。 腺癌转移到特定的COO。此外，我们在乘客之间建立了严格的联系 肺癌中COO的突变模式和COO可能对其他疾病中COO的研究具有更广泛的适用性 流行和致命的人类上皮性癌症。