PQ1: Identification and characterization of genetic alterations for the progression of pre-neoplastic lung lesions by using novel PDx models and deep sequencing

PQ1：通过使用新型 PDx 模型和深度测序来识别和表征肿瘤前肺部病变进展的遗传改变

• 批准号: 9302702
• 负责人: Mohammad Obaidul Hoque
• 金额: $ 65.23万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-01 至 2021-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9302702
• 关键词: Adenocarcinoma; Adenocarcinoma In Situ; Alveolar Cell; Architecture; Atypical adenomatous hyperplasia; BRAF gene; Biological; Biological Assay; Biological Models; Biological Preservation; Biopsy; Bronchiolo-Alveolar Adenocarcinoma; Cancer Patient; Candidate Disease Gene; Cell Line; Characteristics; Clinical; Collection; Copy Number Polymorphism; Cytologic Atypia; Cytology; DNA; DNA Sequence; Data; Development; Disease; ERBB2 gene; Epidermal Growth Factor Receptor; Epithelial Cells; Event; Evolution; Formalin; Frequencies; Future; Gene Expression; Gene Expression Profile; Genes; Genetic; Genetic Heterogeneity; Glandular Neoplasms; Glass; Goals; Heterogeneity; Histologic; Incidence; KRAS2 gene; Lead; Lesion; Light; Lung; Lung Adenocarcinoma; Lung Neoplasms; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of lung; Measures; Methods; Modeling; Molecular; Molecular Analysis; Mus; Mutation; Mutation Analysis; NF1 gene; Neoplasms; Nodule; Non-Small-Cell Lung Carcinoma; Paraffin Embedding; Pathologic; Pathway interactions; Patients; Pattern; Pharmaceutical Preparations; Phenotype; Premalignant; Preventive; Primary Lesion; Primary Neoplasm; Proteins; RNA; Reporting; Research; Research Personnel; Resected; Resources; Role; Route; STK11 gene; Sampling; Series; Site; Solid; Specimen; Spiral Computed Tomography; TP53 gene; Territoriality; Therapeutic; Tissue Sample; Tissues; Tumor Burden; X-Ray Computed Tomography; Xenograft Model; Xenograft procedure; base; cancer cell; cancer invasiveness; clinically actionable; clinically relevant; comparative; deep sequencing; lung carcinogenesis; minimally invasive; molecular marker; mouse model; mutational status; neoplastic; next generation sequencing; novel; prevent; public health relevance; screening; tissue resource; tumor; tumor progression; tumorigenesis

 DESCRIPTION (provided by applicant): Nearly 5-20% of lungs resected for primary adenocarcinomas harbored minute discrete foci of cytologically atypical bronchiolo-alveolar cells that are designated as atypical adenomatous hyperplasia (AAH). AAH is characterized by the proliferation of cuboidal to columnar epithelial cells with various degrees of cytologic atypia (ranging from low to severe) that appears to be in transition with localized noninvasive adenocarcinoma in situ (AIS, formerly known as bronchiolo-alveolar carcinoma or BAC). It was reported that persistently observed small indeterminate nodules, such as ground-glass opacity (GGO) lesions identified by computed tomography, turn out to be pathologically AAH or AIS. If not resected, some of these lesions increase in size and a solid component within the lesion tend to appear and extend. Such GGO lesions, called mixed or part solid nodules, are highly associated with minimally invasive adenocarcinoma (MIA). In light of histo-pathologic and clinical features, it has been postulated that AAH lesions may represent an early stage in glandular neoplasia. In fact, glandular neoplasia of the lung is now viewed along a biological and clinical continuum that progresses from AAH to AIS to MIA. Further support for a developmental sequence from AAH to adenocarcinoma comes from the series of independent studies that have demonstrated that mutually exclusive activating EGFR or KRAS mutations were identified in pre-malignant AAH and pre-invasive AIS lesions, suggesting that these mutations are early events in the multistep carcinogenesis of lung adenocarcinoma. Based on these evidences, many investigators tried to proof the concept of multistep progression by comparing the incidence of these genetic events between AAH, AIS or invasive adenocarcinoma. All the later data's are generated mostly by candidate gene approach and no comprehensive molecular information are available in these lesions partly due to the lack of quantity of samples for comprehensive molecular studies. To delineate clonal heterogeneity as a function of progression, it is essential to develop resources that will provide high quality primary tissue samples that maintained genetic integrity as primary lesions. PDx model that will be developed in this application may provide unlimited tissue resources for multilayered biological assays at DNA, RNA and protein levels. So the primary end point of this application is to develop PDx model of these early lesions and to molecularly compare between engrafted tissues and primary tissues by candidate gene approach. Further studies of this application include genetic characterization of screening positive primary lesions and functional characterization of identified novel mutations that will ultimately allow to develop preventive and therapeutic approaches for these pre-neoplastic lesions.

 描述（由适用提供）：将近5-20％的肺部切除针对原发性腺癌的肺部具有细胞学上非典型的基本支气管肺泡细胞的微小离散灶，这些肺泡被指定为非典型腺瘤增生（AAH）。 AAH的特征在于，立方体向柱状上皮细胞的增殖具有不同程度的细胞学异型（从低到重度），似乎与局部非侵入性腺癌过渡（AIS）（AIS（AIS）（AIS）（AIS，曾经称为支气管溶质 - 紫罗兰病毒或BAC）。据报道，持续观察到小的不确定结节，例如通过计算机断层扫描鉴定的地面玻璃透明度（GGO）病变，结果在病理上是病理上的AAH或AIS。如果未切除，其中一些病变的大小增加，病变内的固体成分往往会出现并延伸。这种GGO病变称为混合或部分固体结节，与微创腺癌（MIA）高度相关。鉴于组织病理学和临床特征，已经据报道，AAH病变可能代表腺肿瘤的早期阶段。实际上，现在沿着从AAH到AIS到MIA的生物和临床连续体观察了肺的腺肿瘤。对从AAH到腺癌的发育序列的进一步支持来自一系列独立研究，这些研究表明，互斥激活的EGFR或KRAS突变是在恶性的AAH和侵入性AIS病变中鉴定的，这表明这些突变是肺化肾上腺菌素症的多阶段癌作用中的早期事件。基于这些证据，许多研究者试图通过比较AAH，AIS或侵入性腺癌之间的这些遗传事件的事件来证明多步进进展的概念。所有后来的数据主要由候选基因方法生成，并且在这些病变中没有全面的分子信息部分，部分原因是缺乏用于全面分子研究的样品。为了描绘克隆异质性作为进展的函数，必须开发将提供高质量的原始组织样品，以保持遗传完整性作为原发性病变。将在此应用中开发的PDX模型可以为DNA，RNA和蛋白质水平的多层生物测定提供无限的组织资源。因此，该应用的主要终点是开发这些早期病变的PDX模型，并通过候选基因方法在雕刻组织和原代组织之间进行分子比较。对该应用的进一步研究包括筛查阳性原发性病变的遗传表征以及确定的新突变的功能表征，这些突变最终将允许发展预防和 这些肿瘤前病变的治疗方法。