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: 9101339
• 负责人: Mohammad Obaidul Hoque
• 金额: $ 68.81万
• 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/9101339
• 关键词: Adenocarcinoma; Adenocarcinoma In Situ; Air; Alveolar Cell; Architecture; Atypical adenomatous hyperplasia; BRAF gene; Biological; Biological Assay; Biological Preservation; Biopsy; Bronchiolo-Alveolar Adenocarcinoma; Cancer Patient; Candidate Disease Gene; Cell Line; Cells; Characteristics; Clinical; Collection; Copy Number Polymorphism; Cytologic Atypia; 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; Invasive Lesion; 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; 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; Staging; TP53 gene; Therapeutic; Tissue Sample; Tissues; Tumor Burden; X-Ray Computed Tomography; Xenograft Model; Xenograft procedure; base; cancer cell; carcinogenesis; clinically actionable; clinically relevant; comparative; deep sequencing; empowered; 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(申请人提供)：近5%-20%的原发腺癌切除的肺含有微小的离散的细胞学上不典型的细支气管肺泡细胞，被指定为非典型腺瘤性增生(AAH)。AAH以立方到柱状上皮细胞的增殖为特征，并伴有不同程度的细胞学异型性(从低到重)，似乎与局限性的非侵袭性原位腺癌(AIS，以前称为细支气管肺泡癌或BAC)过渡。据报道，持续观察到的小的不确定结节，如计算机断层扫描确定的磨玻璃样阴影(GGO)病变，经病理证实为AAH或AIS。如果不切除，这些病变中的一些会增大，病变内的固体成分往往会出现并延伸。这种GGO病变称为混合性或部分实性结节，与微侵袭性腺癌(MIA)高度相关。根据组织病理学和临床特征，推测AAH病变可能是腺瘤形成的早期阶段。事实上，现在可以通过从AAH到AIS再到MIA的生物学和临床连续体来看待肺腺瘤。进一步支持从AAH到腺癌的发展序列的一系列独立研究表明，在癌前AAH和侵袭前AIS病变中发现了相互排斥的激活EGFR或KRAS突变，表明这些突变是肺腺癌多步癌变过程中的早期事件。基于这些证据，许多研究人员试图通过比较AAH、AIS或侵袭性腺癌之间这些遗传事件的发生率来证明多步进展的概念。所有后来的数据大多是通过候选基因方法产生的，在这些病变中没有全面的分子信息，部分原因是缺乏大量的样本进行全面的分子研究。为了描述克隆异质性作为进展的函数，必须开发资源，提供高质量的原始组织样本，以保持遗传完整性作为原发病变。将在本应用中开发的PDX模型可能为DNA、RNA和蛋白质水平的多层生物检测提供无限的组织资源。因此，这一应用的主要目的是建立这些早期病变的PDX模型，并利用候选基因的方法对移植组织和原发组织进行分子比较。这一应用的进一步研究包括筛查阳性原发病变的基因特征和已识别的新突变的功能特征，这些突变最终将允许开发预防性和 这些癌前病变的治疗方法。