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（由申请方提供）：近5-20%因原发性腺癌切除的肺含有细胞学非典型细支气管肺泡细胞的微小离散病灶，称为非典型腺瘤性增生（AAH）。AAH的特征是立方上皮细胞增殖为柱状上皮细胞，伴有不同程度的细胞学异常（从低到严重），似乎处于向局部非浸润性原位腺癌（AIS，以前称为细支气管肺泡癌或BAC）的过渡期。据报告，持续观察到的不确定的小结节，如通过计算机断层扫描识别的毛玻璃样阴影（GGO）病变，在病理学上被证明是AAH或AIS。如果不切除，这些病变中的一些会增大，并且病变内的固体成分倾向于出现和扩展。这种GGO病变称为混合或部分实性结节，与微创腺癌（MIA）高度相关。根据组织病理学和临床特征，推测AAH病变可能是腺肿瘤的早期阶段。事实上，肺腺性肿瘤沿着从AAH到AIS再到MIA的生物学和临床连续体发展。从AAH到腺癌的发展序列的进一步支持来自一系列独立研究，这些研究表明，在癌前AAH和浸润前AIS病变中发现了相互排斥的激活EGFR或KRAS突变，这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，许多研究者试图通过比较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。所有的后期数据主要是通过候选基因的方法产生的，没有全面的分子信息，在这些病变部分是由于缺乏大量的样本进行全面的分子研究。 为了描述作为进展函数的克隆异质性，必须开发资源，以提供高质量的原发性组织样本，保持原发性病变的遗传完整性。本申请中将开发的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，本申请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移植组织和原代组织之间进行分子比较。本申请的进一步研究包括筛选阳性原发性病变的遗传表征和鉴定的新突变的功能表征，所述新突变最终将允许开发预防性和治疗性药物。 这些肿瘤前病变的治疗方法。