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

点击翻译按钮获取中文摘要

 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.