Targeted sequencing of lung adenocarcinoma

Adenocarcinomas represent the most frequent subtype of lung cancer, and they are usually discovered late in the course of the disease even in the setting of vigilant radiographic and cytologic screening. Despite improvements in molecular diagnosis and targeted therapies, the average 5 year-survival rate for lung adenocarcinoma remains only 15%. Novel strategies based on the detection of genetic markers offer new hope for improved risk assessment, early cancer detection, therapeutic intervention and tumor surveillance, but the impact of these strategies has been limited by an incomplete understanding of the biology of lung cancer, particularly in its early developmental stages. Lungs resected for primary adenocarcinomas often harbor minute discrete foci of cytologically atypical pneumocyte proliferations designated as atypical adenomatous hyperplasia (AAH). Evidence suggests that AAH represents an initial step in the progression to adenocarcinoma in situ (AIS), minimally invasive adenocarcinoma (MIA) and ultimately fully invasive adenocarcinoma. This enhanced delineation of early glandular neoplasia provides a rational histologic framework for studying the timing of genetic alterations driving the early stages of lung tumorigenesis. We performed targeted next generation sequencing (NGS) on DNA isolated from 25 distinct AAHs incidentally discovered in the lung resection specimens from 6 patients with invasive adenocarcinoma and samples isolated from different zones of histologic progression within the same AIS and MIA tumors (5 patients each). Three histologically different zones were collected from each AIS tumor and four histologically different zones were collected from each MIA tumor. AAH is the earliest form of glandular neoplasia of the lung, which characterized by the proliferation of slightly atypical epithelial cells lining the slightly thickened by intact septae. AIS is characterized by atypical cells with enlarged hyperchromatic nuclei lining intact alveolated lung parenchyma (zone 1). With progression towards the center of the tumor, the septae become increasingly thickened and the cytologic atypia becomes more pronounced (zone 2 and zone 3). MIA exhibits increasing septal thickening and epithelial atypia with progression from the periphery of the lesion (zone 1) toward its center (zone 2 and zone 3). In addition, there is a small focus (less than 0.5 cm) of invasion at the core of the lesion (zone 4) characterized by irregular acinar glands in a desmoplastic stroma.