Driver Mutations in Normal Airway Epithelium Elucidate Spatiotemporal Resolution of Lung Cancer

Sequencing Lung Cancer’s Sequence

“…The study by Kadara and colleagues provides additional insight into a classic cancer genetics theory. The study identified shared somatic alterations between adjacent airway and tumor with additional somatic event on the same genomic region, effectively enriching an oncogenic allele or losing both alleles of a tumor suppressor only in the tumor, supporting the original Knudson’s two-hit hypothesis (3). However, if these mutations are observed in normal-appearing airways without hyperplasia or dysplasia, presumably because of insufficiency by one hit for overt proliferative phenotype, why are these first events not observed at a similar frequency in the distant or uninvolved airways?…”

“…In this issue of the Journal , Kadara and colleagues (pp. 742–750) present a comprehensive deep sequencing analysis of tumor and nonmalignant airway epithelium specimens from 48 patients with cancer to examine the sequence of the sequence of spatial mutations in the lung (3). This work sheds important light on molecular and genetic processes involved in lung carcinogenesis, especially during an early phase of its evolution.…”

“…The study by Kadara and colleagues describes targeted genomic analyses of the somatic mutational landscape on cancer-panel genes and allelic imbalance of the normal airway epithelium in patients with early-stage NSCLC (3). The study uniquely uses brushing samples from distant airway and nasal epithelia, in addition to multiple normal-appearing airways adjacent to NSCLCs.…”

The Role of the ECM in Lung Cancer Dormancy and Outgrowth

“…Furthermore, intrapulmonary metastases are associated with a longer latency than distant metastases, commonly re-emerging more than 5 years following surgery (13). In addition to genetic changes, widespread and dispersed changes in the structure and composition of the lung ECM as well as the transcriptional profile of normal bronchial epithelia in smokers and lung cancer patients are thought to represent a field of cancerization that promotes tumor initiation and regulates the dissemination of lung tumor cells from the primary site (18)(19)(20)(21)(22). Similarly, the severe extracellular matrix remodeling in chronic lung diseases such as chronic obstructive pulmonary disorder (COPD) and idiopathic pulmonary fibrosis (IPF), which are associated with an increased risk of lung cancer development, may also contribute to this field effect (23,24).…”

Technical advance in targeted NGS analysis enables identification of lung cancer risk-associated low frequency TP53, PIK3CA, and BRAF mutations in airway epithelial cells

“…Advances in next generation sequencing (NGS) technology markedly increase the ability to measure somatic mutations in AEC and other tissues. In a recent study, targeted NGS capable of measuring mutations with variant allele frequency (VAF) > 1.0% was used to assess driver gene somatic mutations in lung cancer tissue and adjacent matched normal tissue from a group of subjects [14]. A large number of mutations known to be drivers for lung cancer were identified in non-cancer lung tissues in close proximity to each cancer.…”