Genetic Clonality as the Hallmark Driving Evolution of Non-Small Cell Lung Cancer

Simple Summary Limited knowledge about NSCLC evolution has affected therapeutic strategies for many decades. The application of NGS-based techniques to studies on ITH has provided genetic insight into the contribution of clonality primary seeding, as well as to distant dissemination. To date, multiregional ITH affects accurate diagnosis and treatment decisions and is considered the main hallmark of anticancer therapy failure. Understanding the evolutionary trajectories that drive the metastatic process is critical for improving treatment strategies for this deadly condition. In this review, we discuss how the clonality of genetic alterations influence the seeding of primary and metastatic lesions of NSCLC, highlighting that wide genetic analyses may reveal the phylogenetic lineages of NSCLC evolution. Data indicate that many driver alterations from the primary tumor of non-small cell lung cancer (NSCLC) are predominantly shared across all metastases; however, disseminating cells may also acquire a new genetic landscape across their journey. By comparing the constituent subclonal mutations between pairs of primary and metastatic samples, it is possible to derive the ancestral relationships between tumor clones, rather than between tumor samples. Current treatment strategies mostly rely on the theory that metastases are genetically similar to the primary lesions from which they arise. However, intratumor heterogeneity (ITH) affects accurate diagnosis and treatment decisions and it is considered the main hallmark of anticancer therapy failure. Understanding the genetic changes that drive the metastatic process is critical for improving the treatment strategies of this deadly condition. Application of next generation sequencing (NGS) techniques has already created knowledge about tumorigenesis and cancer evolution; however, further NGS implementation may also allow to reconstruct phylogenetic clonal lineages and clonal expansion. In this review, we discuss how the clonality of genetic alterations influence the seeding of primary and metastatic lesions of NSCLC. We highlight that wide genetic analyses may reveal the phylogenetic trajectories of NSCLC evolution, and may pave the way to better management of follow-up and treatment.