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

Abstract

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.

Benchmarking Outcomes for Molecularly Characterized Synchronous Oligometastatic Non–Small-Cell Lung Cancer Reveals EGFR Mutations to Be Associated With Longer Overall Survival

“…However, metastatic clones may acquire new genetic alterations, highlighting the importance of adjuncts to systemic therapy to overcome genetic divergence, and consideration of repeat NGS testing, particularly if there is disease progression on a prior systemic agent. 26 In contrast to polymetastatic NSCLC, oligometastatic disease generally has fewer mutations and may have not yet realized its full metastatic potential, underscoring the importance of LCT to eradicate resistant clones. 27 , 28 …”

Genomic Profiling Identifies Putative Pathogenic Alterations in NSCLC Brain Metastases

“…NSCLC-initiating driver events, such as alterations affecting EGFR and ALK genes, are highly concordant between primary NSCLC and matched BM lesions. 47 The initiating drivers could be early (clonal) genomic events during the establishment of primary NSCLC, and simultaneously they might be involved in NSCLC dissemination to the brain. 48 Nevertheless, in NSCLC tumors carrying wild-type EGFR and ALK genes, the brain-seeding metastatic cells acquire additional genetic alterations during the early stages of tumor evolution.…”

Cell-by-Cell: Unlocking Lung Cancer Pathogenesis

“…While the majority of these studies were based on a deep sequencing approach to analyzing admixed populations of cells within a single tumor site, micro-dissected tissues, or clonal outgrowths, the findings provided a much more complex view of tumor evolution and clonal dynamics, as well as clinical implications of ITH, including prognosis, response to therapy, and relapse. For instance, independent groups conducting multiregional sequencing of LUADs revealed a high degree of ITH between different sites within the same tumor which, upon further investigation, revealed a branched evolutionary trajectory across the majority of LUADs [ 54 ], as described further below.…”