Genomic Landscape Established by Allelic Imbalance in the Cancerization Field of a Normal Appearing Airway

Abstract

Visually normal cells adjacent to, and extending from, tumors of the lung may carry molecular alterations characteristics of the tumor itself, an effect referred to as airway field of cancerization. This airway field has been postulated as a model for early events in lung cancer pathogenesis. Yet the genomic landscape of somatically acquired molecular alterations in airway epithelia of lung cancer patients has remained unknown. To begin to fill this void, we sought to comprehensively characterize the genomic architecture of chromosomal alterations inducing allelic imbalance (AI) in the airway field of the most common type of lung tumors, non–small cell lung cancer (NSCLC). To do so, we conducted a genome-wide survey of multiple spatially distributed normal-appearing airways, multiregion tumor specimens, and uninvolved normal tissues or blood from 45 patients with early-stage NSCLC. We detected alterations in airway epithelia from 22 patients, with an increased frequency in NSCLCs of squamous histology. Our data also indicated a spatial gradient of AI in samples at closer proximity to the NSCLC. Chromosome 9 displayed the highest levels of AI and comprised recurrent independent events. Furthermore, the airway field AI included oncogenic gains and tumor suppressor losses in known NSCLC drivers. Our results demonstrate that genome-wide AI is common in the airway field of cancerization, providing insights into early events in the pathogenesis of NSCLC that may comprise targets for early treatment and chemoprevention.

System for Quality‐Assured Data Analysis: Flexible, reproducible scientific workflows

“…In another example, a biologist with knowledge of a limited set of Unix commands (e.g., mkdir, cp, cd, and syqada auto) has performed several CPU‐months of computation in a half‐dozen projects by reusing the same SyQADA workflow while changing only the configuration file to use different microbiome source data. Of note, SyQADA has been used in the analysis of data for publications including analysis of somatic variation in sporadic MEN1 (Romero Arenas et al, ), Familial Adenomatous Polyposis (Borras et al, ), field of cancerization of lung adenocarcinoma (Jakubek et al, ), diet and oral microbiome (Hoffman et al, ), as well as in a comparison of somatic variant calling on Ion Torrent sequencing data (Deshpande et al, ).…”

“…Variant caller comparison for Ion Torrent sequencing (Deshpande et al, 2018) LUAD Somatic variation of Lung adenocarcinoma (Jakubek et al, 2016) SKCM Somatic variation in the field of cancerization of melanoma…”

Evolutionary dynamics in pre-invasive neoplasia

“…There is strong evidence that several mutational processes are active from conception throughout life in normal tissue [13,14]. Observations of multifocal patches of clonal populations with cancer-related genetic aberrations are not restricted to the skin [7], but have amongst others also been found in lung epithelium [15–18], breast epithelium [19,20] and intestinal epithelium in patients with ileocolitis [21] (Figure 1). Collectively, literature points towards mixed mutational processes active in normal tissues from conception, varying in strength over space and time.…”

“…A normal field is the starting point in which a tissue has not yet acquired the molecular aberrations that predisposes to cancer development. In contrast, a carcinogen-exposed field has acquired (epi)genetic oncogenic aberrations either through exogenous factors (such as UV-exposure [29] and smoking [18]) or endogenous processes (such as age-related spontaneous deamination [13] or APOBEC-mutagenesis [30] and can underlie the emergence of a sporadic cancer. A patient with a cancer predisposing germline mutation, harbors a genetically predisposed field of epithelium.…”

Hepatoblastoma modeling in mice places Nrf2 within a cancer field established by mutant β-catenin

“…It is perhaps best exemplified in lung cancer, in which smoking-associated damage in the airway epithelium establishes a preneoplastic field from which tumors later emerge (47). Indeed, recent studies show that half of patients with early-stage non-small-cell lung cancer harbor the same allelic imbalances in histologically normal tumor-adjacent airway cells that are present in tumors (48). Based on our finding that Nrf2 antioxidant signaling was active β-catΔEx3 livers as well as in tumor-naïve and tumor-bearing livers of β-catΔEx3:Myc mice, we propose that Nrf2/nqo1 constitutes a major component of a preneoplastic field orchestrated by mutant β-catenin that drives Myc-driven HB development by promoting the survival of stressed cells.…”