Abstract
Defining detailed genomic characterization of early tumor progression is critical to identifying key regulators and pathways in carcinogenesis as potentially druggable targets. In human lung cancer, work to characterize early cancer development has mainly focused on squamous cancer, as the earliest lesions are more proximal in the airways and often accessible by repeated bronchoscopy. Adenocarcinomas are typically located distally in the lung, limiting accessibility for biopsy of pre-malignant and early stages. Mouse lung cancer models recapitulate many human genomic features and provide a model for tumorigenesis with pre-malignant atypical adenomatous hyperplasia and in situ adenocarcinomas often developing contemporaneously within the same animal. Here, we combined tissue characterization and collection by laser capture microscopy (LCM) with digital droplet PCR (ddPCR) and low-coverage whole genome sequencing (LC-WGS). ddPCR can be used to identify specific missense mutations in Kras (Kirsten rat sarcoma viral oncogene homolog, here focused on Kras Q61) and estimate the percentage of mutation predominance. LC-WGS is a cost-effective method to infer localized copy number alterations (CNAs) across the genome using low-input DNA. Combining these methods, the histological stage of lung cancer can be correlated with appearance of Kras mutations and CNAs. The utility of this approach is adaptable to other mouse models of human cancer.
Highlights
Lung cancer remains a common and deadly disease, associated with a 5-year survival rate of only 19%, largely due to the majority of patients being diagnosed at a late stage when prolonged survival or cure are unlikely [1]
The tumor samples did not exhibit any copy number alterations (CNAs) but, as summarized in Table 1, had Kras Q61 mutations detected by digital droplet PCR (ddPCR) (Q61L and Q61R, respectively)
Sample 1A-5 had a wide variety of large-scale CNA covering chromosomes 4, 5, 7, 8, and X, chromosome 10, and was predicted to have ~40% tumor fraction
Summary
Lung cancer remains a common and deadly disease, associated with a 5-year survival rate of only 19%, largely due to the majority of patients being diagnosed at a late stage when prolonged survival or cure are unlikely [1]. Radiologic findings of pre-malignant and early lung cancers are often non-specific, with many inflammatory or infectious lung diseases presenting with similar radiologic characteristics. AAH is difficult to diagnose due to its small size (typically less than 5 mm diameter) and vague radiologic findings, which are often found incidentally in the lung tissue adjacent to surgically removed lung adenocarcinoma [6]. This has hampered extensive genotypic and molecular classifications of AAH and limited our understanding of the mechanisms underlying the evolution to AAH and to subsequent lung adenocarcinoma
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