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Abstract
Our understanding of genomic heterogeneity in lung cancer is largely based on the analysis of early-stage surgical specimens. Here we used endoscopic sampling of paired primary and intrathoracic metastatic tumors from 11 lung cancer patients to map genomic heterogeneity inoperable lung cancer with deep whole-genome sequencing. Intra-patient heterogeneity in driver or targetable mutations was predominantly in the form of copy number gain. Private mutation signatures, including patterns consistent with defects in homologous recombination, were highly variable both within and between patients. Irrespective of histotype, we observed a smaller than expected number of private mutations, suggesting that ancestral clones accumulated large mutation burdens immediately prior to metastasis. Single-region whole-genome sequencing of from 20 patients showed that tumors in ever-smokers with the strongest tobacco signatures were associated with germline variants in genes implicated in the repair of cigarette-induced DNA damage. Our results suggest that lung cancer precursors in ever-smokers accumulate large numbers of mutations prior to the formation of frank malignancy followed by rapid metastatic spread. In advanced lung cancer, germline variants in DNA repair genes may interact with the airway environment to influence the pattern of founder mutations, whereas similar interactions with the tumor microenvironment may play a role in the acquisition of mutations following metastasis.
Highlights
Genomic heterogeneity is recognized as a major challenge to the success of conventional therapy, targetedThese authors contributed : Tracy L
Except for one sample, all were analyzed with whole-genome sequencing (WGS) to an average depth of 150 ×, including two cases in which two samples were obtained from the primary tumor in addition to the metastases
The propensity of lung cancer to spread within the chest prior to diagnosis is a major barrier to the delivery of curative therapy [28]
Summary
Genomic heterogeneity is recognized as a major challenge to the success of conventional therapy, targeted. The advent of multi-region sequencing has led to the identification of a previously unknown degree of complexity and genomic heterogeneity in solid tumors [2]. These landmark findings have major implications for the understanding of tumor initiation and evolution, with respect to the development of metastasis [3]. They illustrate how analyzing multiple tumor sites from a relatively small number of cases can reveal the complexities of genomic evolution that cannot be resolved by single-site sequencing of large cohorts [1]
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