Non-Small-Cell Lung Cancers with High and Low Risk of Distant Metastasis Demonstrate Distinct Mutational Landscapes

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Abstract
Background: Preventing metastasis is important for improving the survival rates of patients with non-small-cell lung cancer (NSCLC). Our previous investigation suggested that premalignant epithelial changes in small bronchi distant from the primary tumor serve as predictive markers of NSCLC metastasis. Specifically, isolated basal cell hyperplasia (iBCH) is associated with a high risk of distant metastasis, whereas basal cell hyperplasia combined with squamous metaplasia (BCH + SM) correlates with a low risk of distant metastasis. Methods: This exploratory study included patients enrolled both retrospectively and prospectively. A total of 83 NSCLC patients were stratified into two groups: iBCH (high metastatic risk, n = 59, including 37 metastatic events) and BCH + SM (low metastatic risk, n = 24, including 6 metastatic events). Paired peripheral blood and tumor samples from NSCLC patients with iBCH and BCH + SM were subjected to whole exome sequencing. Bioinformatic analysis included tumor mutation quantification, detection of regions with enriched mutations, mutational signatures profiling, and evaluation of metastasis-free survival and hazard ratio modeling. Results: Patients with iBCH were characterized by a higher prevalence of single nucleotide variants and a lower frequency of frameshift mutations. Single-nucleotide indels (mainly insertions) were more frequent in patients with BCH + SM. Additionally, ID1, ID3, ID11, and ID13 mutational signatures were significantly enriched in patients with BCH + SM. Moreover, the combination of SBS3, SBS4, DBS1, DBS2, DBS6, ID8, and ID23 signatures was linked to distant metastasis in NSCLC patients. Finally, a multivariable logistic regression model for assessing the probability of distant metastasis in NSCLC was developed based on the histological subtype, the bronchial lesion, and mutational signature. Conclusions: NSCLC with high and low risk of distant metastasis defined by bronchial lesions have specific mutational landscapes.
Funding Information
  • The Ministry of Education and Science of the Russian Federation (125042105351-3)

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