Abstract / Summary
Background: /Objectives: Non-small cell lung cancer (NSCLC) accounts for approximately 85% of lung cancer cases, yet mechanisms contributing to genomic instability during tumor evolution remain incompletely defined. LINE-1 (L1) and Alu retrotransposons are important sources of somatic genome remodeling. Although somatic L1 mobilization has been demonstrated in NSCLC, its patient-level distribution between tumor and adjacent histologically normal lung remains poorly characterized. We investigated whether somatic retrotransposition is preferentially associated with the tumor or reflects a broader patient-specific pattern.
Methods: Whole-genome sequencing data from 55 paired lung tumors (T) and adjacent normal lung tissues (NT), predominantly adenocarcinoma and squamous cell carcinoma, were analyzed, with matched whole blood (WB) available for 54 patients. L1 and Alu insertions were detected using xTea. Germline insertions detected in WB were excluded, and tissue-specific events were defined by paired T–NT.
Results: Somatic L1 and Alu insertions were detected in both T and NT, without systematic tumor enrichment at the cohort level. Instead, patients showed marked heterogeneity, with higher burden occurring in either compartment. T- and NT-specific burdens were strongly correlated within individuals (L1, ρ = 0.79; Alu, ρ = 0.60; both P < 10⁻⁵). In the technically comparable three-compartment subset (n = 32), WB-specific burden was significantly lower than lung T- and NT-specific burden for both Alu and LINE-1. Alu burden increased with age, whereas cumulative smoking exposure, when available, showed no significant association. Most insertions occurred in repetitive, intergenic, or intronic regions, while a minority involved potentially functional regions, including cancer-associated genes.
Conclusions: Somatic retrotransposition in lung cancer is not confined to the tumor. Strong within-patient concordance combined with marked tissue-specific heterogeneity supports a broader patient-level propensity for retrotransposition upon which tissue-specific processes may be superimposed. The lower WB-specific burden observed in the technically comparable subset further supports known preferential accumulation of detectable somatic retrotransposition in lung tissue and provides a technical validation for the results.