Abstract
BackgroundLung cancer is the leading cause of cancer death worldwide. With the growing number of targeted therapies and the introduction of immuno-oncology (IO), personalized medicine has become standard of care in patients with metastatic disease. The development of predictive and prognostic biomarkers is of great importance. Mutational signatures harbor potential clinical value as predictors of therapy response in cancer. Here we set out to investigate particular mutational processes by assessing mutational signatures and associations with clinical features, tumor mutational burden (TMB) and targetable mutations.MethodsIn this retrospective study, we studied tumor DNA from patients with non-small cell lung cancer (NSCLC) irrespective of stage. The samples were sequenced using a 2 megabase (Mb) gene panel. On each sample TMB was determined and defined as the total number of single nucleotide mutations per Mb (mut/Mb) including non-synonymous mutations. Mutational signature profiling was performed on tumor samples in which at least 30 somatic single base substitutions (SBS) were detected.ResultsIn total 195 samples were sequenced. Median total TMB was 10.3 mut/Mb (range 0–109.3). Mutational signatures were evaluated in 76 tumor samples (39%; median TMB 15.2 mut/Mb). SBS signature 4 (SBS4), associated with tobacco smoking, was prominently present in 25 of 76 samples (33%). SBS2 and/or SBS13, both associated with activity of the AID/APOBEC family of cytidine deaminases, were observed in 11 of 76 samples (14%). SBS4 was significantly more present in early stages (I and II) versus advanced stages (III and IV; P = .005).ConclusionIn a large proportion of NSCLC patients tissue panel sequencing with a 2 Mb panel can be used to determine the mutational signatures. In general, mutational signature SBS4 was more often found in early versus advanced stages of NSCLC. Further studies are needed to determine the clinical utility of mutational signature analyses.
Highlights
Lung cancer is the leading cause of cancer death worldwide
Review of histopathology showed that the majority of tumors represented adenocarcinoma (AC, n = 110; 56.4%), followed by squamous cell carcinoma (SCC, n = 42; 21.5%) and large cell neuroendocrine carcinoma (LCNEC, n = 11; 5.6%)
SBS signatures 2 and/or 13 (SBS2/13), both associated with activity of the AID/APOBEC family of cytidine deaminases, cumulatively contributed to the mutation spectrum in 11 of 76 tumors (14%)
Summary
Lung cancer is the leading cause of cancer death worldwide. With the growing number of targeted therapies and the introduction of immuno-oncology (IO), personalized medicine has become standard of care in patients with metastatic disease. Its high mortality has urged major efforts to optimize the treatment of lung cancer have been made that have resulted in targeted therapies and immunotherapy. These treatments are based on the presence or absence of specific predictive and prognostic van den Heuvel et al Respiratory Research (2021) 22:302 biomarkers. In the last decade several biomarkers predicting immune checkpoint blockade outcomes have been discovered. PD-L1 expression as a predictive biomarker for response to immune checkpoint blockade (ICB) is fairly unreliable due to dynamic and heterogeneous expression in the tumor microenvironment, divergent assay interpretation and lack of PD-L1 platform standardization [4,5,6,7,8]
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