Mutational signature analysis in non-small cell lung cancer patients with a high tumor mutational burden

Abstract

Background 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. 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. Methods In 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. Results In 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). Conclusion In 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.

Characterization of highly active mutational signatures in tumors from a large Chinese population

“…SBS4 was highly prevalent across NSCLCs including lung adenocarcinomas (LUADs) and lung squamous cell carcinomas (LUSCs) as well as in small cell lung cancer (SCLCs) as previously observed 1,25,28,29 ( Figure 1, Figure 4A ). In China, rates of cigarette smoking are much higher among males compared to females 30 .…”

Insight into NSCLC through novel analysis of gene interactions and characteristics

“…For example, presence of mutational signatures in patients has been associated with poly (ADP)-ribose polymerase (PARP) inhibitor sensitivity [23]. The identification of mutational signatures associated with NSCLC can thus advance the field of personalized medicine for NSCLC treatment, among other things [6].…”

“…Identifying mutational signatures associated with cancer has the ability to serve as a biomarker for cancer prognosis [5]. Moreover, mutational signature identification can also be predictors of therapy response in cancer [6].…”

Comprehensive repertoire of the chromosomal alteration and mutational signatures across 16 cancer types from 10,983 cancer patients

“…Similar relationships are apparent in other cancer types. In lung cancer, squamous cell carcinomas (SCC) are enriched for APOBEC signatures (SB2, SBS13) and small cell tumours for the smoking signature SBS92 34,35 . Among haematological malignancies, multiple myeloma (MM) and ALL have the highest mutation rates with APOBEC signatures particularly active in MM likely as a consequence of altered APOBEC3G activity 36 .…”