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 prognos...

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Autores principales:	Guus R. M. van den Heuvel, Leonie I. Kroeze, Marjolijn J. L. Ligtenberg, Katrien Grünberg, Erik A. M. Jansen, Daniel von Rhein, Richarda M. de Voer, Michel M. van den Heuvel
Formato:	article
Lenguaje:	EN
Publicado:	BMC 2021
Materias:	Mutational signatures Next generation sequencing Non-small cell lung cancer Cancer genetics Diseases of the respiratory system RC705-779
Acceso en línea:	https://doaj.org/article/ae1a0ade6c6e4ed78175927614767cf1
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spelling	oai:doaj.org-article:ae1a0ade6c6e4ed78175927614767cf12021-11-28T12:29:16ZMutational signature analysis in non-small cell lung cancer patients with a high tumor mutational burden10.1186/s12931-021-01871-01465-993Xhttps://doaj.org/article/ae1a0ade6c6e4ed78175927614767cf12021-11-01T00:00:00Zhttps://doi.org/10.1186/s12931-021-01871-0https://doaj.org/toc/1465-993XAbstract 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.Guus R. M. van den HeuvelLeonie I. KroezeMarjolijn J. L. LigtenbergKatrien GrünbergErik A. M. JansenDaniel von RheinRicharda M. de VoerMichel M. van den HeuvelBMCarticleMutational signaturesNext generation sequencingNon-small cell lung cancerCancer geneticsDiseases of the respiratory systemRC705-779ENRespiratory Research, Vol 22, Iss 1, Pp 1-7 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Mutational signatures Next generation sequencing Non-small cell lung cancer Cancer genetics Diseases of the respiratory system RC705-779
spellingShingle	Mutational signatures Next generation sequencing Non-small cell lung cancer Cancer genetics Diseases of the respiratory system RC705-779 Guus R. M. van den Heuvel Leonie I. Kroeze Marjolijn J. L. Ligtenberg Katrien Grünberg Erik A. M. Jansen Daniel von Rhein Richarda M. de Voer Michel M. van den Heuvel Mutational signature analysis in non-small cell lung cancer patients with a high tumor mutational burden
description	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.
format	article
author	Guus R. M. van den Heuvel Leonie I. Kroeze Marjolijn J. L. Ligtenberg Katrien Grünberg Erik A. M. Jansen Daniel von Rhein Richarda M. de Voer Michel M. van den Heuvel
author_facet	Guus R. M. van den Heuvel Leonie I. Kroeze Marjolijn J. L. Ligtenberg Katrien Grünberg Erik A. M. Jansen Daniel von Rhein Richarda M. de Voer Michel M. van den Heuvel
author_sort	Guus R. M. van den Heuvel
title	Mutational signature analysis in non-small cell lung cancer patients with a high tumor mutational burden
title_short	Mutational signature analysis in non-small cell lung cancer patients with a high tumor mutational burden
title_full	Mutational signature analysis in non-small cell lung cancer patients with a high tumor mutational burden
title_fullStr	Mutational signature analysis in non-small cell lung cancer patients with a high tumor mutational burden
title_full_unstemmed	Mutational signature analysis in non-small cell lung cancer patients with a high tumor mutational burden
title_sort	mutational signature analysis in non-small cell lung cancer patients with a high tumor mutational burden
publisher	BMC
publishDate	2021
url	https://doaj.org/article/ae1a0ade6c6e4ed78175927614767cf1
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Mutational signature analysis in non-small cell lung cancer patients with a high tumor mutational burden

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