Oncotarget

Research Papers:

Somatic genome alterations in relation to age in lung squamous cell carcinoma

Stefano Meucci, Ulrich Keilholz _, Daniel Heim, Frederick Klauschen and Stefano Cacciatore

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Oncotarget. 2018; 9:32161-32172. https://doi.org/10.18632/oncotarget.25848

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Abstract

Stefano Meucci1, Ulrich Keilholz1, Daniel Heim2, Frederick Klauschen2 and Stefano Cacciatore3,4

1Charité Comprehensive Cancer Center, Charité University Hospital, Berlin, Germany

2Institut für Pathologie, Charité University Hospital, Berlin, Germany

3Imperial College Parturition Research Group, Division of the Institute of Reproductive and Developmental Biology, Imperial College London, London, England, UK

4International Centre for Genetic Engineering and Biotechnology, Cancer Genomics Group, Cape Town, South Africa

Correspondence to:

Ulrich Keilholz, email: Ulrich.Keilholz@charite.de

Stefano Meucci, email: Stefano.Meucci@charite.de

Keywords: lung squamous cell carcinoma; aging; somatic mutations; copy number variations; methylation

Received: January 19, 2018    Accepted: July 12, 2018    Published: August 14, 2018

ABSTRACT

Lung squamous cell carcinoma (LUSC) is the most common cause of global cancer-related mortality and the major risk factors is smoking consumption. By analyzing ~500 LUSC samples from The Cancer Genome Atlas, we detected a higher mutational burden as well as a higher level of methylation changes in younger patients. The SNPs mutational profiling showed enrichments of smoking-related signature 4 and defective DNA mismatch repair (MMR)-related signature 6 in younger patients, while the defective DNA MMR signature 26 was enriched among older patients. Furthermore, gene set enrichment analysis was performed in order to explore functional effect of somatic alterations in relation to patient age. Extracellular Matrix-Receptor Interaction, Nucleotide Excision Repair and Axon Guidance seem crucial disrupted pathways in younger patients. We hypothesize that a higher sensitivity to smoking-related damages and the enrichment of defective DNA MMR related mutations may contribute to the higher mutational burden of younger patients. The two distinct age-related defective DNA MMR signatures 6 and 26 might be crucial mutational patterns in LUSC tumorigenesis which may develop distinct phenotypes. Our study provides indications of age-dependent differences in mutational backgrounds (SNPs and CNVs) as well as epigenetic patterns that might be relevant for age adjusted treatment approaches.


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