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


The cover for issue 63 of Oncotarget features Figure 3, "GSEA value of “ECM-Receptor Interaction” pathway in high-SI6/low-SI26 and low-SI6/high-SI26 patient sub-cohorts," by Meucci, et al.

The SNPs mutational profiling showed enrichments of smoking-related signature 4 and defective DNA mismatch repair -related signature 6 in younger patients, while the defective DNA MMR signature 26 was enriched among older 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.

Dr. Ulrich Keilholz and Dr. Stefano Meucci from the Charité Comprehensive Cancer Center, Charité University Hospital, Berlin, Germany said, "Lung cancer is the most common cause of global cancer-related mortality and the major risk factors are smoking consumption and occupational exposure to carcinogens."

The mutational landscape present in a cancer genome is the cumulative result of endogenous and/or exogenous mutational processes, constant or sporadic and with different strengths along patient ageing. Although the age at diagnosis of lung tumors is very closely correlated with the duration of smoking, the study showed a higher mutational burden as well as a higher level of methylation changes in younger patients by analyzing ~500 LUSC samples from The Cancer Genome Atlas. The overall SNPs mutational profiling and the corresponding correlations with COSMIC signatures showed an enrichment of the smoking-related signature 4 and defective DNA mismatch repair -related signature 6 among younger patients.

Figure 3:

Figure 3: (A) GSEA value of "ECM-Receptor Interaction" pathway in high-SI6/low-SI26 and (B) low-SI6/high-SI26 patient sub-cohorts. Unsupervised hierarchical clustering of SNPs frequencies of genes involved in the "ECM Receptor Interaction" pathway (according to the KEGG database) in (C) high-SI6/low-SI26 and (D) low-SI6/high-SI26.

Furthermore, the research team performed gene-specific correlation analysis in relation to patient age with a particular focus on the significantly mutated genes in LUSC and the most frequently mutated DNA repair genes in lung cancer. Gene set enrichment analysis was as well 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.

The current study may pave the way for future studies of molecular tumorigenesis in relation to human ageing and underlines the need to consider age-adjusted treatments not only based on age and morbidity of older patients, but also on differences in tumor biology.

The Ulrich Keilholz/Stefano Meucci research team concluded, "Multiple mutational processes appear to be simultaneously operative with various dynamic changes due to the endogenous and exogenous environments, lifestyle habits and physiological ageing. Previous hypothesis of a mutator phenotype concealing the effect of age-related accumulation of mutations might have different causing factors in relation to ageing processes."

Full text - https://doi.org/10.18632/oncotarget.25848

Correspondence to - Ulrich Keilholz - [email protected] and Stefano Meucci - [email protected]

Keywords - lung squamous cell carcinoma, aging, somatic mutations, copy number variations, methylation

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