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

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.

Somatic genome alterations in relation to age in lung adenocarcinoma

“…TP53 mutated, transversion-high and current smokers subcohorts showed the same higher somatic mutations and CNAs burden among younger patients, displaying a relation among these factors. These results overlap with our previous investigation on LUSC, 39 which might be indicative of a tissue-specific higher sensitivity to smoking-related damages in younger patients. The group of TP53-mutated patients showed a higher percentage of current smokers and transversion-high profiles as well as a lower age mean compared to TP53 wild-type patients, which instead displayed a lower average number of somatic mutations with no correlation with patient age.…”

Management of Elderly and Old Cancer Patients – Geriatric Oncology

“…37 Furthermore, age-related genetic differences such as single nucleotide variants (SNVs) and copy number variants (CNVs) have also been observed in older cancer patients. 40 In patients with squamous cell carcinoma of the lung, Meucci et al (2018) showed that the defective DNA mismatch repair (MMR)-re-Aging is a major risk factor for cancer development. Indeed, 60% of people with cancer in Switzerland and worldwide are older than 65 years.…”

“…[14][15][16][17] Another challenge is that despite the increasing number of older people in lated signature 6 (SI6) was negatively correlated with patient age. 40 Another step towards targeted, personalized medicine for older cancer patients would be to use gene expression profiling to improve prognostication and thus more appropriate treatment selection. 41…”