Exploring the implications of distinct mutational signatures and mutation rates in aging and cancer

Abstract

Editorial summarySignatures of mutagenesis provide a powerful tool for dissecting the role of somatic mutations in both normal and pathological processes. Significantly, cancer genomes are dominated by mutation signatures distinct from those that accumulate in normal tissues with age, with potentially important translational implications.

Somatic genome alterations in relation to age in lung adenocarcinoma

“…The TP53 ‐mutated subcohort also displayed the concurrent ongoing accumulation of SI1 along patient aging. SI1 is largely made up of C>T substitutions at CpG dinucleotides, which are the results of an endogenous mutational process initiated by spontaneous deamination of 5‐methylcytosine, enzymatic deamination of cytosine or polymerase errors . The SI3 associated with failure of DNA double‐strand break‐repair by homologous recombination was as well increasing along patient age in the TP53 ‐mutated subcohort.…”

“…Mathematical modeling strongly suggests that half or more of somatic passengers mutations in tumors arise before initiation of the tumor, that is, during development and aging . They are classified as either “driver” mutations, which initiate the tumor and confer selected cancer phenotypes, or the far more numerous “passenger” mutations which have minor impact on cell growth and proliferation but they might built strength to cancer progression or confer resistance to the treatments . Indeed, several studies illustrated the ongoing aging‐related process of accumulation of mutations, selection, and clonal expansion .…”

“…4 They are classified as either "driver" mutations, which initiate the tumor and confer selected cancer phenotypes, or the far more numerous "passenger" mutations which have minor impact on cell growth and proliferation but they might built strength to cancer progression or confer resistance to the treatments. [5][6][7] Indeed, several studies illustrated the ongoing aging-related process of accumulation of mutations, selection, and clonal expansion. 8 Furthermore, the age at diagnosis is very closely correlated with the duration of smoking, therefore aging-and smoking-related mutations should be simultaneously taken into account.…”

Chemically-Induced DNA Damage, Mutagenesis, and Cancer

“…Resveratrol triggered apoptosis within human T-cell acute lymphoblastic leukemia MOLT-4 cells by abrogating Akt phosphorylation, and subsequently preventing GSK3β from being activated [135]. Similarly, resveratrol induced apoptosis in ovarian, [136] breast, [137] uterine, [138] prostate, [120] and multiple myeloma cells [121], via inhibiting Akt phosphorylation. Chen et al [139] determined that resveratrol inhibited the phosphorylation of PI3K/Akt (i.e., PI3K/Akt inactivation) in prostate cancer cells, resulting in decreased Forkhead box protein (FOXO) activation.…”

“…The advent of next-generation sequencing technologies has enabled large-scale sequencing of all protein-coding exons (whole-exome sequencing) or even whole cancer genomes (whole-genome sequencing) in a single experiment [132][133][134][135][136][137][138]. These sequencing efforts have enabled the identification of many thousands of mutations per cancer which provided sufficient power to detect different mutational patterns or "signatures."…”