The etiology of clonal mosaicism in human aging and disease

Our DNA is consistently assaulted by a variety of intrinsic and extrinsic mutational factors. Fortunately, DNA repair provides for protective barriers that limit the full manifestation of DNA damage. Yet, DNA repair represents no panacea as DNA damage continuously slips through these erected defense...

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Bibliographic Details
Published in:Aging and cancer Vol. 4; no. 1; pp. 3 - 20
Main Authors: Massaar, Sanne, Sanders, Mathijs A.
Format: Journal Article
Language:English
Published: Hoboken John Wiley & Sons, Inc 01.03.2023
Wiley
Subjects:
Age
Aging
Amino acids
Cancer
cancer & DNA repair
Cell division
clonal expansion
DNA damage
DNA methylation
DNA repair
Epigenetics
Genes
Genomes
Mutation
Radiation
somatic mutation
Stem cells
ISSN:2643-8909, 2643-8909
Online Access:Get full text
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Summary:Our DNA is consistently assaulted by a variety of intrinsic and extrinsic mutational factors. Fortunately, DNA repair provides for protective barriers that limit the full manifestation of DNA damage. Yet, DNA repair represents no panacea as DNA damage continuously slips through these erected defenses and materializes as mutation, which can have undesirable consequences as seen for cancer. Acquisition of early driver mutations can engender mutated stem cells with increased cellular fitness resulting in clonal expansion (CE) and increased risk of malignant disease. Tissue clonal mosaicism as observed in the elderly is therefore the natural outcome of continuous driver mutation acquisition in stem cells and their subsequent clonal outgrowth. Hence, a major emerging theme is that CE is an idiosyncrasy of the aging human tissue. This phenomenon can have diverse health consequences that we here divide into three categories: cancer, non‐cancer morbidity, and disease protection. This review outlines current day knowledge on clonal outgrowth, how it relates to health and aging, and how in the framework of DNA repair deficiencies these subjects are consolidated. Our DNA is consistently assaulted by a variety of intrinsic and extrinsic mutational factors. Fortunately, DNA repair provides for protective barriers that limit the full manifestation of DNA damage. Yet, DNA repair represents no panacea as DNA damage continuously slips through these erected defenses and materializes as mutation, which can have undesirable consequences as seen for cancer. Acquisition of early driver mutations can engender mutated stem cells with increased cellular fitness resulting in clonal expansion (CE) and increased risk of malignant disease. Tissue clonal mosaicism as observed in the elderly is therefore the natural outcome of continuous driver mutation acquisition in stem cells and their subsequent clonal outgrowth. Hence, a major emerging theme is that CE is an idiosyncrasy of the aging human tissue. This phenomenon can have diverse health consequences that we here divide into three categories: cancer, non‐cancer morbidity, and disease protection. This review outlines current day knowledge on clonal outgrowth, how it relates to health and aging and how in the framework of DNA repair deficiencies these subjects are consolidated.
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ISSN:2643-8909
2643-8909
DOI:10.1002/aac2.12061