Aging and the rise of somatic cancer-associated mutations in normal tissues - PubMed (original) (raw)

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Aging and the rise of somatic cancer-associated mutations in normal tissues

Rosa Ana Risques et al. PLoS Genet. 2018.

Abstract

DNA mutations are inevitable. Despite proficient DNA repair mechanisms, somatic cells accumulate mutations during development and aging, generating cells with different genotypes within the same individual, a phenomenon known as somatic mosaicism. While the existence of somatic mosaicism has long been recognized, in the last five years, advances in sequencing have provided unprecedented resolution to characterize the extent and nature of somatic genetic variation. Collectively, these new studies are revealing a previously uncharacterized aging phenotype: the accumulation of clones with cancer driver mutations. Here, we summarize the most recent findings, which converge in the novel notion that cancer-associated mutations are prevalent in normal tissue and accumulate with aging.

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Conflict of interest statement

Scott Kennedy has read the journal's policy and has the following conflicts to report: 1) He is a paid consultant and equity holder of TwinStrand BioSciences Inc; 2) he has a submitted two patent application concerning methods to detect low frequency mutations with a priority date of 3/23/17; 3) he is the recipient of patent royalty payments concerning Duplex Sequencing; and 4) he has a research program funded by three grants from the Department of Defense and one from the National Institute of Justice. Rosa Ana Risques has read the journal's policy and is declaring that her research program is funded by two grants from the National Institutes of Health, one of which is a SBIR grant with TwinStrand BioSciences, Inc., a grant from the Rivkin Center for Ovarian Cancer, and a grant from the Mary Kay Foundation.

Figures

Fig 1

Fig 1. The hidden burden of somatic mutations.

The extent of somatic mutations in healthy tissues can be thought of as an iceberg, such that the true prevalence of these mutations is only now being recognized as technologies have improved (right column). The limit of detection refers to the ability to identify a certain mutation within a given biopsy. The cumulative results of recent studies have shown that cancer-associated mutations (left column) are found in the population with a prevalence (middle column) that is indirectly proportional to the size of the clones and the age of the individuals. That is, large clones (>10% MAF of a given biopsy) have low prevalence and are typically found only in old individuals, whereas small clones (<0.1%) are very prevalent, also at mid age. CNV, Copy Number Variant; ddPCR, Digital Droplet PCR; in/dels, insertions and deletions; iPSC, Induced Pluripotent Stem-Cell; MAF, Mutant Allele Fraction; NGS, Next Generation Sequencing; RT-PCR, Real Time Polymerase Chain Reaction; SNP, Single Nucleotide Polymorphism; SNV, Single Nucleotide Variant.

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