Genomic-Destabilization-Associated Mutagenesis and Clonal Evolution of Cells with Mutations in Tumor-Suppressor Genes

Yoshioka, Kenichi; Matsuno, Yusuke; Hyodo, Mai; Fujimori, Haruka

doi:10.3390/cancers11111643

Cited by 12 publications

(16 citation statements)

References 95 publications

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“…The conventional view is that most mutations, including cancer-driver mutations, are randomly induced during DNA replication; therefore, the majority of cancers are unavoidable 41 . However, a recent study reported that, unlike mutations induced during canonical replication, those caused by replication stress along with genomic destabilisation can be avoided through genome stability maintenance 42 . Mutations induced during canonical replication are limited, even in MMR-deficient cells that cannot repair errors caused by replication forks; however, massive numbers of mutations occur under replication stress in association with genomic destabilisation, leading to clonal evolution of cells with abrogated defence systems 2 .…”

Section: Discussionmentioning

confidence: 99%

Resveratrol and its Related Polyphenols Contribute to the Maintenance of Genome Stability

Matsuno

Atsumi²,

Alauddin

et al. 2020

Sci Rep

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Genomic destabilisation is associated with the induction of mutations, including those in cancer-driver genes, and subsequent clonal evolution of cells with abrogated defence systems. Such mutations are not induced when genome stability is maintained; however, the mechanisms involved in genome stability maintenance remain elusive. Here, resveratrol (and related polyphenols) is shown to enhance genome stability in mouse embryonic fibroblasts, ultimately protecting the cells against the induction of mutations in the ARF/p53 pathway. Replication stress-associated DNA double-strand breaks (DSBs) that accumulated with genomic destabilisation were effectively reduced by resveratrol treatment. In addition, resveratrol transiently stabilised the expression of histone H2AX, which is involved in DSB repair. Similar effects on the maintenance of genome stability were observed for related polyphenols. Accordingly, we propose that polyphenol consumption can contribute to the suppression of cancers that develop with genomic instability, as well as lifespan extension. Most cancers are associated with genomic instability, which can be categorised as chromosomal instability or microsatellite instability (MSI) 1. Genomic destabilisation is a major cause of mutations, including those in cancer-driver genes, and can lead to clonal evolution of cells with abrogated defence systems, such as those containing mutations in the ARF/p53 pathway 2. Genome stability maintenance would likely prevent the formation of mutations and suppress cancer development; however, it is still unclear if genome stability can be maintained in vivo and whether this process can indeed suppress the occurrence of cancer. Genomic instability is caused by the erroneous repair of DNA double-strand breaks (DSBs); paradoxically, the DNA repair systems of most cancers that develop with genomic instability are genetically normal 3. The mechanisms by which normal cells accumulate DSBs remain unclear, but DSBs widely accumulate in pre-cancerous cells and are accompanied by genomic instability 2,4-6. In vitro, replication stress-associated DSBs and the associated genomic instability are observed in cells subjected to aberrant growth stimulation 2 or overexpression of oncogenes such as c-Myc and E2F1 6-8. Possibly reflecting the correlation between cancer development and age, DSBs accumulate with age in vivo and with cultivating passages in vitro 9 , suggesting that ageing cells are defective in DSB repair. DSB repair deficiency is probably related at least in part to a reduction in the level of H2AX. This histone mediates DSB repair and is required for genome stability maintenance, and H2AX expression levels are attenuated when the growth rate of normal cells slows down 10,11. In fact, such cells are defective in repairing replication stress-associated DSBs 10 ,

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Section: Discussionmentioning

confidence: 99%

Resveratrol and its Related Polyphenols Contribute to the Maintenance of Genome Stability

Matsuno

Atsumi²,

Alauddin

et al. 2020

Sci Rep

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“…Polymerase slippage induced MSI has been observed to show preference for contraction than extension (6, 31, 38, 39), although the underlying mechanism has not entirely been clear (40). We have demonstrated in this study that deletion-ratio is a good abstraction of allele count information.…”

Section: Discussionmentioning

confidence: 99%

bMSI-CAST: a systematic method for next generation sequencing-based microsatellite instability detection in plasma cell-free DNA

Huang

Zhao

Xie

et al. 2021

Preprint

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Microsatellite instability (MSI) is a phenotypic manifestation of mismatch repair (MMR) deficiency and has been used as a biomarker through NGS-based assays to aid clinical cancer diagnosis and prognosis, as being advantageous over traditional electrophoresis-based tests and immunohistochemistry. Critical to detection accuracy but seldomly systematically discussed and poorly resolved by currently available methods are topics such as influences of changing experimental conditions, MSI-specific duplication removal and tradeoffs associated with loci selection strategies. In seeking solution to these questions, we have developed b/tMSI-CAST (blood/tissue MSI Caller Adjusted with Sequence duplicaTes), an integrated method consisting of a set of loci selection principles, an MSI-specific duplication removal strategy and a two-mode calling algorithm targeting both blood and tissue samples, equipped with a baseline construction method based on duplication distributions. We benchmarked b/tMSI-CAST against two established tools, mSINGS and MSIsensor-pro and found b/tMSI-CAST showed matched performance as MSIsensor-pro and outperformed mSINGS. We further applied it to a retrospective cohort of 18084 clinical samples to present a comprehensive landscape view on MSI prevalence across 26 cancer types, the largest of its kind in Chinese population so far, and demonstrated it on presurgical cfDNA samples of patients with early stage cancers.

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“…CIN was proposed to arise when the DSBs are not effectively repaired in S and G2 phases by the HR. Following a defective mitosis, such DNA breaks activate DDR in the G1 phase of the next cell cycle and eventually are ligated to incorrect broken ends by NHEJ, leading to chromosomal alterations [90,91]. Tumors with CIN represent distinct type of genomic instability in CRC (about 60% of all cases), characterized by chromosomal rearrangements and aneuploidy, gene amplifications and deletions, loss of heterozygosity (LOH), and micronuclei [92].…”

Section: Mmr-deficient Phenotypes In Colorectal Cancersmentioning

confidence: 99%

Analyzing the Opportunities to Target DNA Double-Strand Breaks Repair and Replicative Stress Responses to Improve Therapeutic Index of Colorectal Cancer

Tomasini

Guecheva²,

Leguisamo³

et al. 2021

Cancers

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Despite the ample improvements of CRC molecular landscape, the therapeutic options still rely on conventional chemotherapy-based regimens for early disease, and few targeted agents are recommended for clinical use in the metastatic setting. Moreover, the impact of cytotoxic, targeted agents, and immunotherapy combinations in the metastatic scenario is not fully satisfactory, especially the outcomes for patients who develop resistance to these treatments need to be improved. Here, we examine the opportunity to consider therapeutic agents targeting DNA repair and DNA replication stress response as strategies to exploit genetic or functional defects in the DNA damage response (DDR) pathways through synthetic lethal mechanisms, still not explored in CRC. These include the multiple actors involved in the repair of DNA double-strand breaks (DSBs) through homologous recombination (HR), classical non-homologous end joining (NHEJ), and microhomology-mediated end-joining (MMEJ), inhibitors of the base excision repair (BER) protein poly (ADP-ribose) polymerase (PARP), as well as inhibitors of the DNA damage kinases ataxia-telangiectasia and Rad3 related (ATR), CHK1, WEE1, and ataxia-telangiectasia mutated (ATM). We also review the biomarkers that guide the use of these agents, and current clinical trials with targeted DDR therapies.

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Genomic-Destabilization-Associated Mutagenesis and Clonal Evolution of Cells with Mutations in Tumor-Suppressor Genes

Cited by 12 publications

References 95 publications

Resveratrol and its Related Polyphenols Contribute to the Maintenance of Genome Stability

Resveratrol and its Related Polyphenols Contribute to the Maintenance of Genome Stability

bMSI-CAST: a systematic method for next generation sequencing-based microsatellite instability detection in plasma cell-free DNA

Analyzing the Opportunities to Target DNA Double-Strand Breaks Repair and Replicative Stress Responses to Improve Therapeutic Index of Colorectal Cancer

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