Exome‐wide single‐base substitutions in tissues and derived cell lines of the constitutive Fhit knockout mouse

Paisie, Carolyn; Schrock, Morgan S.; Karras, Jenna R.; Zhang, Jie; Miuma, Satoshi; Ouda, Iman M.; Waters, Catherine E.; Saldivar, Joshua C.; Druck, Teresa; Huebner, Kay

doi:10.1111/cas.12887

Cited by 13 publications

(21 citation statements)

References 39 publications

(71 reference statements)

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“…T>C mutations may be due to the misincorporation of dUTP in place of dTTP, a consequence of TK1 downregulation in FHIT-deficient cells. This FHIT loss mutation profile is comparable to previously published mutation signatures reported for bladder cancer, human papillary kidney cancer, and an "age at diagnosis" signature, or aging signature, that represents accumulation of mutations in normal tissues over time [Alexandrov et al, 2013;Paisie et al, 2016]. As FHITdeficient genomes accumulate mutations, it is not surprising then that many of these mutations are found within important genes which, when altered, contribute to cellular transformation and preneoplastic changes.…”

Section: Fhit Loss-induced Cnas and Point Mutations Promote Clonal Exsupporting

confidence: 83%

“…FHIT-deficient liver tissues exhibited almost a 4-fold increase in total SBSs compared to wild-type liver tissue. Further examination of the types of transition and transversion mutations observed among these SBSs demonstrated that FHIT-deficient cells and tissues displayed prominent increases in C>T and T>C mutations, as well as slightly elevated levels of C>A, C>G, and T>A mutations [Paisie et al, 2016]. C>T mutations can be generated by spontaneous deamination or DNA replication errors.…”

Section: Fhit Loss-induced Cnas and Point Mutations Promote Clonal Exmentioning

confidence: 99%

“…This criterion is not met by FHIT loss-induced replication stress. Therefore, FHIT loss causes mild replication stress that persists through each cell division and contributes to accumulation of genome-wide instability Karras et al, 2014;Paisie et al, 2016]. Coupled with the fact that loss of FHIT expression is one of the earliest changes in the preneoplasia process, FHIT deletion is a strong candidate for being an initiator of genome instability that fuels the development of many cancers.…”

Section: Fhit Loss Causes Genome Instabilitymentioning

confidence: 99%

“…As FHITdeficient genomes accumulate mutations, it is not surprising then that many of these mutations are found within important genes which, when altered, contribute to cellular transformation and preneoplastic changes. Such genes include Mutyh , Tpx2 , Nek9 , Zfat , and Dlc1 , which are essential for DNA repair, chromosomal stability, replication stress response, cell survival, and regulation of the Wnt/β-catenin signaling pathway [Paisie et al, 2016].…”

Section: Fhit Loss-induced Cnas and Point Mutations Promote Clonal Exmentioning

confidence: 99%

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Fragile Genes That Are Frequently Altered in Cancer: Players Not Passengers

Karras¹,

Schrock²,

Batar³

et al. 2016

Cytogenet Genome Res

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FHIT, located at FRA3B, is one of the most commonly deleted genes in human cancers, and loss of FHIT protein is one of the earliest events in cancer initiation. However, location of FHIT at a chromosomal fragile site, a locus prone to breakage and gap formation under even mild replication stress, has encouraged claims that FHIT loss is a passenger event in cancers. We summarize accumulated evidence that FHIT protein functions as a genome “caretaker” required to protect the stability of genomes of normal cells of most tissues from agents causing intrinsic and extrinsic DNA damage. FHIT loss leads to intracellular replication stress and subsequent genome instability, which provides an opportunistic mutational landscape in preneoplasias for selection of a variety of other cancer-driving mutations. We also review evidence showing that FHIT loss leads to enhanced activation of other common fragile sites, including the FRA16D/WWOX locus, and creates optimal single-stranded DNA substrates for the hypermutator enzyme, APOBEC3B.

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Section: Fhit Loss-induced Cnas and Point Mutations Promote Clonal Exsupporting

confidence: 83%

Section: Fhit Loss-induced Cnas and Point Mutations Promote Clonal Exmentioning

confidence: 99%

Section: Fhit Loss Causes Genome Instabilitymentioning

confidence: 99%

Section: Fhit Loss-induced Cnas and Point Mutations Promote Clonal Exmentioning

confidence: 99%

See 2 more Smart Citations

Fragile Genes That Are Frequently Altered in Cancer: Players Not Passengers

Karras¹,

Schrock²,

Batar³

et al. 2016

Cytogenet Genome Res

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show abstract

“…In a recent report, the Huebner group analyzed whole exome sequences of Fhit -deficient tissues and cells and compared them to a control C57Bl6 genome, identifying hundreds of single-base substitutions associated with FHIT deficiency. The mutation signature is characterized by increased C>T and T>C mutations, in accordance with the signature identified in human malignancies [66]. …”

Section: Cfs Gene Products With Roles In the Ddrmentioning

confidence: 72%

Tumor Suppressor Genes within Common Fragile Sites Are Active Players in the DNA Damage Response

2016

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The role of common fragile sites (CFSs) in cancer remains controversial. Two main views dominate the discussion: one suggests that CFS loci are hotspots of genomic instability leading to inactivation of genes encoded within them, while the other view proposes that CFSs are functional units and that loss of the encoded genes confers selective pressure, leading to cancer development. The latter view is supported by emerging evidence showing that expression of a given CFS is associated with genome integrity and that inactivation of CFS-resident tumor suppressor genes leads to dysregulation of the DNA damage response (DDR) and increased genomic instability. These two viewpoints of CFS function are not mutually exclusive but rather coexist; when breaks at CFSs are not repaired accurately, this can lead to deletions by which cells acquire growth advantage because of loss of tumor suppressor activities. Here, we review recent advances linking some CFS gene products with the DDR, genomic instability, and carcinogenesis and discuss how their inactivation might represent a selective advantage for cancer cells.

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Mechanisms shaping the mutational landscape of the FRA3B/FHIT‐deficient cancer genome

Saldivar

Park

2018

Genes Chromosomes & Cancer

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Genome instability is an enabling characteristic of cancer that facilitates the acquisition of oncogenic mutations that drive tumorigenesis. Underlying much of the instability in cancer is DNA replication stress, which causes both chromosome structural changes and single base‐pair mutations. Common fragile sites are some of the earliest and most frequently altered loci in tumors. Notably, the fragile locus, FRA3B, lies within the fragile histidine triad (FHIT) gene, and consequently deletions within FHIT are common in cancer. We review the evidence in support of FHIT as a DNA caretaker and discuss the mechanism by which FHIT promotes genome stability. FHIT increases thymidine kinase 1 (TK1) translation to balance the deoxyribonucleotide triphosphates (dNTPs) for efficient DNA replication. Consequently, FHIT‐loss causes replication stress, DNA breaks, aneuploidy, copy‐number changes (CNCs), small insertions and deletions, and point mutations. Moreover, FHIT‐loss‐induced replication stress and DNA breaks cooperate with APOBEC3B overexpression to catalyze DNA hypermutation in cancer, as APOBEC family enzymes prefer single‐stranded DNA (ssDNA) as substrates and ssDNA is enriched at sites of both replication stress and DNA breaks. Consistent with the frequent loss of FHIT across a broad spectrum of cancer types, FHIT‐deficiency is highly associated with the ubiquitous, clock‐like mutation signature 5 occurring in all cancer types thus far examined. The ongoing destabilization of the genome caused by FHIT loss underlies recurrent inactivation of tumor suppressors and activation of oncogenes. Considering that more than 50% of cancers are FHIT‐deficient, we propose that FRA3B/FHIT fragility shapes the mutational landscape of cancer genomes.

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Exome‐wide single‐base substitutions in tissues and derived cell lines of the constitutive Fhit knockout mouse

Cited by 13 publications

References 39 publications

Fragile Genes That Are Frequently Altered in Cancer: Players Not Passengers

Fragile Genes That Are Frequently Altered in Cancer: Players Not Passengers

Tumor Suppressor Genes within Common Fragile Sites Are Active Players in the DNA Damage Response

Mechanisms shaping the mutational landscape of the FRA3B/FHIT‐deficient cancer genome

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