Studies of genomic copy number changes in human cancers reveal signatures of DNA replication stress

Dereli-Öz, Aygül; Versini, Gwennaëlle; Halazonetis, Thanos D.

doi:10.1016/j.molonc.2011.05.002

Cited by 72 publications

(60 citation statements)

References 50 publications

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“…Overall, the characterization of oncogene-induced FSs demonstrates that they share prominent features with aphidicolin-induced FSs such as colocalization with cancer genomic instability hotspots and large genes. Our results showing an overlap between oncogene-induced FSs and large genes further support the possibility that most large genes are actually FSs under specific replication stress conditions that were not yet discovered 18,27 .…”

Section: Discussionsupporting

confidence: 80%

Oncogenes create a unique landscape of fragile sites

et al. 2015

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Recurrent genomic instability in cancer is attributed to positive selection and/or the sensitivity of specific genomic regions to breakage. Among these regions are fragile sites (FSs), genomic regions sensitive to replication stress conditions induced by the DNA polymerase inhibitor aphidicolin. However, the basis for the majority of cancer genomic instability hotspots remains unclear. Aberrant oncogene expression induces replication stress, leading to DNA breaks and genomic instability. Here we map the cytogenetic locations of oncogene-induced FSs and show that in the same cells, each oncogene creates a unique fragility landscape that only partially overlaps with aphidicolin-induced FSs. Oncogene-induced FSs colocalize with cancer breakpoints and large genes, similar to aphidicolin-induced FSs. The observed plasticity in the fragility landscape of the same cell type following oncogene expression highlights an additional level of complexity in the molecular basis for recurrent fragility in cancer.

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Section: Discussionsupporting

confidence: 80%

Oncogenes create a unique landscape of fragile sites

et al. 2015

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“…Genes encoding proteins that are implicated in the EGFR/PI3K pathway are labeled in red. DNA alterations are known to be influenced by chromatin structure and features of the neighboring DNA sequence (40,41). Our data here suggest that CNAs in these four components of the EGFR/PI3K pathway are important for pathway activation in HNSCC, although we cannot definitively rule out involvement of other genes within the regions of CNA.…”

Section: Protein Tyrosine Phosphatase Receptor S (Ptprs) Is Frequentlymentioning

confidence: 58%

Genomic dissection of the epidermal growth factor receptor (EGFR)/PI3K pathway reveals frequent deletion of the EGFR phosphatase PTPRS in head and neck cancers

Morris¹,

Taylor²,

Bivona³

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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Activation of the PI3K and epidermal growth factor receptor (EGFR) pathway is able to drive oncogenesis in multiple human cancers, including head and neck squamous cell carcinoma. Targeted agents such as cetuximab and erlotinib are currently used in patients with head and neck squamous cell carcinoma, but, in this disease, the genomic alterations that cause pathway activation and determine response to pharmacologic inhibition remain ill-defined. Here, we present a detailed dissection of the EGFR/PI3K pathway, composed of sequencing of the core pathway components, and high-resolution genomic copy number assessment. Mutations were found in PIK3CA (6%), but no point mutations were observed in other pathway genes such as PTEN and EGFR . In contrast, we observed frequent copy number alterations of genes in the pathway, including PIK3CA , EGFR , protein tyrosine phosphatase receptor S ( PTPRS ), and RICTOR . In total, activating genetic pathway alterations were identified in 74% of head and neck tumors. Importantly, intragenic microdeletions of the EGFR phosphatase PTPRS were frequent (26%), identifying this gene as a target of 19p13 loss. PTPRS loss promoted EGFR/PI3K pathway activation, modulated resistance to EGFR inhibition, and strongly determined survival in lung cancer patients with activating EGFR mutations. These findings have important implications for our understanding of head and neck cancer tumorigenesis and for the use of targeted agents for this malignancy.

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“…Incomplete replication causes DNA damage and has been linked to rearrangements at common fragile sites and chromosomal instability, the most common form of genomic instability in sporadic cancers. [45][46][47] Higher levels of origin firing mean that more replication forks are active simultaneously, and it appears likely that replication elongation factors such as deoxyribonucelotides (dNTPs) become limiting under these conditions. Indeed, it was recently reported that Cyclin E overexpression decreased dNTP pools, resulting in decreased replication fork progression and replication stress.…”

Section: Discussionmentioning

confidence: 99%

Increased replication initiation and conflicts with transcription underlie Cyclin E-induced replication stress

et al. 2012

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It has become increasingly clear that oncogenes not only provide aberrant growth signals to cells but also cause DNA damage at replication forks (replication stress), which activate the ataxia telangiectasia mutated (ATM)/p53-dependent tumor barrier. Here we studied underlying mechanisms of oncogene-induced replication stress in cells overexpressing the oncogene Cyclin E. Cyclin E overexpression is associated with increased firing of replication origins, impaired replication fork progression and DNA damage that activates RAD51-mediated recombination. By inhibiting replication initiation factors, we show that Cyclin E-induced replication slowing and DNA damage is a consequence of excessive origin firing. A significant amount of Cyclin E-induced replication slowing is due to interference between replication and transcription, which also underlies the activation of homologous recombination. Our data suggest that Cyclin E-induced replication stress is caused by deregulation of replication initiation and increased interference between replication and transcription, which results in impaired replication fork progression and DNA damage triggering the tumor barrier or cancer-promoting mutations.Oncogene ( Keywords: Cyclin E; replication fork; origin firing; DNA damage; homologous recombination INTRODUCTION Faithful replication of the genome is essential to maintain genomic stability and prevent cancer-promoting mutations. If the progression of replication forks is impaired, this can lead to replicationassociated DNA damage, also known as replication stress. It is now recognized that replication stress induced by oncogenes is an important factor that underlies the activation of the ataxia telangiectasia mutated (ATM)-and p53-mediated tumor barriers of senescence and apoptosis. [1][2][3][4][5][6][7] There is currently no coherent model to explain how oncogenes induce replication stress and DNA damage. Oncogenes of the growth factor signaling pathways generally activate cell proliferation by deregulating the transition from G1 to S phase of the cell cycle.8 Deregulated S-phase entry leading to aberrant DNA replication is therefore likely a principal mechanism of oncogene-induced replication stress. It has been reported that overexpression of the oncogenes HPV-16 E6/E7 and Cyclin E leads to S-phase entry in the presence of insufficient nucleotide pools, leading to impaired DNA replication fork progression and DNA damage.9 However, the underlying mechanism for the nucleotide depletion observed in the presence of oncogenes is not clear, and not all oncogenes that deregulate S-phase entry induce DNA damage. 10 The mechanisms of aberrant DNA replication and oncogene-induced replication stress therefore deserve further scrutiny.During a normal cell cycle, not only entry into S phase but also the timing of DNA replication initiation during S phase is carefully regulated by cell cycle and checkpoint signaling pathways.

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Studies of genomic copy number changes in human cancers reveal signatures of DNA replication stress

Cited by 72 publications

References 50 publications

Oncogenes create a unique landscape of fragile sites

Oncogenes create a unique landscape of fragile sites

Genomic dissection of the epidermal growth factor receptor (EGFR)/PI3K pathway reveals frequent deletion of the EGFR phosphatase PTPRS in head and neck cancers

Increased replication initiation and conflicts with transcription underlie Cyclin E-induced replication stress

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