A high resolution genomic portrait of bladder cancer: correlation between genomic aberrations and the DNA damage response

Schepeler, Troels; Lamy, Philippe; Hvidberg, V; Laurberg, Jens R.; Fristrup, Niels; Reinert, Thomas; Bártková, Jiřina; Tropia, Laurence; Bártek, Jiří; Halazonetis, Thanos D.; Pan, C-C; Borre, Michael; Dyrskjøt, Lars; Ørntoft, Torben F.

doi:10.1038/onc.2012.381

Cited by 34 publications

(31 citation statements)

References 55 publications

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“…Furthermore, in various experimental models, activated oncogenes induce DNA replication stress and deletions within CFSs that are very similar to the deletions induced by aphidicolin and hydroxyurea (13)(14)(15). Finally, DNA replication stress is prevalent in human precancerous lesions and cancers and is associated with focal deletions within CFSs (16)(17)(18). Taken together, these observations suggest that oncogene-induced DNA replication stress is responsible for the focal deletions and LOH observed at CFSs in human precancerous lesions and cancers (4)(5)(6).…”

Section: Introductionsupporting

confidence: 54%

A Single-Nucleotide Substitution Mutator Phenotype Revealed by Exome Sequencing of Human Colon Adenomas

et al. 2012

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Oncogene-induced DNA replication stress is thought to drive genomic instability in cancer. In particular, replication stress can explain the high prevalence of focal genomic deletions mapping within very large genes in human tumors. However, the origin of single-nucleotide substitutions (SNS) in nonfamilial cancers is strongly debated. Some argue that cancers have a mutator phenotype, whereas others argue that the normal DNA replication error rates are sufficient to explain the number of observed SNSs. Here, we sequenced the exomes of 24, mostly precancerous, colon polyps. Analysis of the sequences revealed mutations in the APC, CTNNB1, and BRAF genes as the presumptive cancer-initiating events and many passenger SNSs. We used the number of SNSs in the various lesions to calculate mutation rates for normal colon and adenomas and found that colon adenomas exhibit a mutator phenotype. Interestingly, the SNSs in the adenomas mapped more often than expected within very large genes, where focal deletions in response to DNA replication stress also map. We propose that single-stranded DNA generated in response to oncogene-induced replication stress compromises the repair of deaminated cytosines and other damaged bases, leading to the observed SNS mutator phenotype. Cancer Res; 72(23); 6279-89. Ó2012 AACR.

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Section: Introductionsupporting

confidence: 54%

A Single-Nucleotide Substitution Mutator Phenotype Revealed by Exome Sequencing of Human Colon Adenomas

et al. 2012

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“…Furthermore, numerical chromosomal instability and one-off events such as whole-genome duplications and a newly described phenomenon known as ‘chromothripsis’ can all prevent the accurate measurement of HRD-related scars [32]. Chromothripsis, which is a single chromosomal shattering event followed by reconstitution of the genomic fragments, results in localized, complex rearrangements that, even if they have a basis in a targetable HR deficiency, can result in an overestimate of the gravity, and hence exploitability, of the defect [38,39]. In contrast, events that spatially overlap in such a way that only the effects of one are countable can lead to an underestimate of the extent of genomic instability [29].…”

Section: Genomic Scars As Reporters Of Homologous Recombination Deficmentioning

confidence: 99%

Genomic scars as biomarkers of homologous recombination deficiency and drug response in breast and ovarian cancers

et al. 2014

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Poly (ADP-ribose) polymerase (PARP) inhibitors and platinum-based chemotherapies have been found to be particularly effective in tumors that harbor deleterious germline or somatic mutations in the BRCA1 or BRCA2 genes, the products of which contribute to the conservative homologous recombination repair of DNA double-strand breaks. Nonetheless, several setbacks in clinical trial settings have highlighted some of the issues surrounding the investigation of PARP inhibitors, especially the identification of patients who stand to benefit from such drugs. One potential approach to finding this patient subpopulation is to examine the tumor DNA for evidence of a homologous recombination defect. However, although the genomes of many breast and ovarian cancers are replete with aberrations, the presence of numerous factors able to shape the genomic landscape means that only some of the observed DNA abnormalities are the outcome of a cancer cell’s inability to faithfully repair DNA double-strand breaks. Consequently, recently developed methods for comprehensively capturing the diverse ways in which homologous recombination deficiencies may arise beyond BRCA1/2 mutation have used DNA microarray and sequencing data to account for potentially confounding features in the genome. Scores capturing telomeric allelic imbalance, loss of heterozygosity (LOH) and large scale transition score, as well as the total number of coding mutations are measures that summarize the total burden of certain forms of genomic abnormality. By contrast, other studies have comprehensively catalogued different types of mutational pattern and their relative contributions to a given tumor sample. Although at least one study to explore the use of the LOH scar in a prospective clinical trial of a PARP inhibitor in ovarian cancer is under way, limitations that result in a relatively low positive predictive value for these biomarkers remain. Tumors whose genome has undergone one or more events that restore high-fidelity homologous recombination are likely to be misclassified as double-strand break repair-deficient and thereby sensitive to PARP inhibitors and DNA damaging chemotherapies as a result of prior repair deficiency and its genomic scarring. Therefore, we propose that integration of a genomic scar-based biomarker with a marker of resistance in a high genomic scarring burden context may improve the performance of any companion diagnostic for PARP inhibitors.

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“…In bladder cancer, TIM expression is correlated with risk of progression to muscle-invasive disease [12]. TIM is upregulated in lung cancer, and patients with high TIM expression have a poor prognosis [10].…”

Section: Introductionmentioning

confidence: 99%

TIMELESS contributes to the progression of breast cancer through activation of MYC

et al. 2017

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BackgroundBreast cancer is the most common malignancy and the leading cause of cancer death among women. TIMELESS (TIM), a circadian rhythm regulator, has been recently implicated in the progression of human cancer. However, the role of TIM in the progression of breast cancer has not been well-characterized.MethodsImmunohistochemistry (IHC) staining was used to examine TIM levels in breast cancer specimens. Mammosphere formation analysis and side population analysis were used to examine the effect of TIM on the self-renewal of breast cancer stem cells. A wound healing assay and a Transwell assay were used to determine the role of TIM in breast cancer cell migration and invasion. A soft agar growth assay in vitro and tumorigenicity in vivo were used to determine the role of TIM in tumorigenicity.ResultsTIM levels in both breast cancer cell lines and tissues were significantly upregulated. Patients with high TIM had poorer prognosis than patients with low TIM. Overexpression of TIM dramatically enhanced, while knockdown of TIM suppressed the self-renewal of cancer stem cells (CSCs), cell invasion and migration abilities of breast cancer cells in vitro. Moreover, overexpression of TIM significantly augmented, while knockdown of TIM reduced the tumorigenicity of breast cancer cells in vivo. Mechanism studies revealed that TIM upregulated the expression and the trans-activity of the well-known oncogene MYC. Inhibition of MYC significantly blocked the effects of TIM on CSC population, cell invasion and anchor-independent cell growth.ConclusionTIM plays an important role in promoting breast cancer progression and may represent a novel therapeutic target for breast cancer.Electronic supplementary materialThe online version of this article (doi:10.1186/s13058-017-0838-1) contains supplementary material, which is available to authorized users.

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A high resolution genomic portrait of bladder cancer: correlation between genomic aberrations and the DNA damage response

Cited by 34 publications

References 55 publications

A Single-Nucleotide Substitution Mutator Phenotype Revealed by Exome Sequencing of Human Colon Adenomas

A Single-Nucleotide Substitution Mutator Phenotype Revealed by Exome Sequencing of Human Colon Adenomas

Genomic scars as biomarkers of homologous recombination deficiency and drug response in breast and ovarian cancers

TIMELESS contributes to the progression of breast cancer through activation of MYC

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