Functional Mutations Form at CTCF-Cohesin Binding Sites in Melanoma Due to Uneven Nucleotide Excision Repair across the Motif

Poulos, Rebecca C.; Thoms, Julie A.I.; Guan, Yi Fang; Unnikrishnan, Ashwin; Pimanda, John E.; Wong, Jason

doi:10.1016/j.celrep.2016.11.055

Cited by 68 publications

(95 citation statements)

References 28 publications

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“…Strikingly, dypirimidine positions 10 and 11 comprised the vast majority of all mutations, whereas mutation density was comparably low at other dipyrimidine or cytosine positions (Figure 3c, 3d). This is consistent with findings by Poulos et al (2016), who suggest that differential rates of repair at specific motif positions cause this asymmetry.…”

Section: Uv-induced Mutations At Insulator Sitessupporting

confidence: 92%

“…However, an adequate determination of differential expression would require much larger cohorts (including UV-affected normal skin) and gene panels. Poulos et al ( 2016) reported similar issues even when using RNA-Seq in 36 melanoma samples. Nevertheless, they were able to show that expression of cancerassociated genes in affected TAD loops was statistically different from wildtype TAD loops.…”

Section: Uv-induced Mutations At Insulator Sitesmentioning

confidence: 86%

“…To assess mutations at CTCFbs, filtering occurred in two steps to limit false positives, as reported by Poulos et al (2016). First, we selected CTCFbs harboring a strict motif including the central 13 bp of the 19 bp consensus motif (Mathelier et al, 2016).…”

Section: Ctcf Binding Site Mutation Assessmentmentioning

confidence: 99%

“…Here, we analyze genome-wide mutations in regard to their trinucleotide context, present the first signature analysis of cSCC metastases and explore its clinical utility. We further assess the distribution of UV-induced mutations across the genome, and assess the potential impact on CTCF using the approach described by Poulos et al (2016) in melanoma.…”

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confidence: 99%

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Mutational Patterns in Metastatic Cutaneous Squamous Cell Carcinoma

Mueller

Gauthier

Ashford

et al. 2019

Journal of Investigative Dermatology

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Cutaneous squamous cell carcinoma from the head and neck typically metastasize to the lymph nodes of the neck and parotid glands. When a primary is not identified, they are difficult to distinguish from metastases of mucosal origin and primary salivary gland squamous cell carcinoma. UV radiation causes a mutation pattern that predominantly features cytosine to thymine transitions at dipyrimidine sites and has been associated with cutaneous squamous cell carcinoma. In this study, we used whole genome sequencing data from 15 cutaneous squamous cell carcinoma metastases and show that a UV mutation signature is pervasive across the cohort and distinct from mucosal squamous cell carcinoma. The mutational burden was exceptionally high and concentrated in some regions of the genome, especially insulator elements (mean 162 mutations/megabase). We therefore evaluated the likely impact of UVinduced mutations on the dipyrimidine-rich binding site of the main human insulator protein, CCCTCbinding factor, and the possible implications on CCCTC-binding factor function and the spatial organization of the genome. Our findings suggest that mutation signature analysis may be useful in determining the origin of metastases in the neck and the parotid gland. Furthermore, UV-induced DNA damage to insulator binding sites may play a role in the carcinogenesis and progression of cutaneous squamous cell carcinoma.

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Section: Uv-induced Mutations At Insulator Sitessupporting

confidence: 92%

Section: Uv-induced Mutations At Insulator Sitesmentioning

confidence: 86%

Section: Ctcf Binding Site Mutation Assessmentmentioning

confidence: 99%

mentioning

confidence: 99%

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Mutational Patterns in Metastatic Cutaneous Squamous Cell Carcinoma

Mueller

Gauthier

Ashford

et al. 2019

Journal of Investigative Dermatology

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“…2a.14-21), which are all part of the cohesin complex 32 . Recently, an elevated SNV rate at binding sites of the cohesin complex have been reported for several cancer types by others 33,34 . The cohesin complex is a key player in formation and maintenance of topological chromatin domains 35,36 , suggesting that noncoding mutations could play a role shaping the chromatin structure during cancer development.…”

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confidence: 95%

Pan-cancer screen for mutations in non-coding elements with conservation and cancer specificity reveals correlations with expression and survival

Hornshøj

Nielsen

Sinnott‐Armstrong

et al. 2017

Preprint

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Cancer develops by accumulation of somatic driver mutations, which impact cellular function. Noncoding mutations in non-coding regulatory regions can now be studied genome-wide and further characterized by correlation with gene expression and clinical outcome to identify driver candidates. Using a new two-stage procedure, called ncDriver, we first screened 507 ICGC wholegenomes from ten cancer types for non-coding elements, in which mutations are both recurrent and have elevated conservation or cancer specificity. This identified 160 significant non-coding elements, including the TERT promoter, a well-known non-coding driver element, as well as elements associated with known cancer genes and regulatory genes (e.g., PAX5, TOX3, PCF11, MAPRE3). However, in some significant elements, mutations appear to stem from localized mutational processes rather than recurrent positive selection in some cases. To further characterize the driver potential of the identified elements and shortlist candidates, we identified elements where presence of mutations correlated significantly with expression levels (e.g. TERT and CDH10) and survival (e.g. CDH9 and CDH10) in an independent set of 505 TCGA whole-genome samples. In a larger pan-cancer set of 4,128 TCGA exomes with expression profiling, we identified mutational correlation with expression for additional elements (e.g., near GATA3, CDC6, ZNF217 and CTCF transcription factor binding sites). Survival analysis further pointed to MIR122, a known marker of poor prognosis in liver cancer. This screen for significant mutation patterns followed by correlative mutational analysis identified new individual driver candidates and suggest that some non-coding mutations recurrently affect expression and play a role in cancer development.

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cis ‐Regulatory Driver Mutations in Cancer Genomes

Poulos

Wong

2017

Encyclopedia of Life Sciences

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The increasing availability of large‐scale whole cancer genome sequencing data sets has enabled research efforts to focus on cancer driver mutations within the noncoding genome. cis ‐Regulatory elements are sites responsible for the control of gene expression. Mutations at such loci may modify transcription factor binding sites, disrupt enhancer–promoter interactions or affect epigenetic marks. cis ‐Regulatory driver mutations have been found in some cancer types to‐date, with initial discoveries of point mutations in the TERT promoter, small insertions creating an enhancer regulating TAL1 and genomic rearrangements leading to simultaneous enhancer dysregulation of EVI1 and GATA2 . However, recent discoveries have also revealed mechanisms responsible for the accumulation of recurrent, and even functional, somatic single‐nucleotide mutations in regulatory regions, wholly apart from selective pressure. Close scrutiny of candidate cis ‐regulatory mutations is necessary in order to effectively identify mutations that have undergone positive selection and to accurately distinguish driver from passenger mutations. Key Concepts Improvements in DNA sequencing technology, and the commencement of large‐scale cancer genome sequencing projects, have made discoveries in the noncoding genome possible. cis ‐Regulatory elements, such as promoters and enhancers, are responsible for the control of gene expression. Transcription factors bind to cis ‐regulatory elements, influencing the rate of transcription of DNA to mRNA. Mutations in cis ‐regulatory elements can drive cancer development by altering transcription factor binding sites, enhancer–promoter interactions or the epigenetic landscape of the cell. Alterations to cis ‐regulatory elements can lead to gene dysregulation, potentially impacting the expression of oncogenes or tumour suppressor genes. Recurrent somatic driver mutations affecting cis ‐regulatory elements have already been identified in cancer genomes, including point mutations, insertions and deletions (indels) and structural rearrangements. cis ‐Regulatory elements may appear recurrently mutated in cancer due to selective pressures or due to other mechanisms driving the formation of mutation hot spots. Transcription factor binding can inhibit access to nucleotide excision repair (NER) enzymes, leading to increased mutation rates at transcription factor binding sites in some cancers. DNA modifications and nucleotide composition can both influence the propensity for certain sites to become mutated. Close scrutiny of candidate cis ‐regulatory mutations is necessary in order to effectively identify sites under selective pressure and to accurately distinguish driver from passenger mutations.

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Functional Mutations Form at CTCF-Cohesin Binding Sites in Melanoma Due to Uneven Nucleotide Excision Repair across the Motif

Cited by 68 publications

References 28 publications

Mutational Patterns in Metastatic Cutaneous Squamous Cell Carcinoma

Mutational Patterns in Metastatic Cutaneous Squamous Cell Carcinoma

Pan-cancer screen for mutations in non-coding elements with conservation and cancer specificity reveals correlations with expression and survival

cis ‐Regulatory Driver Mutations in Cancer Genomes

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