OncoCis: annotation of cis- regulatory mutations in cancer

Perera, D. S.; Chacon, Diego; Thoms, Julie A.I.; Poulos, Rebecca C.; Beck, Dominik; Campbell, Peter J.; Pimanda, John E.; Wong, Jason

doi:10.1186/preaccept-1191661878133753

Cited by 15 publications

(26 citation statements)

References 30 publications

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“…This suggests that conservation may not be a sufficient predictor of whether a mutated base has functional consequences in vivo or in vitro. In fact, the TERT promoter mutations also do not fall within conserved regions (15), lending support to this hypothesis.…”

Section: Relative Promoter Activitysupporting

confidence: 52%

“…It is vital to account for tissue specificity when identifying active promoter regions (15). In our analysis, we utilized matchedtumor COLO-829 DNase-seq data to identify putative promoter mutations.…”

Section: Relative Promoter Activitymentioning

confidence: 99%

“…Half of the 20 validated COLO-829 putative promoter mutations were deemed to be highly conserved, as they lie within a 15 bp region (mutation AE 7 bp) with a greater average PhastCons conservation score (29) than the surrounding COLO-829 DHS region (Table 1). Furthermore, 19 of the 20 validated mutations alter transcription factor motifs (Table 1) based on mutation motif analysis using OncoCis (15). See Fig.…”

Section: Annotation and Validation Of Promoter Mutations In Colo-829mentioning

confidence: 99%

“…Transcription factor motifs created or removed by each mutation were identified by use of the OncoCis tool (15), which utilizes transcription factor motifs from the JASPAR database (30).…”

Section: Mutation Analysismentioning

confidence: 99%

“…A number of computational approaches are now available to functionally annotate and prioritize mutations with potential cisregulatory function (15)(16)(17)(18). However, to our knowledge, experimental analyses that systematically evaluate the functional consequence of potential cis-regulatory mutations have not yet been performed in any cancer genome.…”

Section: Introductionmentioning

confidence: 99%

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Systematic Screening of Promoter Regions Pinpoints Functional Cis-Regulatory Mutations in a Cutaneous Melanoma Genome

Poulos

Thoms

Shah

et al. 2015

Molecular Cancer Research

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With the recent discovery of recurrent mutations in the TERT promoter in melanoma, identification of other somatic causal promoter mutations is of considerable interest. Yet, the impact of sequence variation on the regulatory potential of gene promoters has not been systematically evaluated. This study assesses the impact of promoter mutations on promoter activity in the wholegenome sequenced malignant melanoma cell line COLO-829. Combining somatic mutation calls from COLO-829 with genome-wide chromatin accessibility and histone modification data revealed mutations within promoter elements. Interestingly, a high number of potential promoter mutations (n ¼ 23) were found, a result mirrored in subsequent analysis of TCGA wholemelanoma genomes. The impact of wild-type and mutant promoter sequences were evaluated by subcloning into luciferase reporter vectors and testing their transcriptional activity in COLO-829 cells. Of the 23 promoter regions tested, four mutations significantly altered reporter activity relative to wild-type sequences. These data were then subjected to multiple computational algorithms that score the cis-regulatory altering potential of mutations. These analyses identified one mutation, located within the promoter region of NDUFB9, which encodes the mitochondrial NADH dehydrogenase (ubiquinone) 1 beta subcomplex 9, to be recurrent in 4.4% (19 of 432) of TCGA wholemelanoma exomes. The mutation is predicted to disrupt a highly conserved SP1/KLF transcription factor binding motif and its frequent co-occurrence with mutations in the coding sequence of NF1 supports a pathologic role for this mutation in melanoma. Taken together, these data show the relatively high prevalence of promoter mutations in the COLO-829 melanoma genome, and indicate that a proportion of these significantly alter the regulatory potential of gene promoters.

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Section: Relative Promoter Activitysupporting

confidence: 52%

Section: Relative Promoter Activitymentioning

confidence: 99%

Section: Annotation and Validation Of Promoter Mutations In Colo-829mentioning

confidence: 99%

“…Transcription factor motifs created or removed by each mutation were identified by use of the OncoCis tool (15), which utilizes transcription factor motifs from the JASPAR database (30).…”

Section: Mutation Analysismentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Systematic Screening of Promoter Regions Pinpoints Functional Cis-Regulatory Mutations in a Cutaneous Melanoma Genome

Poulos

Thoms

Shah

et al. 2015

Molecular Cancer Research

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Transcriptional networks in acute myeloid leukemia

Thoms

Beck

Pimanda

2019

Genes Chromosomes & Cancer

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Acute myeloid leukemia (AML) is a complex disease characterized by a diverse range of recurrent molecular aberrations that occur in many different combinations. Components of transcriptional networks are a common target of these aberrations, leading to network‐wide changes and deployment of novel or developmentally inappropriate transcriptional programs. Genome‐wide techniques are beginning to reveal the full complexity of normal hematopoietic stem cell transcriptional networks and the extent to which they are deregulated in AML, and new understandings of the mechanisms by which AML cells maintain self‐renewal and block differentiation are starting to emerge. The hope is that increased understanding of the network architecture in AML will lead to identification of key oncogenic dependencies that are downstream of multiple network aberrations, and that this knowledge will be translated into new therapies that target these dependencies. Here, we review the current state of knowledge of network perturbation in AML with a focus on major mechanisms of transcription factor dysregulation, including mutation, translocation, and transcriptional dysregulation, and discuss how these perturbations propagate across transcriptional networks. We will also review emerging mechanisms of network disruption, and briefly discuss how increased knowledge of network disruption is already being used to develop new therapies.

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Quantifying the Impact of Non-coding Variants on Transcription Factor-DNA Binding

Zhao

Seo

et al. 2017

Lecture Notes in Computer Science

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Many recent studies have emphasized the importance of genetic variants and mutations in cancer and other complex human diseases. The overwhelming majority of these variants occur in non-coding portions of the genome, where they can have a functional impact by disrupting regulatory interactions between transcription factors (TFs) and DNA. Here, we present a method for assessing the impact of non-coding mutations on TF-DNA interactions, based on regression models of DNA-binding specificity trained on high-throughput in vitro data. We use ordinary least squares (OLS) to estimate the parameters of the binding model for each TF, and we show that our predictions of TF-binding changes due to DNA mutations correlate well with measured changes in gene expression. In addition, by leveraging distributional results associated with OLS estimation, for each predicted change in TF binding we also compute a normalized score (z-score) and a significance value (p-value) reflecting our confidence that the mutation affects TF binding. We use this approach to analyze a large set of pathogenic non-coding variants, and we show that these variants lead to significant differences in TF binding between alleles, compared to a control set of common variants. Thus, our results indicate that there is a strong regulatory component to the pathogenic non-coding variants identified thus far.

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OncoCis: annotation of cis- regulatory mutations in cancer

Cited by 15 publications

References 30 publications

Systematic Screening of Promoter Regions Pinpoints Functional Cis-Regulatory Mutations in a Cutaneous Melanoma Genome

Systematic Screening of Promoter Regions Pinpoints Functional Cis-Regulatory Mutations in a Cutaneous Melanoma Genome

Transcriptional networks in acute myeloid leukemia

Quantifying the Impact of Non-coding Variants on Transcription Factor-DNA Binding

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