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  1. Article ; Online: Genetic and functional interaction network analysis reveals global enrichment of regulatory T cell genes influencing basal cell carcinoma susceptibility

    Christelle Adolphe / Angli Xue / Atefeh Taherian Fard / Laura A. Genovesi / Jian Yang / Brandon J. Wainwright

    Genome Medicine, Vol 13, Iss 1, Pp 1-

    2021  Volume 12

    Abstract: Abstract Background Basal cell carcinoma (BCC) of the skin is the most common form of human cancer, with more than 90% of tumours presenting with clear genetic activation of the Hedgehog pathway. However, polygenic risk factors affecting mechanisms such ... ...

    Abstract Abstract Background Basal cell carcinoma (BCC) of the skin is the most common form of human cancer, with more than 90% of tumours presenting with clear genetic activation of the Hedgehog pathway. However, polygenic risk factors affecting mechanisms such as DNA repair and cell cycle checkpoints or which modulate the tumour microenvironment or host immune system play significant roles in determining whether genetic mutations culminate in BCC development. We set out to define background genetic factors that play a role in influencing BCC susceptibility via promoting or suppressing the effects of oncogenic drivers of BCC. Methods We performed genome-wide association studies (GWAS) on 17,416 cases and 375,455 controls. We subsequently performed statistical analysis by integrating data from population-based genetic studies of multi-omics data, including blood- and skin-specific expression quantitative trait loci and methylation quantitative trait loci, thereby defining a list of functionally relevant candidate BCC susceptibility genes from our GWAS loci. We also constructed a local GWAS functional interaction network (consisting of GWAS nearest genes) and another functional interaction network, consisting specifically of candidate BCC susceptibility genes. Results A total of 71 GWAS loci and 46 functional candidate BCC susceptibility genes were identified. Increased risk of BCC was associated with the decreased expression of 26 susceptibility genes and increased expression of 20 susceptibility genes. Pathway analysis of the functional candidate gene regulatory network revealed strong enrichment for cell cycle, cell death, and immune regulation processes, with a global enrichment of genes and proteins linked to TReg cell biology. Conclusions Our genome-wide association analyses and functional interaction network analysis reveal an enrichment of risk variants that function in an immunosuppressive regulatory network, likely hindering cancer immune surveillance and effective antitumour immunity.
    Keywords BCC ; GWAS ; Cancer susceptibility ; Immune surveillance ; Protein interaction networks ; Medicine ; R ; Genetics ; QH426-470
    Language English
    Publishing date 2021-02-01T00:00:00Z
    Publisher BMC
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  2. Article ; Online: Systems pharmacogenomics identifies novel targets and clinically actionable therapeutics for medulloblastoma

    Laura A. Genovesi / Amanda Millar / Elissa Tolson / Matthew Singleton / Emily Hassall / Marija Kojic / Caterina Brighi / Emily Girard / Clara Andradas / Mani Kuchibhotla / Dharmesh D. Bhuva / Raelene Endersby / Nicholas G. Gottardo / Anne Bernard / Christelle Adolphe / James M. Olson / Michael D. Taylor / Melissa J. Davis / Brandon J. Wainwright

    Genome Medicine, Vol 13, Iss 1, Pp 1-

    2021  Volume 15

    Abstract: Abstract Background Medulloblastoma (MB) is the most common malignant paediatric brain tumour and a leading cause of cancer-related mortality and morbidity. Existing treatment protocols are aggressive in nature resulting in significant neurological, ... ...

    Abstract Abstract Background Medulloblastoma (MB) is the most common malignant paediatric brain tumour and a leading cause of cancer-related mortality and morbidity. Existing treatment protocols are aggressive in nature resulting in significant neurological, intellectual and physical disabilities for the children undergoing treatment. Thus, there is an urgent need for improved, targeted therapies that minimize these harmful side effects. Methods We identified candidate drugs for MB using a network-based systems-pharmacogenomics approach: based on results from a functional genomics screen, we identified a network of interactions implicated in human MB growth regulation. We then integrated drugs and their known mechanisms of action, along with gene expression data from a large collection of medulloblastoma patients to identify drugs with potential to treat MB. Results Our analyses identified drugs targeting CDK4, CDK6 and AURKA as strong candidates for MB; all of these genes are well validated as drug targets in other tumour types. We also identified non-WNT MB as a novel indication for drugs targeting TUBB, CAD, SNRPA, SLC1A5, PTPRS, P4HB and CHEK2. Based upon these analyses, we subsequently demonstrated that one of these drugs, the new microtubule stabilizing agent, ixabepilone, blocked tumour growth in vivo in mice bearing patient-derived xenograft tumours of the Sonic Hedgehog and Group 3 subtype, providing the first demonstration of its efficacy in MB. Conclusions Our findings confirm that this data-driven systems pharmacogenomics strategy is a powerful approach for the discovery and validation of novel therapeutic candidates relevant to MB treatment, and along with data validating ixabepilone in PDX models of the two most aggressive subtypes of medulloblastoma, we present the network analysis framework as a resource for the field.
    Keywords Medulloblastoma ; Genetic screen ; Protein interaction network ; Drug target ; Microtubule stabilization ; Medicine ; R ; Genetics ; QH426-470
    Subject code 616
    Language English
    Publishing date 2021-06-01T00:00:00Z
    Publisher BMC
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  3. Article ; Online: Elongator mutation in mice induces neurodegeneration and ataxia-like behavior

    Marija Kojic / Monika Gaik / Bence Kiska / Anna Salerno-Kochan / Sarah Hunt / Angelo Tedoldi / Sergey Mureev / Alun Jones / Belinda Whittle / Laura A. Genovesi / Christelle Adolphe / Darren L. Brown / Jennifer L. Stow / Kirill Alexandrov / Pankaj Sah / Sebastian Glatt / Brandon J. Wainwright

    Nature Communications, Vol 9, Iss 1, Pp 1-

    2018  Volume 13

    Abstract: Elp6 is a component of the Elongator complex that regulates tRNAs and translation. Here the authors identify a mutation in the Elp6 gene that contributes to the cerebellar ataxia-like phenotype in a mutant mouse. ...

    Abstract Elp6 is a component of the Elongator complex that regulates tRNAs and translation. Here the authors identify a mutation in the Elp6 gene that contributes to the cerebellar ataxia-like phenotype in a mutant mouse.
    Keywords Science ; Q
    Language English
    Publishing date 2018-08-01T00:00:00Z
    Publisher Nature Publishing Group
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  4. Article ; Online: Elongator mutation in mice induces neurodegeneration and ataxia-like behavior

    Marija Kojic / Monika Gaik / Bence Kiska / Anna Salerno-Kochan / Sarah Hunt / Angelo Tedoldi / Sergey Mureev / Alun Jones / Belinda Whittle / Laura A. Genovesi / Christelle Adolphe / Darren L. Brown / Jennifer L. Stow / Kirill Alexandrov / Pankaj Sah / Sebastian Glatt / Brandon J. Wainwright

    Nature Communications, Vol 9, Iss 1, Pp 1-

    2018  Volume 13

    Abstract: Elp6 is a component of the Elongator complex that regulates tRNAs and translation. Here the authors identify a mutation in the Elp6 gene that contributes to the cerebellar ataxia-like phenotype in a mutant mouse. ...

    Abstract Elp6 is a component of the Elongator complex that regulates tRNAs and translation. Here the authors identify a mutation in the Elp6 gene that contributes to the cerebellar ataxia-like phenotype in a mutant mouse.
    Keywords Science ; Q
    Language English
    Publishing date 2018-08-01T00:00:00Z
    Publisher Nature Portfolio
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  5. Article ; Online: Sonic hedgehog and notch signaling can cooperate to regulate neurogenic divisions of neocortical progenitors.

    Richa K Dave / Tammy Ellis / Melissa C Toumpas / Jonathan P Robson / Elaine Julian / Christelle Adolphe / Perry F Bartlett / Helen M Cooper / Brent A Reynolds / Brandon J Wainwright

    PLoS ONE, Vol 6, Iss 2, p e

    2011  Volume 14680

    Abstract: Hedgehog (Hh) signaling is crucial for the generation and maintenance of both embryonic and adult stem cells, thereby regulating development and tissue homeostasis. In the developing neocortex, Sonic Hedgehog (Shh) regulates neural progenitor cell ... ...

    Abstract Hedgehog (Hh) signaling is crucial for the generation and maintenance of both embryonic and adult stem cells, thereby regulating development and tissue homeostasis. In the developing neocortex, Sonic Hedgehog (Shh) regulates neural progenitor cell proliferation. During neurogenesis, radial glial cells of the ventricular zone (VZ) are the predominant neocortical progenitors that generate neurons through both symmetric and asymmetric divisions. Despite its importance, relatively little is known of the molecular pathways that control the switch from symmetric proliferative to differentiative/neurogenic divisions in neural progenitors.Here, we report that conditional inactivation of Patched1, a negative regulator of the Shh pathway, in Nestin positive neural progenitors of the neocortex leads to lamination defects due to improper corticogenesis and an increase in the number of symmetric proliferative divisions of the radial glial cells. Hedgehog-activated VZ progenitor cells demonstrated a concomitant upregulation of Hes1 and Blbp, downstream targets of Notch signaling. The Notch signaling pathway plays a pivotal role in the maintenance of stem/progenitor cells and the regulation of glial versus neuronal identity. To study the effect of Notch signaling on Hh-activated neural progenitors, we inactivated both Patched1 and Rbpj, a transcriptional mediator of Notch signaling, in Nestin positive cells of the neocortex.Our data indicate that by mid neurogenesis (embryonic day 14.5), attenuation of Notch signaling reverses the effect of Patched1 deletion on neurogenesis by restoring the balance between symmetric proliferative and neurogenic divisions. Hence, our results demonstrate that correct corticogenesis is an outcome of the interplay between the Hh and Notch signaling pathways.
    Keywords Medicine ; R ; Science ; Q
    Subject code 571
    Language English
    Publishing date 2011-02-01T00:00:00Z
    Publisher Public Library of Science (PLoS)
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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