Sanket Desai, Bhasker Dharavath, Sujith Manavalan, A. Rane, A. K. Redhu, Roma Sunder, A. Butle, Rohit Mishra, Asim Joshi, Trupti Togar, S. Apte, P. Bala, P. Chandrani, S. Chopra, M. Bashyam, A. Banerjee, K. Prabhash, S. Nair, A. Dutt
Abstract Persistent pathogen infection is a known cause of malignancy, although with sparse systematic evaluation across tumor types. We present a comprehensive landscape of 1060 infectious pathogens across 239 whole exomes and 1168 transcriptomes of breast, lung, gallbladder, cervical, colorectal, and head and neck tumors. We identify known cancer-associated pathogens consistent with the literature. In addition, we identify a significant prevalence of Fusobacterium in head and neck tumors, comparable to colorectal tumors. The Fusobacterium-high subgroup of head and neck tumors occurs mutually exclusive to human papillomavirus, and is characterized by overexpression of miRNAs associated with inflammation, elevated innate immune cell fraction and nodal metastases. We validate the association of Fusobacterium with the inflammatory markers IL1B, IL6 and IL8, miRNAs hsa-mir-451a, hsa-mir-675 and hsa-mir-486-1, and MMP10 in the tongue tumor samples. A higher burden of Fusobacterium is also associated with poor survival, nodal metastases and extracapsular spread in tongue tumors defining a distinct subgroup of head and neck cancer.
{"title":"Fusobacterium nucleatum is associated with inflammation and poor survival in early-stage HPV-negative tongue cancer","authors":"Sanket Desai, Bhasker Dharavath, Sujith Manavalan, A. Rane, A. K. Redhu, Roma Sunder, A. Butle, Rohit Mishra, Asim Joshi, Trupti Togar, S. Apte, P. Bala, P. Chandrani, S. Chopra, M. Bashyam, A. Banerjee, K. Prabhash, S. Nair, A. Dutt","doi":"10.1093/narcan/zcac006","DOIUrl":"https://doi.org/10.1093/narcan/zcac006","url":null,"abstract":"Abstract Persistent pathogen infection is a known cause of malignancy, although with sparse systematic evaluation across tumor types. We present a comprehensive landscape of 1060 infectious pathogens across 239 whole exomes and 1168 transcriptomes of breast, lung, gallbladder, cervical, colorectal, and head and neck tumors. We identify known cancer-associated pathogens consistent with the literature. In addition, we identify a significant prevalence of Fusobacterium in head and neck tumors, comparable to colorectal tumors. The Fusobacterium-high subgroup of head and neck tumors occurs mutually exclusive to human papillomavirus, and is characterized by overexpression of miRNAs associated with inflammation, elevated innate immune cell fraction and nodal metastases. We validate the association of Fusobacterium with the inflammatory markers IL1B, IL6 and IL8, miRNAs hsa-mir-451a, hsa-mir-675 and hsa-mir-486-1, and MMP10 in the tongue tumor samples. A higher burden of Fusobacterium is also associated with poor survival, nodal metastases and extracapsular spread in tongue tumors defining a distinct subgroup of head and neck cancer.","PeriodicalId":94149,"journal":{"name":"NAR cancer","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2022-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"49293727","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
C. Zou, Qinju He, Yuanling Feng, Mengjie Chen, Dingxiao Zhang
Abstract The molecular mechanisms underpinning prostate cancer (PCa) progression are incompletely understood, and precise stratification of aggressive primary PCa (pri-PCa) from indolent ones poses a major clinical challenge. Here, we comprehensively dissect, genomically and transcriptomically, the m6A (N6-methyladenosine) pathway as a whole in PCa. Expression, but not the genomic alteration, repertoire of the full set of 24 m6A regulators at the population level successfully stratifies pri-PCa into three m6A clusters with distinct molecular and clinical features. These three m6A modification patterns closely correlate with androgen receptor signaling, stemness, proliferation and tumor immunogenicity of cancer cells, and stroma activity and immune landscape of tumor microenvironment (TME). We observe a discrepancy between a potentially higher neoantigen production and a deficiency in antigen presentation processes in aggressive PCa, offering insights into the failure of immunotherapy. Identification of PCa-specific m6A phenotype-associated genes provides a basis for construction of m6Avalue to measure m6A methylation patterns in individual patients. Tumors with lower m6Avalue are relatively indolent with abundant immune cell infiltration and stroma activity. Interestingly, m6Avalue separates PCa TME into fibrotic and nonfibrotic phenotypes (instead of previously reported immune-proficient or -desert phenotypes in other cancer types). Significantly, m6Avalue can be used to predict drug response and clinical immunotherapy efficacy in both castration-resistant PCa and other cancer types. Therefore, our study establishes m6A methylation modification pattern as a determinant in PCa progression via impacting cancer cell aggressiveness and TME remodeling.
{"title":"A m6Avalue predictive of prostate cancer stemness, tumor immune landscape and immunotherapy response","authors":"C. Zou, Qinju He, Yuanling Feng, Mengjie Chen, Dingxiao Zhang","doi":"10.1093/narcan/zcac010","DOIUrl":"https://doi.org/10.1093/narcan/zcac010","url":null,"abstract":"Abstract The molecular mechanisms underpinning prostate cancer (PCa) progression are incompletely understood, and precise stratification of aggressive primary PCa (pri-PCa) from indolent ones poses a major clinical challenge. Here, we comprehensively dissect, genomically and transcriptomically, the m6A (N6-methyladenosine) pathway as a whole in PCa. Expression, but not the genomic alteration, repertoire of the full set of 24 m6A regulators at the population level successfully stratifies pri-PCa into three m6A clusters with distinct molecular and clinical features. These three m6A modification patterns closely correlate with androgen receptor signaling, stemness, proliferation and tumor immunogenicity of cancer cells, and stroma activity and immune landscape of tumor microenvironment (TME). We observe a discrepancy between a potentially higher neoantigen production and a deficiency in antigen presentation processes in aggressive PCa, offering insights into the failure of immunotherapy. Identification of PCa-specific m6A phenotype-associated genes provides a basis for construction of m6Avalue to measure m6A methylation patterns in individual patients. Tumors with lower m6Avalue are relatively indolent with abundant immune cell infiltration and stroma activity. Interestingly, m6Avalue separates PCa TME into fibrotic and nonfibrotic phenotypes (instead of previously reported immune-proficient or -desert phenotypes in other cancer types). Significantly, m6Avalue can be used to predict drug response and clinical immunotherapy efficacy in both castration-resistant PCa and other cancer types. Therefore, our study establishes m6A methylation modification pattern as a determinant in PCa progression via impacting cancer cell aggressiveness and TME remodeling.","PeriodicalId":94149,"journal":{"name":"NAR cancer","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2022-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"43224568","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Martin Fischer, Konstantin Riege, R. Schwarz, J. Decaprio, Steve Hoffmann
In recent years, our web-atlas at www.TargetGeneReg.org has enabled many researchers to uncover new biological insights and to identify novel regulatory mechanisms that affect p53 and the cell cycle – signaling pathways that are frequently dysregulated in diseases like cancer. Here, we provide a substantial upgrade of the database that comprises an extension to include non-coding genes and the transcription factors ΔNp63 and RFX7. TargetGeneReg 2.0 combines gene expression profiling and transcription factor DNA binding data to determine, for each gene, the response to p53, ΔNp63, and cell cycle signaling. It can be used to dissect common, cell type, and treatment-specific effects, identify the most promising candidates, and validate findings. We demonstrate the increased power and more intuitive layout of the resource using realistic examples.
{"title":"TargetGeneReg 2.0: a comprehensive web-atlas for p53, p63, and cell cycle-dependent gene regulation","authors":"Martin Fischer, Konstantin Riege, R. Schwarz, J. Decaprio, Steve Hoffmann","doi":"10.1093/narcan/zcac009","DOIUrl":"https://doi.org/10.1093/narcan/zcac009","url":null,"abstract":"In recent years, our web-atlas at www.TargetGeneReg.org has enabled many researchers to uncover new biological insights and to identify novel regulatory mechanisms that affect p53 and the cell cycle – signaling pathways that are frequently dysregulated in diseases like cancer. Here, we provide a substantial upgrade of the database that comprises an extension to include non-coding genes and the transcription factors ΔNp63 and RFX7. TargetGeneReg 2.0 combines gene expression profiling and transcription factor DNA binding data to determine, for each gene, the response to p53, ΔNp63, and cell cycle signaling. It can be used to dissect common, cell type, and treatment-specific effects, identify the most promising candidates, and validate findings. We demonstrate the increased power and more intuitive layout of the resource using realistic examples.","PeriodicalId":94149,"journal":{"name":"NAR cancer","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2021-12-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"42293377","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
S. Penninckx, Eloise Pariset, Egle Cekanaviciute, S. Costes
Radiation-induced foci (RIF) are nuclear puncta visualized by immunostaining of proteins that regulate DNA double-strand break (DSB) repair after exposure to ionizing radiation. RIF are a standard metric for measuring DSB formation and repair in clinical, environmental and space radiobiology. The time course and dose dependence of their formation has great potential to predict in vivo responses to ionizing radiation, predisposition to cancer and probability of adverse reactions to radiotherapy. However, increasing complexity of experimentally and therapeutically setups (charged particle, FLASH …) is associated with several confounding factors that must be taken into account when interpreting RIF values. In this review, we discuss the spatiotemporal characteristics of RIF development after irradiation, addressing the common confounding factors, including cell proliferation and foci merging. We also describe the relevant endpoints and mathematical models that enable accurate biological interpretation of RIF formation and resolution. Finally, we discuss the use of RIF as a biomarker for quantification and prediction of in vivo radiation responses, including important caveats relating to the choice of the biological endpoint and the detection method. This review intends to help scientific community design radiobiology experiments using RIF as a key metric and to provide suggestions for their biological interpretation.
{"title":"Quantification of radiation-induced DNA double strand break repair foci to evaluate and predict biological responses to ionizing radiation.","authors":"S. Penninckx, Eloise Pariset, Egle Cekanaviciute, S. Costes","doi":"10.1093/narcan/zcab046","DOIUrl":"https://doi.org/10.1093/narcan/zcab046","url":null,"abstract":"Radiation-induced foci (RIF) are nuclear puncta visualized by immunostaining of proteins that regulate DNA double-strand break (DSB) repair after exposure to ionizing radiation. RIF are a standard metric for measuring DSB formation and repair in clinical, environmental and space radiobiology. The time course and dose dependence of their formation has great potential to predict in vivo responses to ionizing radiation, predisposition to cancer and probability of adverse reactions to radiotherapy. However, increasing complexity of experimentally and therapeutically setups (charged particle, FLASH …) is associated with several confounding factors that must be taken into account when interpreting RIF values. In this review, we discuss the spatiotemporal characteristics of RIF development after irradiation, addressing the common confounding factors, including cell proliferation and foci merging. We also describe the relevant endpoints and mathematical models that enable accurate biological interpretation of RIF formation and resolution. Finally, we discuss the use of RIF as a biomarker for quantification and prediction of in vivo radiation responses, including important caveats relating to the choice of the biological endpoint and the detection method. This review intends to help scientific community design radiobiology experiments using RIF as a key metric and to provide suggestions for their biological interpretation.","PeriodicalId":94149,"journal":{"name":"NAR cancer","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2021-10-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"46362143","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Jørgen Ankill, M. R. Aure, Sunniva Bjørklund, Severin R. E. Langberg, V. Kristensen, V. Vitelli, X. Tekpli, Thomas Fleischer
Breast cancer is a highly heterogeneous disease driven by multiple factors including genetic and epigenetic alterations. DNA methylation patterns have been shown to be altered on a genome-wide scale and previous studies have highlighted the critical role of aberrant DNA methylation on gene expression and breast cancer pathogenesis. Here, we perform genome-wide expression-methylation Quantitative Trait Loci (emQTL), a method for integration of CpG methylation and gene expression to identify disease-driving genes under epigenetic control. By grouping these emQTLs by biclustering we identify associations representing important biological processes associated with breast cancer pathogenesis such as proliferation and tumor infiltrating fibroblasts. We report hypomethylation at enhancers carrying transcription factor binding sites of key proliferation-driving transcription factors such as CEBP-β, FOSL1, and FOSL2, with concomitant high expression of cell cycle- and proliferation-related genes in aggressive breast tumors. The identified CpGs and genes were found to be connected through chromatin loops, together indicating that proliferation in aggressive breast tumors is under epigenetic regulation by DNA methylation. Interestingly, there was a significant correlation between proliferation-related DNA methylation and gene expression also within subtypes of breast cancer, thereby showing that varying proliferation may be explained by epigenetic profiles across breast cancer subtypes. Indeed, the identified proliferation gene signature was prognostic both in the Luminal A and Luminal B subtypes. Taken together, we show that proliferation in breast cancer is linked to hypomethylation at specific enhancers and transcription factor binding mediated through chromatin loops.
{"title":"Epigenetic alterations at distal enhancers are linked to proliferation in human breast cancer","authors":"Jørgen Ankill, M. R. Aure, Sunniva Bjørklund, Severin R. E. Langberg, V. Kristensen, V. Vitelli, X. Tekpli, Thomas Fleischer","doi":"10.1093/narcan/zcac008","DOIUrl":"https://doi.org/10.1093/narcan/zcac008","url":null,"abstract":"Breast cancer is a highly heterogeneous disease driven by multiple factors including genetic and epigenetic alterations. DNA methylation patterns have been shown to be altered on a genome-wide scale and previous studies have highlighted the critical role of aberrant DNA methylation on gene expression and breast cancer pathogenesis. Here, we perform genome-wide expression-methylation Quantitative Trait Loci (emQTL), a method for integration of CpG methylation and gene expression to identify disease-driving genes under epigenetic control. By grouping these emQTLs by biclustering we identify associations representing important biological processes associated with breast cancer pathogenesis such as proliferation and tumor infiltrating fibroblasts. We report hypomethylation at enhancers carrying transcription factor binding sites of key proliferation-driving transcription factors such as CEBP-β, FOSL1, and FOSL2, with concomitant high expression of cell cycle- and proliferation-related genes in aggressive breast tumors. The identified CpGs and genes were found to be connected through chromatin loops, together indicating that proliferation in aggressive breast tumors is under epigenetic regulation by DNA methylation. Interestingly, there was a significant correlation between proliferation-related DNA methylation and gene expression also within subtypes of breast cancer, thereby showing that varying proliferation may be explained by epigenetic profiles across breast cancer subtypes. Indeed, the identified proliferation gene signature was prognostic both in the Luminal A and Luminal B subtypes. Taken together, we show that proliferation in breast cancer is linked to hypomethylation at specific enhancers and transcription factor binding mediated through chromatin loops.","PeriodicalId":94149,"journal":{"name":"NAR cancer","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2021-04-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"43383208","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Shilpita Karmakar, Oscar Ramirez, Kiran V. Paul, A. Gupta, Valentina Botti, Igor Ruiz de los Mozos, Nils Neuenkirchen, R. J. Ross, K. Neugebauer, Manoj M. Pillai
Musashi 2 (MSI2) is an RNA binding protein (RBP) that regulates asymmetric cell division and cell fate decisions in normal and cancer stem cells. MSI2 appears to repress translation by binding to 3’ untranslated regions (3’UTRs) of mRNA, but the identity of functional targets remains unknown. Here we used iCLIP to identify direct RNA binding partners of MSI2 and integrated these data with polysome profiling to obtain insights into MSI2 function. iCLIP revealed specific MSI2 binding to thousands of target mRNAs largely in 3’UTRs, but translational differences were restricted to a small fraction of these transcripts, indicating that MSI2 regulation is not triggered by simple binding. Instead, the functional targets identified here were bound at higher density and contain more “U/TAG” motifs compared to targets bound non-productively. To further distinguish direct and indirect targets, MSI2 was acutely depleted. Surprisingly, only 50 transcripts were found to undergo translational induction on acute MSI2 loss. Eukaryotic elongation factor 3A (EIF3A) was determined to be an immediate, direct target. We propose that MSI2 down-regulation of EIF3A amplifies these effects on the proteome. Our results also underscore the challenges in defining functional targets of RBP since mere binding does not imply a discernible functional interaction.
{"title":"Integrative genome-wide analysis reveals EIF3A as a key downstream regulator of translational repressor protein Musashi 2 (MSI2)","authors":"Shilpita Karmakar, Oscar Ramirez, Kiran V. Paul, A. Gupta, Valentina Botti, Igor Ruiz de los Mozos, Nils Neuenkirchen, R. J. Ross, K. Neugebauer, Manoj M. Pillai","doi":"10.1093/narcan/zcac015","DOIUrl":"https://doi.org/10.1093/narcan/zcac015","url":null,"abstract":"Musashi 2 (MSI2) is an RNA binding protein (RBP) that regulates asymmetric cell division and cell fate decisions in normal and cancer stem cells. MSI2 appears to repress translation by binding to 3’ untranslated regions (3’UTRs) of mRNA, but the identity of functional targets remains unknown. Here we used iCLIP to identify direct RNA binding partners of MSI2 and integrated these data with polysome profiling to obtain insights into MSI2 function. iCLIP revealed specific MSI2 binding to thousands of target mRNAs largely in 3’UTRs, but translational differences were restricted to a small fraction of these transcripts, indicating that MSI2 regulation is not triggered by simple binding. Instead, the functional targets identified here were bound at higher density and contain more “U/TAG” motifs compared to targets bound non-productively. To further distinguish direct and indirect targets, MSI2 was acutely depleted. Surprisingly, only 50 transcripts were found to undergo translational induction on acute MSI2 loss. Eukaryotic elongation factor 3A (EIF3A) was determined to be an immediate, direct target. We propose that MSI2 down-regulation of EIF3A amplifies these effects on the proteome. Our results also underscore the challenges in defining functional targets of RBP since mere binding does not imply a discernible functional interaction.","PeriodicalId":94149,"journal":{"name":"NAR cancer","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2021-02-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"47690977","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2020-03-26DOI: 10.1101/2020.03.25.008391
T. R. Nicholas, Peter C. Hollenhorst
Ewing sarcoma breakpoint region 1 (EWSR1) encodes a multifunctional protein that can cooperate with the transcription factor ERG to promote prostate cancer. The EWSR1 gene is also commonly involved in oncogenic gene rearrangements in Ewing sarcoma. Despite the cancer relevance of EWSR1, its regulation is poorly understood. Here we find that in prostate cancer, androgen signaling upregulates a 5’ EWSR1 isoform by promoting usage of an intronic polyadenylation site. This isoform encodes a cytoplasmic protein that can strongly promote cell migration and clonogenic growth. Deletion of an Androgen Receptor (AR) binding site near the 5’ EWSR1 polyadenylation site abolished androgen-dependent upregulation. This polyadenylation site is also near the Ewing sarcoma breakpoint hotspot, and androgen signaling promoted R-loop and breakpoint formation. RNase H overexpression reduced breakage and 5’ EWSR1 isoform expression suggesting an R-loop dependent mechanism. These data suggest that androgen signaling can promote R-loops internal to the EWSR1 gene leading to early transcription termination and breakpoint formation.
{"title":"Androgen signaling connects short isoform production to breakpoint formation at Ewing sarcoma breakpoint region 1","authors":"T. R. Nicholas, Peter C. Hollenhorst","doi":"10.1101/2020.03.25.008391","DOIUrl":"https://doi.org/10.1101/2020.03.25.008391","url":null,"abstract":"Ewing sarcoma breakpoint region 1 (EWSR1) encodes a multifunctional protein that can cooperate with the transcription factor ERG to promote prostate cancer. The EWSR1 gene is also commonly involved in oncogenic gene rearrangements in Ewing sarcoma. Despite the cancer relevance of EWSR1, its regulation is poorly understood. Here we find that in prostate cancer, androgen signaling upregulates a 5’ EWSR1 isoform by promoting usage of an intronic polyadenylation site. This isoform encodes a cytoplasmic protein that can strongly promote cell migration and clonogenic growth. Deletion of an Androgen Receptor (AR) binding site near the 5’ EWSR1 polyadenylation site abolished androgen-dependent upregulation. This polyadenylation site is also near the Ewing sarcoma breakpoint hotspot, and androgen signaling promoted R-loop and breakpoint formation. RNase H overexpression reduced breakage and 5’ EWSR1 isoform expression suggesting an R-loop dependent mechanism. These data suggest that androgen signaling can promote R-loops internal to the EWSR1 gene leading to early transcription termination and breakpoint formation.","PeriodicalId":94149,"journal":{"name":"NAR cancer","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2020-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"42845089","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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