NAR cancer最新文献_第6页

Comprehensive and realistic simulation of tumour genomic sequencing data. 肿瘤基因组测序数据的全面而现实的模拟。

NAR cancer Pub Date : 2023-09-22 eCollection Date: 2023-09-01 DOI: 10.1093/narcan/zcad051

Brian O'Sullivan, Cathal Seoighe

{"title":"Comprehensive and realistic simulation of tumour genomic sequencing data.","authors":"Brian O'Sullivan, Cathal Seoighe","doi":"10.1093/narcan/zcad051","DOIUrl":"10.1093/narcan/zcad051","url":null,"abstract":"Accurate identification of somatic mutations and allele frequencies in cancer has critical research and clinical applications. Several computational tools have been developed for this purpose but, in the absence of comprehensive 'ground truth' data, assessing the accuracy of these methods is challenging. We created a computational framework to simulate tumour and matched normal sequencing data for which the source of all loci that contain non-reference bases is known, based on a phased, personalized genome. Unlike existing methods, we account for sampling errors inherent in the sequencing process. Using this framework, we assess accuracy and biases in inferred mutations and their frequencies in an established somatic mutation calling pipeline. We demonstrate bias in existing methods of mutant allele frequency estimation and show, for the first time, the observed mutation frequency spectrum corresponding to a theoretical model of tumour evolution. We highlight the impact of quality filters on detection sensitivity of clinically actionable variants and provide definitive assessment of false positive and false negative mutation calls. Our simulation framework provides an improved means to assess the accuracy of somatic mutation calling pipelines and a detailed picture of the effects of technical parameters and experimental factors on somatic mutation calling in cancer samples.","PeriodicalId":94149,"journal":{"name":"NAR cancer","volume":"5 3","pages":"zcad051"},"PeriodicalIF":0.0,"publicationDate":"2023-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10516706/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41165532","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

GSK-3484862 targets DNMT1 for degradation in cells GSK-3484862靶向DNMT1降解细胞

NAR cancer Pub Date : 2022-11-04 DOI: 10.1101/2022.11.03.514954

Qin Chen, Yang Zeng, J. Hwang, Bigang Liu, Nan Dai, Ivan R. Corrêa, Marcos Estecio, Xing Zhang, Margarida Santos, Taiping Chen, Xiaodong Cheng

{"title":"GSK-3484862 targets DNMT1 for degradation in cells","authors":"Qin Chen, Yang Zeng, J. Hwang, Bigang Liu, Nan Dai, Ivan R. Corrêa, Marcos Estecio, Xing Zhang, Margarida Santos, Taiping Chen, Xiaodong Cheng","doi":"10.1101/2022.11.03.514954","DOIUrl":"https://doi.org/10.1101/2022.11.03.514954","url":null,"abstract":"Maintenance of genomic methylation patterns at DNA replication forks by DNMT1 is the key to faithful mitotic inheritance. DNMT1 is often overexpressed in cancer cells and the DNA hypomethylating agents azacytidine and decitabine are currently used in the treatment of hematologic malignancies. However, the toxicity of these cytidine analogs and their ineffectiveness in treating solid tumors have limited wider clinical use. GSK-3484862 is a newly-developed, dicyanopyridine containing, non-nucleoside DNMT1-selective inhibitor with low cellular toxicity. Here, we show that GSK-3484862 targets DNMT1 for protein degradation in both cancer cell lines and murine embryonic stem cells (mESCs). DNMT1 depletion was rapid, taking effect within hours following GSK-3484862 treatment, leading to global hypomethylation. Inhibitor-induced DNMT1 degradation was proteasome-dependent, with no discernible loss of DNMT1 mRNA. In mESCs, GSK-3484862-induced Dnmt1 degradation requires Uhrf1, an accessory factor of Dnmt1 with E3 ubiquitin ligase activity. We also show that Dnmt1 depletion and DNA hypomethylation induced by the compound are reversible after its removal. Together, these results indicate that this DNMT1-selective degrader/inhibitor will be a valuable tool for dissecting both coordinated events linking DNA methylation to gene expression and identifying downstream effectors that ultimately regulate cellular response to altered DNA methylation patterns in a tissue/cell-specific manner. Highlights GSK-3484862 targets DNMT1 for protein degradation in a wide-range of cancer cell lines, without a decrease in DNMT1 mRNA levels DNMT1 depletion leads to a >50% loss of global DNA methylation in cells within 2-days of treatment with GSK-3484862 GSK-3484862-induced DNMT1 degradation is proteasome-dependent In mESCs, Uhrf1 is required for GSK-3484862 to induce Dnmt1 degradation","PeriodicalId":94149,"journal":{"name":"NAR cancer","volume":"5 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2022-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"46018773","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}

引用次数: 3

Heterogeneity in the gene regulatory landscape of leiomyosarcoma 平滑肌肉瘤基因调控格局的异质性

NAR cancer Pub Date : 2022-10-27 DOI: 10.1101/2022.04.13.488196

T. Belova, Nicola Biondi, Ping-Han Hsieh, P. Lutsik, Priya Chudasama, M. Kuijjer

{"title":"Heterogeneity in the gene regulatory landscape of leiomyosarcoma","authors":"T. Belova, Nicola Biondi, Ping-Han Hsieh, P. Lutsik, Priya Chudasama, M. Kuijjer","doi":"10.1101/2022.04.13.488196","DOIUrl":"https://doi.org/10.1101/2022.04.13.488196","url":null,"abstract":"Soft-tissue sarcomas are group of rare, tremendously heterogeneous, and highly aggressive malignancies. Characterizing inter-tumor heterogeneity is crucial for selecting suitable sarcoma therapy, as the presence of diverse molecular subgroups of patients can be associated with disease outcome or response to treatment. While cancer subtypes are often characterized by differences in gene expression, the mechanisms that drive these differences are generally unknown. We therefore set out to model the regulatory mechanisms driving sarcoma heterogeneity. We subtyped soft-tissue sarcomas based on patient-specific, genome-wide gene regulatory networks and found pronounced regulatory heterogeneity in leiomyosarcoma—one of the most common soft-tissue sarcomas subtypes that arises in smooth muscle tissue. To characterize this regulatory heterogeneity, we developed a new computational framework. This method, PORCUPINE, combines knowledge on biological pathways with permutation-based network analysis to identify pathways that exhibit significant regulatory heterogeneity across a patient population. We applied PORCUPINE to patient-specific leiomyosarcoma networks modeled on data from The Cancer Genome Atlas and validated our results in an independent dataset from the German Cancer Research Center. PORCUPINE identified 37 heterogeneously regulated pathways, including pathways that represent potential targets for treatment of subgroups of leiomyosarcoma patients, such as FGFR and CTLA4 inhibitory signaling. We validated the detected regulatory heterogeneity through analysis of networks and chromatin states in leiomyosarcoma cell lines. In addition, we showed that the heterogeneity identified with PORCUPINE is not associated with methylation profiles or clinical features, thereby suggesting an independent mechanism of patient heterogeneity driven by the complex landscape of gene regulatory interactions.","PeriodicalId":94149,"journal":{"name":"NAR cancer","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2022-10-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"47201035","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}

引用次数: 2

High replication stress and limited Rad51-mediated DNA repair capacity, but not oxidative stress, underlie oligodendrocyte precursor cell radiosensitivity. 高复制应激和有限的Rad51介导的DNA修复能力，而不是氧化应激，是少突胶质细胞前体细胞放射敏感性的基础

IF 3.4

NAR cancer Pub Date : 2022-04-12 eCollection Date: 2022-06-01 DOI: 10.1093/narcan/zcac012

N Daniel Berger, Peter M Brownlee, Myra J Chen, Hali Morrison, Katalin Osz, Nicolas P Ploquin, Jennifer A Chan, Aaron A Goodarzi

{"title":"High replication stress and limited Rad51-mediated DNA repair capacity, but not oxidative stress, underlie oligodendrocyte precursor cell radiosensitivity.","authors":"N Daniel Berger, Peter M Brownlee, Myra J Chen, Hali Morrison, Katalin Osz, Nicolas P Ploquin, Jennifer A Chan, Aaron A Goodarzi","doi":"10.1093/narcan/zcac012","DOIUrl":"10.1093/narcan/zcac012","url":null,"abstract":"Cranial irradiation is part of the standard of care for treating pediatric brain tumors. However, ionizing radiation can trigger serious long-term neurologic sequelae, including oligodendrocyte and brain white matter loss enabling neurocognitive decline in children surviving brain cancer. Oxidative stress-mediated oligodendrocyte precursor cell (OPC) radiosensitivity has been proposed as a possible explanation for this. Here, however, we demonstrate that antioxidants fail to improve OPC viability after irradiation, despite suppressing oxidative stress, suggesting an alternative etiology for OPC radiosensitivity. Using systematic approaches, we find that OPCs have higher irradiation-induced and endogenous γH2AX foci compared to neural stem cells, neurons, astrocytes and mature oligodendrocytes, and these correlate with replication-associated DNA double strand breakage. Furthermore, OPCs are reliant upon ATR kinase and Mre11 nuclease-dependent processes for viability, are more sensitive to drugs increasing replication fork collapse, and display synthetic lethality with PARP inhibitors after irradiation. This suggests an insufficiency for homology-mediated DNA repair in OPCs-a model that is supported by evidence of normal RPA but reduced RAD51 filament formation at resected lesions in irradiated OPCs. We therefore propose a DNA repair-centric mechanism of OPC radiosensitivity, involving chronically-elevated replication stress combined with 'bottlenecks' in RAD51-dependent DNA repair that together reduce radiation resilience.","PeriodicalId":94149,"journal":{"name":"NAR cancer","volume":"4 1","pages":"zcac012"},"PeriodicalIF":3.4,"publicationDate":"2022-04-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9004414/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41524595","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Multi-omics data integration analysis identifies the spliceosome as a key regulator of DNA double-strand break repair 多组学数据整合分析确定剪接体是DNA双链断裂修复的关键调节因子

NAR cancer Pub Date : 2022-04-08 DOI: 10.1093/narcan/zcac013

Dana Sherill-Rofe, O. Raban, Steven Findlay, Dolev Rahat, Irene Unterman, Arash Samiei, A. Yasmeen, Zafir Kaiser, H. Kuasne, Morag Park, W. Foulkes, Idit Bloch, A. Zick, W. Gotlieb, Y. Tabach, Alexandre Orthwein

{"title":"Multi-omics data integration analysis identifies the spliceosome as a key regulator of DNA double-strand break repair","authors":"Dana Sherill-Rofe, O. Raban, Steven Findlay, Dolev Rahat, Irene Unterman, Arash Samiei, A. Yasmeen, Zafir Kaiser, H. Kuasne, Morag Park, W. Foulkes, Idit Bloch, A. Zick, W. Gotlieb, Y. Tabach, Alexandre Orthwein","doi":"10.1093/narcan/zcac013","DOIUrl":"https://doi.org/10.1093/narcan/zcac013","url":null,"abstract":"Abstract DNA repair by homologous recombination (HR) is critical for the maintenance of genome stability. Germline and somatic mutations in HR genes have been associated with an increased risk of developing breast (BC) and ovarian cancers (OvC). However, the extent of factors and pathways that are functionally linked to HR with clinical relevance for BC and OvC remains unclear. To gain a broader understanding of this pathway, we used multi-omics datasets coupled with machine learning to identify genes that are associated with HR and to predict their sub-function. Specifically, we integrated our phylogenetic-based co-evolution approach (CladePP) with 23 distinct genetic and proteomic screens that monitored, directly or indirectly, DNA repair by HR. This omics data integration analysis yielded a new database (HRbase) that contains a list of 464 predictions, including 76 gold standard HR genes. Interestingly, the spliceosome machinery emerged as one major pathway with significant cross-platform interactions with the HR pathway. We functionally validated 6 spliceosome factors, including the RNA helicase SNRNP200 and its co-factor SNW1. Importantly, their RNA expression correlated with BC/OvC patient outcome. Altogether, we identified novel clinically relevant DNA repair factors and delineated their specific sub-function by machine learning. Our results, supported by evolutionary and multi-omics analyses, suggest that the spliceosome machinery plays an important role during the repair of DNA double-strand breaks (DSBs).","PeriodicalId":94149,"journal":{"name":"NAR cancer","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2022-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"45069848","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}

引用次数: 4

Colorectal microbiota after removal of colorectal cancer 结直肠癌切除后的结肠菌群

NAR cancer Pub Date : 2022-04-08 DOI: 10.1093/narcan/zcac011

Peter Cronin, C. Murphy, M. Barrett, T. Ghosh, P. Pellanda, E. O'Connor, S. Zulquernain, Shane Kileen, M. Mccourt, E. Andrews, Micheal O’Riordain, F. Shanahan, P. O’Toole

{"title":"Colorectal microbiota after removal of colorectal cancer","authors":"Peter Cronin, C. Murphy, M. Barrett, T. Ghosh, P. Pellanda, E. O'Connor, S. Zulquernain, Shane Kileen, M. Mccourt, E. Andrews, Micheal O’Riordain, F. Shanahan, P. O’Toole","doi":"10.1093/narcan/zcac011","DOIUrl":"https://doi.org/10.1093/narcan/zcac011","url":null,"abstract":"Abstract The colonic microbiome has been implicated in the pathogenesis of colorectal cancer (CRC) and intestinal microbiome alterations are not confined to the tumour. Since data on whether the microbiome normalises or remains altered after resection of CRC are conflicting, we studied the colonic microbiota of patients after resection of CRC. We profiled the microbiota using 16S rRNA gene amplicon sequencing in colonic biopsies from patients after resection of CRC (n = 63) in comparison with controls (n = 52), subjects with newly diagnosed CRC (n = 93) and polyps (i = 28). The colonic microbiota after surgical resection remained significantly different from that of controls in 65% of patients. Genus-level profiling and beta-diversity confirmed two distinct groups of patients after resection of CRC: one with an abnormal microbiota similar to that of patients with newly diagnosed CRC and another similar to non-CRC controls. Consumption levels of several dietary ingredients and cardiovascular drugs co-varied with differences in microbiota composition suggesting lifestyle factors may modulate differential microbiome trajectories after surgical resection. This study supports investigation of the colonic microbiota as a marker of risk for development of CRC.","PeriodicalId":94149,"journal":{"name":"NAR cancer","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2022-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"43061391","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}

引用次数: 5

Mouse model and human patient data reveal critical roles for Pten and p53 in suppressing POLE mutant tumor development 小鼠模型和人类患者数据揭示了Pten和p53在抑制POLE突变体肿瘤发展中的关键作用

NAR cancer Pub Date : 2022-01-13 DOI: 10.1093/narcan/zcac004

Vivian S. Park, Meijuan J S Sun, Wesley D. Frey, Leonard G. Williams, K. Hodel, Juliet D. Strauss, Sydney J. Wellens, J. Jackson, Z. Pursell

{"title":"Mouse model and human patient data reveal critical roles for Pten and p53 in suppressing POLE mutant tumor development","authors":"Vivian S. Park, Meijuan J S Sun, Wesley D. Frey, Leonard G. Williams, K. Hodel, Juliet D. Strauss, Sydney J. Wellens, J. Jackson, Z. Pursell","doi":"10.1093/narcan/zcac004","DOIUrl":"https://doi.org/10.1093/narcan/zcac004","url":null,"abstract":"Abstract Mutations in the exonuclease domain of POLE are associated with tumors harboring very high mutation burdens. The mechanisms linking this significant mutation accumulation and tumor development remain poorly understood. Pole+/P286R;Trp53+/– mice showed accelerated cancer mortality compared to Pole+/P286R;Trp53+/+ mice. Cells from Pole+/P286R mice showed increased p53 activation, and subsequent loss of p53 permitted rapid growth, implicating canonical p53 loss of heterozygosity in POLE mutant tumor growth. However, p53 status had no effect on tumor mutation burden or single base substitution signatures in POLE mutant tumors from mice or humans. Pten has important roles in maintaining genome stability. We find that PTEN mutations are highly enriched in human POLE mutant tumors, including many in POLE signature contexts. One such signature mutation, PTEN-F341V, was previously shown in a mouse model to specifically decrease nuclear Pten and lead to increased DNA damage. We found tumors in Pole+/P286R mice that spontaneously acquired PtenF341V mutations and were associated with significantly reduced nuclear Pten and elevated DNA damage. Re-analysis of human TCGA (The Cancer Genome Atlas) data showed that all PTEN-F341V mutations occurred in tumors with mutations in POLE. Taken together with recent published work, our results support the idea that development of POLE mutant tumors may involve disabling surveillance of nuclear DNA damage in addition to POLE-mediated hypermutagenesis.","PeriodicalId":94149,"journal":{"name":"NAR cancer","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2022-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"46304872","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}

引用次数: 3

Fusobacterium nucleatum is associated with inflammation and poor survival in early-stage HPV-negative tongue cancer 有核梭杆菌与早期HPV-阴性舌癌症的炎症和低生存率相关

NAR cancer Pub Date : 2022-01-13 DOI: 10.1093/narcan/zcac006

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

{"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":" ","pages":""},"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}

引用次数: 12

A m6Avalue predictive of prostate cancer stemness, tumor immune landscape and immunotherapy response 前列腺癌干细胞、肿瘤免疫景观和免疫治疗反应的m6value预测

NAR cancer Pub Date : 2022-01-13 DOI: 10.1093/narcan/zcac010

C. Zou, Qinju He, Yuanling Feng, Mengjie Chen, Dingxiao Zhang

{"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":" ","pages":""},"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}

引用次数: 6

TargetGeneReg 2.0: a comprehensive web-atlas for p53, p63, and cell cycle-dependent gene regulation TargetGeneReg 2.0：p53、p63和细胞周期依赖性基因调控的综合网络图谱

NAR cancer Pub Date : 2021-12-07 DOI: 10.1093/narcan/zcac009

Martin Fischer, Konstantin Riege, R. Schwarz, J. Decaprio, Steve Hoffmann

引用次数: 13