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  • American Association for Cancer Research (AACR)  (7)
  • 1
    Online Resource
    Online Resource
    ID1 Is Critical for Tumorigenesis and Regulates Chemoresistance in Glioblastoma
    American Association for Cancer Research (AACR) ; 2019
    In:  Cancer Research Vol. 79, No. 16 ( 2019-08-15), p. 4057-4071
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 79, No. 16 ( 2019-08-15), p. 4057-4071
    Abstract: Glioblastoma is the most common primary brain tumor in adults. While the introduction of temozolomide chemotherapy has increased long-term survivorship, treatment failure and rapid tumor recurrence remains universal. The transcriptional regulatory protein, inhibitor of DNA-binding-1 (ID1), is a key regulator of cell phenotype in cancer. We show that CRISPR-mediated knockout of ID1 in glioblastoma cells, breast adenocarcinoma cells, and melanoma cells dramatically reduced tumor progression in all three cancer systems through transcriptional downregulation of EGF, which resulted in decreased EGFR phosphorylation. Moreover, ID1-positive cells were enriched by chemotherapy and drove tumor recurrence in glioblastoma. Addition of the neuroleptic drug pimozide to inhibit ID1 expression enhanced the cytotoxic effects of temozolomide therapy on glioma cells and significantly prolonged time to tumor recurrence. Conclusively, these data suggest ID1 could be a promising therapeutic target in patients with glioblastoma. Significance: These findings show that the transcriptional regulator ID1 is critical for glioblastoma initiation and chemoresistance and that inhibition of ID1 enhances the effect of temozolomide, delays tumor recurrence, and prolongs survival.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/0008-5472.CAN-18-1357
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2019
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  • 2
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    Online Resource
    Abstract 1508: Chromatin accessibility of primary human cancers ties regional mutational processes with tissues of origin
    American Association for Cancer Research (AACR) ; 2022
    In:  Cancer Research Vol. 82, No. 12_Supplement ( 2022-06-15), p. 1508-1508
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 82, No. 12_Supplement ( 2022-06-15), p. 1508-1508
    Abstract: Cancer genomes are shaped by mutational processes with complex spatial variation at multiple scales. However, the underlying mechanisms of this mutagenesis and its functional and genetic determinants remain poorly understood. Somatic regional mutagenesis is known to correlate with DNA replication timing and chromatin accessibility; however, these studies have used epigenetic information from common cell lines while the epigenomes of primary human cancers remain uncharacterized in this context. Here we model megabase-scale mutation frequencies of single nucleotide variants (SNVs) in thousands of whole cancer genomes using hundreds of genome-wide profiles of chromatin accessibility and replication timing spanning primary cancer samples, normal tissues, and cell lines. Using a machine learning framework, we show that CA profiles of primary cancers, rather than those of normal cells, predict regional mutagenesis and single base substitution (SBS) signatures in most cancer types. Thus the majority of passenger mutations follow the epigenetic landscapes of transformed cells of matching cancer sites and tissues. Mutational signatures associated with carcinogen exposure, as well as signatures of unknown origin, show the strongest associations with epigenomes while associations with endogenous signatures are weaker. In most cases, overall mutation burden and SBS signatures inversely correlate with chromatin accessibility, however certain signatures are instead enriched in chromatin-accessible elements. Lastly, the genomic regions with excess mutations unexplained by the epigenetic profiles in our models likely represent a combination of localized mutagenesis and positive selection of functional oncogenic mutations. Our computational models highlight an enrichment of known driver mutations, point out novel intergenic regions with putative non-coding drivers, and indicate an over-representation of developmental and lineage-specific genes in these frequently mutated genomic regions. These results characterize the complex interplay of mutational processes, genome function, and somatic evolution in cancer and its tissues of origin, and also outline strategies for distinguishing driver and passenger mutations. Citation Format: Jüri Reimand, Oliver Ocsenas. Chromatin accessibility of primary human cancers ties regional mutational processes with tissues of origin [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1508.
    Type of Medium: Online Resource
    ISSN: 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2022-1508
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2022
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  • 3
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    Abstract A047: Panorama of complex structural variants in primary localized prostate cancer
    American Association for Cancer Research (AACR) ; 2023
    In:  Cancer Research Vol. 83, No. 11_Supplement ( 2023-06-02), p. A047-A047
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 83, No. 11_Supplement ( 2023-06-02), p. A047-A047
    Abstract: Prostate cancer (PCa) is a hormone-driven disease characterized by an abundance of structural variations (SV). Deconvolving the SV patterns can both inform on prior mutational processes leading to cancer, and be leveraged to identify patients with more aggressive disease. Under the auspices of the Pan Prostate Cancer Group (PPCG) consortium, we used whole genome sequencing of 812 treatment naive PCa patients to study both simple and complex SVs. In total, we classified 15,708 simple SVs and 1,448 complex SV events. Complex SVs such as chromothripsis, chromoplexy and templated insertion were found in more than half of the cohort. We also detected tandem duplicator phenotype (TDP) in a subset of the patients associated with CDK12 aberrations. Breakpoint recurrence analysis of driver genes revealed disruption of e.g. PTEN and formation of TMPRSS2-ERG fusion genes frequently coincide with occurrences of specific complex SV types, suggesting specific mutational processes driving these alterations of these cancer genes. Based on the simple and complex SV classifications we extracted six SV signatures, including two TDP-like signatures, distinct deletion-specific SV signatures and a signature characteristic of AR binding sites. We found signatures associated with disease markers, including Gleason score, risk scores, as well as age. Together, these findings provide insights into mechanisms driving SV formation and driver gene alterations in PCa, with potential for identifying markers of aggressive disease. Citation Format: André Olsen, Francesco Favero, Yilong Li, Etsehiwot Girma, Breon Feran, Tony Papenfuss, Kristian Helin, Jüri Reimand, Joachim Weischenfeldt. Panorama of complex structural variants in primary localized prostate cancer [abstract]. In: Proceedings of the AACR Special Conference: Advances in Prostate Cancer Research; 2023 Mar 15-18; Denver, Colorado. Philadelphia (PA): AACR; Cancer Res 2023;83(11 Suppl):Abstract nr A047.
    Type of Medium: Online Resource
    ISSN: 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.PRCA2023-A047
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2023
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  • 4
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    Abstract 385: Network-driven discovery of cancer drivers and pathways using 2,500 whole cancer genomes
    American Association for Cancer Research (AACR) ; 2017
    In:  Cancer Research Vol. 77, No. 13_Supplement ( 2017-07-01), p. 385-385
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 77, No. 13_Supplement ( 2017-07-01), p. 385-385
    Abstract: Cancer driver genes exhibit unexpectedly high mutation rates in large cancer genomic datasets. We hypothesize that driver mutations specifically alter molecular interaction networks by disrupting “active sites” - interaction interfaces in proteins and DNA. We present ActiveDriverWGS, a novel computational method to discover cancer drivers in whole-genome sequencing (WGS) data. ActiveDriverWGS finds genome regions that are significantly enriched in somatic single nucleotide variants (SNVs) and indels and ascertains whether these associate to known active sites. Analysis of active sites allows us to predict the mechanisms of mutation on three layers of the central dogma: regulatory DNA with transcription factor (TF) binding sites (TFBS), mRNA with microRNA binding sites in untranslated regions (UTRs), and post-translational modification (PTM) sites in proteins. To discover cancer driver genes and pathways, we analysed the WGS dataset of & gt;2,500 samples from the International Cancer Genome Consortium (ICGC) Pan-Cancer Analysis Working Group (PCAWG). We found 61 protein-coding candidates with 34 known drivers (P=10-40), validating the high accuracy of our method. 40 genes have significant mutations of PTM sites, suggesting that rewiring of PTM signalling networks is a common oncogenic mechanism. For example, the BRAF V600E SNV flanks two phosphorylation sites and one ubiquitination site (FDR P=10-44), a novel interpretation and potential avenue for precision therapies targeting the kinase and ubiquitin network of BRAF. In the non-coding genome, we detected known lncRNAs (NEAT1, MALAT1), promoters (TERT, WDR74) and novel candidates with mutation enrichment. For example, an enhancer on chr6 has a mutation hotspot in 33 patients (FDR P=10-19), with 20 SNVs affecting binding motifs of cancer-associated TFs FOXO3, SOX2, HMGA2 (FDR P=10-10). Thus our method discovers non-coding drivers and their candidate mechanisms in a single analysis. Our ActiveDriverPW method extends coding and non-coding mutations to biological pathways. We found & gt;600 mutation-enriched pathways in the PCAWG pan-cancer dataset. Of these ~200 are also significant when only non-coding mutations are analysed, showing that the non-coding genome includes previously unstudied mutations in pathways. The DNA double-strand break response pathway (FDR p=10-10) includes non-coding SNVs in ~20 histones and chromatin modifiers, such as the demethylase KDM4B with 46 SNVs in its promoter and enhancers. ActiveDriverPW maps mutations of the long tail that affect genes in hallmark cancer processes yet remain undiscovered in gene-focused analyses. Our methods accurately capture known drivers in the ICGC-PCAWG dataset and suggest specific mechanistic details. Our benchmarks also emphasize the robust performance of our methods. ActiveDriverWGS and ActiveDriverPW are valuable additions to the toolbox for cancer genome analysis. Citation Format: Jüri Reimand. Network-driven discovery of cancer drivers and pathways using 2,500 whole cancer genomes [abstract] . In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 385. doi:10.1158/1538-7445.AM2017-385
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2017-385
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2017
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  • 5
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    Mutations in Noncoding Cis -Regulatory Elements Reveal Cancer Driver Cistromes in Luminal Breast Cancer
    American Association for Cancer Research (AACR) ; 2022
    In:  Molecular Cancer Research Vol. 20, No. 1 ( 2022-01-01), p. 102-113
    Details
    In: Molecular Cancer Research, American Association for Cancer Research (AACR), Vol. 20, No. 1 ( 2022-01-01), p. 102-113
    Abstract: Whole-genome sequencing of primary breast tumors enabled the identification of cancer driver genes and noncoding cancer driver plexuses from somatic mutations. However, differentiating driver from passenger events among noncoding genetic variants remains a challenge. Herein, we reveal cancer-driver cis-regulatory elements linked to transcription factors previously shown to be involved in development of luminal breast cancers by defining a tumor-enriched catalogue of approximately 100,000 unique cis-regulatory elements from 26 primary luminal estrogen receptor (ER)+ progesterone receptor (PR)+ breast tumors. Integrating this catalog with somatic mutations from 350 publicly available breast tumor whole genomes, we uncovered cancer driver cistromes, defined as the sum of binding sites for a transcription factor, for ten transcription factors in luminal breast cancer such as FOXA1 and ER, nine of which are essential for growth in breast cancer with four exclusive to the luminal subtype. Collectively, we present a strategy to find cancer driver cistromes relying on quantifying the enrichment of noncoding mutations over cis-regulatory elements concatenated into a functional unit. Implications: Mapping the accessible chromatin of luminal breast cancer led to discovery of an accumulation of mutations within cistromes of transcription factors essential to luminal breast cancer. This demonstrates coopting of regulatory networks to drive cancer and provides a framework to derive insight into the noncoding space of cancer.
    Type of Medium: Online Resource
    ISSN: 1541-7786 , 1557-3125
    URL: Article
    DOI: 10.1158/1541-7786.MCR-21-0471
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2022
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    SSG: 12
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  • 6
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    Abstract B29: Defining subclonal signaling heterogeneity in glioblastoma multiforme (GBM)
    American Association for Cancer Research (AACR) ; 2013
    In:  Cancer Research Vol. 73, No. 19_Supplement ( 2013-10-01), p. B29-B29
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 73, No. 19_Supplement ( 2013-10-01), p. B29-B29
    Abstract: Glioblastoma Multiforme (GBM, WHO grade IV) is the most common and malignant brain tumor of the adult central nervous system, with a median survival of between 12 and 15 months. Interestingly, the presence of genetically unique subclones in GBMs has been previously implicated in GBMs using Fluorescence in situ hybridization (FISH) and surgical multisampling approaches.1,2 The purpose of this study are to unequivocally demonstrate clinically relevant phenotypic heterogeneity in GBM subclones, and to identify genetic and phenotypic biomarkers predictive of subclonal drug responses. Previous work in the Dirks laboratory has allowed for the generation of 44 single-cell derived clonal cultures from 4 GBM tumors, by Fluorescence Activated Cell Sorting (FACS) and clonal expansion in vitro. Comparisons of clones derived from the same tumor uniquely allows for the identification and characterization of genetic and functional intratumoral diversity in GBM. We demonstrate that single-cell derived clonal cultures from the same primary tumor can differ in key phenotypes such as proliferation in vitro and responsiveness to the chemotherapeutic Temozolomide. Our work has also shown that expression of the oncogene EGFRvIII is exclusive to some clones within a tumor, and not others. Profiling of basal and activated EGFR signaling states also revealed subclonal variability in pERK and pS6 activity, suggesting subclonal differences in pathway dependencies which could be exploited for targeted therapies. Importantly, we observed clonal differences in sensitivity to the EGFR small molecule inhibitor Erlotinib, suggesting that clonal phenotypes can be correlated to differences in signaling activity between tumor subclones. The existence of inherently drug resistant clones in GBM tumors may lead to ineffective therapies and tumor relapses, and subclonal interrogation of patient specimens may lead to better treatment stratification. References 1) Snuderl, M., L. Fazlollahi, et al. “Mosaic amplification of multiple receptor tyrosine kinase genes in glioblastoma.” Cancer Cell 20, 810-817(2011). 2) Sottoriva, A., I. Spiteri, et al. (2013). “Intratumor heterogeneity in human glioblastoma reflects cancer evolutionary dynamics.” Proc Natl Acad Sci USA 110, 4009-4014(2013). Citation Format: Xiaoyang Lan, Mona Meyer, Jüri Reimand, Xueming Zhu, Michelle Kushida, Renee Head, Ian Clarke, Gary Bader, Peter Dirks. Defining subclonal signaling heterogeneity in glioblastoma multiforme (GBM). [abstract]. In: Proceedings of the Third AACR International Conference on Frontiers in Basic Cancer Research; Sep 18-22, 2013; National Harbor, MD. Philadelphia (PA): AACR; Cancer Res 2013;73(19 Suppl):Abstract nr B29.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.FBCR13-B29
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2013
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  • 7
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    Abstract 2057: Pan-cancer analysis of ion channel genes reveals patterns of large-scale transcriptional dysregulation and novel oncogenes with functions in cellular connectivity
    American Association for Cancer Research (AACR) ; 2023
    In:  Cancer Research Vol. 83, No. 7_Supplement ( 2023-04-04), p. 2057-2057
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 83, No. 7_Supplement ( 2023-04-04), p. 2057-2057
    Abstract: Ion channels (IC) are one of the largest families of highly druggable proteins targeted in therapies for many human diseases; however, their role in cancer remains understudied. IC drug repurposing for cancer therapies is an appealing avenue; however, prioritizing ICs for pre-clinical research, mechanistic elucidation, and target development remains a challenge. Here we performed a systematic, pan-cancer analysis to prioritize IC genes as putative targets for therapeutic and biomarker development. Using machine learning, we studied ~10,000 human transcriptomes from 32 cancer types of The Cancer Genome Atlas (TCGA) to identify ICs whose expression significantly associated with patient survival. IC genes showed dysregulation in all cancer types: elevated IC expression was characteristic of a subset of tumors often associated with poor patient prognosis. Excessive IC expression was unexpectedly frequent and high-magnitude compared to control sets of protein-coding genes and genes of major druggable families. We focused on ICs in glioblastoma (GBM), the most prevalent and lethal form of brain cancer in adults, prioritizing GJB2 (gap junction protein beta 2) and SCN9A (sodium voltage-gated channel alpha subunit 9) as potential GBM oncogenes. High expression of these ICs associated with poor GBM prognosis in TCGA and independent transcriptomics datasets. GJB2 and SCN9A expression was higher in GBMs than normal brain tissues and associated with GBM subtypes, histological features, and immune cell infiltration. At the single-cell level, GJB2 and SCN9A were predominantly expressed in malignant cell types in GBMs. We validated GJB2 and SCN9A with shRNA-mediated knockdowns (KDs) in patient-derived GBM cell lines and mouse xenograft models. First, GJB2 and SCN9A KDs significantly impaired cell viability and spheroid formation. We then validated survival associations, showing that GJB2 and SCN9A KDs prolonged survival of mice with GBM xenografts. Finally, we showed GBJ2 KD impaired tunneling nanotube length in GBM cells. Transcriptome-wide profiling of IC KD cells revealed hundreds of differentially expressed genes. Integrative pathway enrichment across IC KDs in GBM cells and IC-stratified TCGA samples identified dysregulated pathways with functional themes of neuronal development, cancer hallmarks, and regulation of glial cells, including tumor cell connectivity pathways in GBM, corroborating the phenotypes observed in our functional validations. Our pan-cancer analysis prioritized ICs for further pre-clinical development and mechanistic study. The functional validation experiments of GJB2 and SCN9A highlight their possible roles in GBM pathology and lends confidence to our analysis. This study demonstrates the utility of investigating ICs as avenues for drug repurposing and the development of novel cancer therapeutics. Citation Format: Alexander Bahcheli, Hyun Min, Xi Huang, Jüri Reimand. Pan-cancer analysis of ion channel genes reveals patterns of large-scale transcriptional dysregulation and novel oncogenes with functions in cellular connectivity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2057.
    Type of Medium: Online Resource
    ISSN: 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2023-2057
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2023
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    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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