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  • American Association for Cancer Research (AACR)  (5)
  • 1
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    Abstract 849: Molecular characterization of primary tumor & the paired liver metastatic biopsies of colorectal cancer reveals a critical role of immunosuppression, EMT & angiogenesis in cancer metastasis
    American Association for Cancer Research (AACR) ; 2017
    In:  Cancer Research Vol. 77, No. 13_Supplement ( 2017-07-01), p. 849-849
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 77, No. 13_Supplement ( 2017-07-01), p. 849-849
    Abstract: Colorectal cancer (CRC) is one of the leading causes of cancer-related mortality worldwide. In United States alone, it was estimated that nearly 137,000 people were diagnosed, and more than 50,000 were dead from the disease each year. CRC primary tumors often metastasize to liver which accounts for most of CRC death. The molecular mechanism of tumor metastasis is complicate and remains poorly understood. In this study, we have collected 79 human CRC samples, and 60 of them are paired primary tumor and liver metastatic surgically resected samples. Molecular characterization of these samples was conducted by exome and RNA sequencing, as well as SNP6.0 analysis. Genetic analysis revealed no significant difference in genetic alterations including common oncogenic mutations, whole genome mutations and copy number variations between primary and their matched liver metastatic tumors. To further characterize the molecular mechanism of metastatic progression, we have assembled gene correlation networks by utilizing a genome-wide interrogation of co-regulated networks based on RNA sequencing data of these CRC samples. Computational analysis of these correlation networks has identified gene signatures of immune-suppression, epithelial-mesenchymal transition (EMT) and angiogenesis as the key events and potentially synergistic drivers associated with CRC metastasis. Further independent cohort validation using published datasets verified that these specific gene networks of tumor microenvironment were progressively up-regulated throughout the carcinogenesis, and represented distinct biological processes. These gene networks were capable of discriminating the previously categorized CRC molecular subclasses. In addition, we also showed an association of type I interferon network with good clinical outcome of CRC, and gene networks of EMT, angiogenesis, immune-suppression and T cell exhaustion are closely associated with the poor patient outcome. We further demonstrated that the networks of EMT and angiogenesis were related to innate anti-PD-1 resistance, and the networks of immunosuppression and T cell exhaustion were associated with resistance to radiation and checkpoint blockade. Overall, we conclude that a genome-wide interrogation of co-regulated networks utilized in this study represents a valuable strategy to identify molecular mechanisms of cancer metastasis, and gene networks of immune-suppression, EMT and angiogenesis are among the key events associated with CRC metastasis. Citation Format: Jiangang Liu, Yong Beom Cho, Hye kyung Hong, Song Wu, Philip J. Ebert, Steven M. Bray, Swee Seong Wong, Jason C. Ting, John N. Calley, Catherine F. Whittington, Shripad Bhagwat, Emma Bowden, Amit Aggarwal, Christoph Reinhard, Robert Wild, Do-Hyun Nam, Woo Yong Lee, Sheng-Bin Peng. Molecular characterization of primary tumor & the paired liver metastatic biopsies of colorectal cancer reveals a critical role of immunosuppression, EMT & angiogenesis in cancer metastasis [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 849. doi:10.1158/1538-7445.AM2017-849
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2017-849
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2017
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  • 2
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    Janus Kinase 3–Activating Mutations Identified in Natural Killer/T-cell Lymphoma
    American Association for Cancer Research (AACR) ; 2012
    In:  Cancer Discovery Vol. 2, No. 7 ( 2012-07-01), p. 591-597
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    In: Cancer Discovery, American Association for Cancer Research (AACR), Vol. 2, No. 7 ( 2012-07-01), p. 591-597
    Abstract: The molecular pathogenesis of natural killer/T-cell lymphoma (NKTCL) is not well understood. We conducted whole-exome sequencing and identified Janus kinase 3 (JAK3) somatic–activating mutations (A572V and A573V) in 2 of 4 patients with NKTCLs. Further validation of the prevalence of JAK3 mutations was determined by Sanger sequencing and high-resolution melt (HRM) analysis in an additional 61 cases. In total, 23 of 65 (35.4%) cases harbored JAK3 mutations. Functional characterization of the JAK3 mutations support its involvement in cytokine-independent JAK/STAT constitutive activation leading to increased cell growth. Moreover, treatment of both JAK3-mutant and wild-type NKTCL cell lines with a novel pan-JAK inhibitor, CP-690550, resulted in dose-dependent reduction of phosphorylated STAT5, reduced cell viability, and increased apoptosis. Hence, targeting the deregulated JAK/STAT pathway could be a promising therapy for patients with NKTCLs. Significance: Gene mutations causing NKTCL have not been fully identified. Through exome sequencing, we identified activating mutations of JAK3 that may play a significant role in the pathogenesis of NKTCLs. Our findings have important implications for the management of patients with NKTCLs. Cancer Discov; 2(7); 591–7. ©2012 AACR. This article is highlighted in the In This Issue feature, p. 569.
    Type of Medium: Online Resource
    ISSN: 2159-8274 , 2159-8290
    URL: Article
    DOI: 10.1158/2159-8290.CD-12-0028
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2012
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  • 3
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    Abstract LB-313: Integrative genomic profiling of Asian gastric cancers identifies four subgroups with distinct pathobiology and prognosis
    American Association for Cancer Research (AACR) ; 2014
    In:  Cancer Research Vol. 74, No. 19_Supplement ( 2014-10-01), p. LB-313-LB-313
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 74, No. 19_Supplement ( 2014-10-01), p. LB-313-LB-313
    Abstract: Gastric cancer is the 2nd most common cause of cancer related mortality and 4th most common cancer worldwide. The molecular classification of Gastric Cancers and the relevance of pre-clinical models are not well established, creating challenges in discovering novel molecularly targeted therapies. In order to address that, we conducted integrated molecular data analysis of 300 Asian Gastric tumors through the Asian Cancer Research Group (ACRG). We identified four cancer subtypes, based on RNA/DNA profiling, Lauren's histological classification (Intestinal and Diffused) and Epstein Barr Virus (EBV) status, exhibiting differential pathobiology as well as prognosis. The groups are 1) Mesenchymal subgroup characterized by Diffused tumors with hallmarks of Epithelial to Mesenchymal transition such as CDH1 loss and co-occurring with IGF2 over-expression; 2) Microsatellite instable (MSI) subgroup characterized by predominantly hypermutated Intestinal tumors (including majority of mutations in KRAS) with likely MLH1 loss through promoter methylation; 3) TP53 pathway active subgroup with Epstein-Barr virus (EBV) infection or mutated oncogenes (e.g. PIK3CA) and 4) TP53 pathway inactive characterized by p53 loss through deleterious mutations in TP53 or MDM2 amplification and further characterized by both focal amplifications in oncogenes such as HER2, EGFR, cMET, CCNE1 as well as large scale chromosomal gains and losses. The above subtypes exhibited differential prognosis with the Mesenchymal subtype displaying the worst prognosis and the MSI subtype the best prognosis among the subtypes. The subtypes and their association with prognosis were independently validated in an additional large Gastric cancer cohort (N=277). We studied the applicability of this classification in other gastrointestinal (GI) cancers and show the presence of our proposed molecular subtypes of Gastric cancer in Colorectal cancers as well thereby suggesting commonalities in biological processes that give rise to Gastric and Colorectal tumors and providing a common ground to classify GI cancers. We also checked the presence of Gastric cancer subtypes in pre-clinical models of GI tract cancers and found that cell line panels often used for drug discovery shown an under-representation of p53 pathway active subtype, thus possibly creating challenges in translation to clinical studies. Overall, we provide a stratification that will lay a more solid groundwork for rationally targeting Gastric Cancer by helping focus on specific altered mechanisms and/or oncogenes as well as allowing for a more rational choice of pre-clinical models in drug discovery and development. Citation Format: Razvan Cristescu, Jeeyun Lee, Michael Nebozhyn, Amit Aggarwal, Jason Ting, Swee Seong Wong, Yong Yue, Christoph Reinhard, Kyoung Kim, Ingu Do, Hongyue Dai, Andrey Loboda. Integrative genomic profiling of Asian gastric cancers identifies four subgroups with distinct pathobiology and prognosis. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr LB-313. doi:10.1158/1538-7445.AM2014-LB-313
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2014-LB-313
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2014
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  • 4
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    Patterns of Oncogene Coexpression at Single-Cell Resolution Influence Survival in Lymphoma
    American Association for Cancer Research (AACR) ; 2023
    In:  Cancer Discovery Vol. 13, No. 5 ( 2023-05-04), p. 1144-1163
    Details
    In: Cancer Discovery, American Association for Cancer Research (AACR), Vol. 13, No. 5 ( 2023-05-04), p. 1144-1163
    Abstract: Cancers often overexpress multiple clinically relevant oncogenes, but it is not known if combinations of oncogenes in cellular subpopulations within a cancer influence clinical outcomes. Using quantitative multispectral imaging of the prognostically relevant oncogenes MYC, BCL2, and BCL6 in diffuse large B-cell lymphoma (DLBCL), we show that the percentage of cells with a unique combination MYC+BCL2+BCL6− (M+2+6−) consistently predicts survival across four independent cohorts (n = 449), an effect not observed with other combinations including M+2+6+. We show that the M+2+6− percentage can be mathematically derived from quantitative measurements of the individual oncogenes and correlates with survival in IHC (n = 316) and gene expression (n = 2,521) datasets. Comparative bulk/single-cell transcriptomic analyses of DLBCL samples and MYC/BCL2/BCL6-transformed primary B cells identify molecular features, including cyclin D2 and PI3K/AKT as candidate regulators of M+2+6− unfavorable biology. Similar analyses evaluating oncogenic combinations at single-cell resolution in other cancers may facilitate an understanding of cancer evolution and therapy resistance. Significance: Using single-cell–resolved multiplexed imaging, we show that selected subpopulations of cells expressing specific combinations of oncogenes influence clinical outcomes in lymphoma. We describe a probabilistic metric for the estimation of cellular oncogenic coexpression from IHC or bulk transcriptomes, with possible implications for prognostication and therapeutic target discovery in cancer. This article is highlighted in the In This Issue feature, p. 1027
    Type of Medium: Online Resource
    ISSN: 2159-8274 , 2159-8290
    URL: Article
    DOI: 10.1158/2159-8290.CD-22-0998
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2023
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  • 5
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    Abstract 5557: Patterns of oncogene co-expression at single cell resolution influence survival in diffuse large B-cell lymphoma
    American Association for Cancer Research (AACR) ; 2023
    In:  Cancer Research Vol. 83, No. 7_Supplement ( 2023-04-04), p. 5557-5557
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 83, No. 7_Supplement ( 2023-04-04), p. 5557-5557
    Abstract: Background: Cancers often overexpress multiple clinically relevant oncogenes. However, it is not known if multiple oncogenes within a cancer combineuniquely in specific cellular sub-populations to influence clinical outcome.We studied this phenomenon using the prognostically relevantoncogenes MYC, BCL2 and BCL6 in Diffuse Large B-Cell Lymphoma(DLBCL). Methods: Quantitative multispectral imaging simultaneously measured oncogene co-expression at single-cell resolution in reactive lymphoid tissue (n=12)and four independent cohorts (n=409) of DLBCL. Mathematically derived co-expression phenotypes were evaluated in DLBCLs with immunohistochemistry (n=316) and nine DLBCL cohorts with gene expression data (n=3974). Bulk and single-cell RNA sequencing was performed on patient-derived B-cells with induced co-expression of MYC,BCL2 and BCL6. Results: Unlike in non-malignant lymphoid tissue where the co-expression of MYC, BCL2 and BCL6 in a B-cell is limited, DLBCLs show multiple permutations of oncogenic co-expression in malignant B-cells. The percentage of cells with a unique combination MYC+BCL2+BCL6-(M+2+6-) consistently predicts survival in contrast to that of other combinations (including M+2+6+). An estimated percentage of M+2+6-cells can be derived from any quantitative measurement of the component individual oncogenes, and correlates with survival in immunohistochemistry and gene expression datasets. Comparative transcriptomic analysis of DLBCLs and transformed patient-derived B-cells identifies cyclin D2 (CCND2) as a potential BCL6-repressedregulator of proliferation in the M+2+6- population. Conclusions: Unique patterns of oncogene co-expression at single-cell resolution affect clinical outcomes in DLBCL. Similar analyses evaluating oncogenic combinations at the cellular level may impact diagnostics and target discovery in other cancers. Citation Format: Michal M. Hoppe, Patrick Jaynes, Shuangyi Fan, Yanfen Peng, Shruti Sridhar, Phuong Mai Hoang, Xin Liu, Sanjay de Mel, Limei Poon, Esther Chan, Joanne Lee, Choon Kiat Ong, Tiffany Tang, Soon Thye Lim, Chandramouli Nagarajan, Nicholas F. Grigoropoulos, Soo-Yong Tan, Susan Swee-Shan Hue, Sheng-Tsung Chang, Shih-Sung Chuang, Shaoying Li, Joseph D. Khoury, Hyungwon Choi, Pedro Farinha, Anja Mottok, David W. Scott, Carl Harris, Alessia Bottos, Gayatri Kumar, Kasthuri Kannan, Laura J. Gay, Hendrik F. Runge, Ilias Moutsopoulos, Irina Mohorianu, Daniel J. Hodson, Yen-Chee Lin, Wee-Joo Chng, Siok-Bian Ng, Claudio Tripodo, Anand D. Jeyasekharan. Patterns of oncogene co-expression at single cell resolution influence survival in diffuse large B-cell lymphoma. [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 5557.
    Type of Medium: Online Resource
    ISSN: 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2023-5557
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2023
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