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  • American Association for Cancer Research (AACR)  (22)
  • 1
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    PLA2R1 Mediates Tumor Suppression by Activating JAK2
    American Association for Cancer Research (AACR) ; 2013
    In:  Cancer Research Vol. 73, No. 20 ( 2013-10-15), p. 6334-6345
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 73, No. 20 ( 2013-10-15), p. 6334-6345
    Abstract: Little is known about the physiological role of the phospholipase A2 receptor (PLA2R1). PLA2R1 has been described as regulating the replicative senescence, a telomerase-dependent proliferation arrest. The downstream PLA2R1 signaling and its role in cancer are currently unknown. Senescence induction in response to activated oncogenes is a failsafe program of tumor suppression that must be bypassed for tumorigenesis. We now present evidence that PLA2R1 functions in vitro as a tumor suppressor, the depletion of which is sufficient to escape oncogene-induced senescence (OIS), thereby facilitating oncogenic cell transformation. Furthermore, mice that are genetically deficient in PLA2R1 display increased sensitivity to RAS-induced tumorigenesis by facilitating OIS escape, highlighting its physiological role as a tumor suppressor. Unexpectedly, PLA2R1 activated JAK2 and its effector signaling, with PLA2R1-mediated inhibition of cell transformation largely reverted in JAK2-depleted cells. This finding was unexpected as the JAK2 pathway has been associated mainly with protumoral functions and several inhibitors are currently in clinical trials. Taken together, our findings uncover an unanticipated tumor suppressive role for PLA2R1 that is mediated by targeting downstream JAK2 effector signaling. Cancer Res; 73(20); 6334–45. ©2013 AACR.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/0008-5472.CAN-13-0318
    RVK:
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    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2013
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  • 2
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    Common Breast Cancer Susceptibility Alleles and the Risk of Breast Cancer for BRCA1 and BRCA2 Mutation Carriers: Implications for Risk Prediction
    American Association for Cancer Research (AACR) ; 2010
    In:  Cancer Research Vol. 70, No. 23 ( 2010-12-01), p. 9742-9754
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 70, No. 23 ( 2010-12-01), p. 9742-9754
    Abstract: The known breast cancer susceptibility polymorphisms in FGFR2, TNRC9/TOX3, MAP3K1, LSP1, and 2q35 confer increased risks of breast cancer for BRCA1 or BRCA2 mutation carriers. We evaluated the associations of 3 additional single nucleotide polymorphisms (SNPs), rs4973768 in SLC4A7/NEK10, rs6504950 in STXBP4/COX11, and rs10941679 at 5p12, and reanalyzed the previous associations using additional carriers in a sample of 12,525 BRCA1 and 7,409 BRCA2 carriers. Additionally, we investigated potential interactions between SNPs and assessed the implications for risk prediction. The minor alleles of rs4973768 and rs10941679 were associated with increased breast cancer risk for BRCA2 carriers (per-allele HR = 1.10, 95% CI: 1.03–1.18, P = 0.006 and HR = 1.09, 95% CI: 1.01–1.19, P = 0.03, respectively). Neither SNP was associated with breast cancer risk for BRCA1 carriers, and rs6504950 was not associated with breast cancer for either BRCA1 or BRCA2 carriers. Of the 9 polymorphisms investigated, 7 were associated with breast cancer for BRCA2 carriers (FGFR2, TOX3, MAP3K1, LSP1, 2q35, SLC4A7, 5p12, P = 7 × 10−11 − 0.03), but only TOX3 and 2q35 were associated with the risk for BRCA1 carriers (P = 0.0049, 0.03, respectively). All risk-associated polymorphisms appear to interact multiplicatively on breast cancer risk for mutation carriers. Based on the joint genotype distribution of the 7 risk-associated SNPs in BRCA2 mutation carriers, the 5% of BRCA2 carriers at highest risk (i.e., between 95th and 100th percentiles) were predicted to have a probability between 80% and 96% of developing breast cancer by age 80, compared with 42% to 50% for the 5% of carriers at lowest risk. Our findings indicated that these risk differences might be sufficient to influence the clinical management of mutation carriers. Cancer Res; 70(23); 9742–54. ©2010 AACR.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/0008-5472.CAN-10-1907
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2010
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  • 3
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    SIGMAR1 Regulates Membrane Electrical Activity in Response to Extracellular Matrix Stimulation to Drive Cancer Cell Invasiveness
    American Association for Cancer Research (AACR) ; 2016
    In:  Cancer Research Vol. 76, No. 3 ( 2016-02-01), p. 607-618
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 76, No. 3 ( 2016-02-01), p. 607-618
    Abstract: The sigma 1 receptor (Sig1R) is a stress-activated chaperone that regulates ion channels and is associated with pathologic conditions, such as stroke, neurodegenerative diseases, and addiction. Aberrant expression levels of ion channels and Sig1R have been detected in tumors and cancer cells, such as myeloid leukemia and colorectal cancer, but the link between ion channel regulation and Sig1R overexpression during malignancy has not been established. In this study, we found that Sig1R dynamically controls the membrane expression of the human voltage-dependent K+ channel human ether-à-go-go-related gene (hERG) in myeloid leukemia and colorectal cancer cell lines. Sig1R promoted the formation of hERG/β1-integrin signaling complexes upon extracellular matrix stimulation, triggering the activation of the PI3K/AKT pathway. Consequently, the presence of Sig1R in cancer cells increased motility and VEGF secretion. In vivo, Sig1R expression enhanced the aggressiveness of tumor cells by potentiating invasion and angiogenesis, leading to poor survival. Collectively, our findings highlight a novel function for Sig1R in mediating cross-talk between cancer cells and their microenvironment, thus driving oncogenesis by shaping cellular electrical activity in response to extracellular signals. Given the involvement of ion channels in promoting several hallmarks of cancer, our study also offers a potential strategy to therapeutically target ion channel function through Sig1R inhibition. Cancer Res; 76(3); 607–18. ©2015 AACR.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/0008-5472.CAN-15-1465
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2016
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  • 4
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    Association of Genomic Domains in BRCA1 and BRCA2 with Prostate Cancer Risk and Aggressiveness
    American Association for Cancer Research (AACR) ; 2020
    In:  Cancer Research Vol. 80, No. 3 ( 2020-02-01), p. 624-638
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 80, No. 3 ( 2020-02-01), p. 624-638
    Abstract: Pathogenic sequence variants (PSV) in BRCA1 or BRCA2 (BRCA1/2) are associated with increased risk and severity of prostate cancer. We evaluated whether PSVs in BRCA1/2 were associated with risk of overall prostate cancer or high grade (Gleason 8+) prostate cancer using an international sample of 65 BRCA1 and 171 BRCA2 male PSV carriers with prostate cancer, and 3,388 BRCA1 and 2,880 BRCA2 male PSV carriers without prostate cancer. PSVs in the 3′ region of BRCA2 (c.7914+) were significantly associated with elevated risk of prostate cancer compared with reference bin c.1001-c.7913 [HR = 1.78; 95% confidence interval (CI), 1.25–2.52; P = 0.001], as well as elevated risk of Gleason 8+ prostate cancer (HR = 3.11; 95% CI, 1.63–5.95; P = 0.001). c.756-c.1000 was also associated with elevated prostate cancer risk (HR = 2.83; 95% CI, 1.71–4.68; P = 0.00004) and elevated risk of Gleason 8+ prostate cancer (HR = 4.95; 95% CI, 2.12–11.54; P = 0.0002). No genotype–phenotype associations were detected for PSVs in BRCA1. These results demonstrate that specific BRCA2 PSVs may be associated with elevated risk of developing aggressive prostate cancer. Significance: Aggressive prostate cancer risk in BRCA2 mutation carriers may vary according to the specific BRCA2 mutation inherited by the at-risk individual.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/0008-5472.CAN-19-1840
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2020
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  • 5
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    Abstract P4-12-07: Single pre-operative radiation therapy (SPORT) trial for low risk breast cancer: A phase 1 study comparing pathological findings in immediate versus delayed surgery
    American Association for Cancer Research (AACR) ; 2020
    In:  Cancer Research Vol. 80, No. 4_Supplement ( 2020-02-15), p. P4-12-07-P4-12-07
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 80, No. 4_Supplement ( 2020-02-15), p. P4-12-07-P4-12-07
    Abstract: Introduction: Estrogen receptor (ER)-positive/HER2-negative breast cancers are known to be less immunogenic than triple negative and HER2-positive breast cancers. As increasing levels of tumor-infiltrating lymphocytes (TILs) have been associated with increased rates of pathological complete response (pCR) and improved prognosis, there is interest in exploring ways to render ER-positive/HER2-negative breast cancers more immunogenic. Few studies have analysed the histological response to neoadjuvant radiation therapy (RT) as the only pre-operative treatment modality; in most case series, chemotherapy was concomitantly given, as these studies focused on the treatment of advanced breast cancer. Aims: The objectives of this study are to assess pathological and immunological responses induced by a single dose of pre-operative RT in early breast cancer. Material and methods: women aged 60 years or older diagnosed with invasive breast carcinoma were prospectively identified. Only cT1N0 unifocal tumors that were low to intermediate grade and ER-positive/HER2 negative were eligible. Patients received a single pre-operative radiation dose of 20Gy in a single fraction. Surgery was performed either 24-72 hours after RT (SPORT group) or 11-13 weeks after RT (SPORT -DS [delayed surgery] group). Assessment of pathological response was performed using the Miller-Payne system and Residual Cancer Burden was calculated. Immunohistochemistry for Ki67 was performed on the biopsy and excision specimens. CD8 immunostain was used to evaluate the immune infiltrate. Both groups (SPORT and SPORT-DS) were compared using the independent t-test and Fisher exact test. Results: a total of thirteen patients were included, with an average age of 73 years (range 60-84). All patients received a single 20Gy radiation dose, and surgery was performed either 24-72 hours after RT (SPORT group, n=5) or on average 95 days after RT in the SPORT-DS group (range 75-133 days; n=8). All patients underwent partial mastectomy with sentinel lymph node biopsy. Histologically, all tumors were invasive ductal carcinomas, except for one invasive micropapillary carcinoma and one invasive tubular carcinoma (both in the SPORT group). Tumor bed changes, similar to what is observed in the post-neoadjuvant chemotherapy setting, were identified in all but one patients in the SPORT-DS group (7/8 patients) but was not seen in the SPORT group (0/5 patients, p=0.005). Using the Miller-Payne system, there was no evidence of response in the SPORT cohort (grade 1/5 in all patients), while 6/8 patients in the SPORT-DS cohort had a partial pathological response (grade 3/5 in 2 patients and grade 4/5 in 4 patients, p = 0.02). No pCR were observed. Comparing Ki67 on the biopsy and surgical specimens, an average decrease of 7.5% in the SPORT group and 6.3% in the SPORT-DS group was observed (p=0.8). A significant lymphocytic infiltrate was not present in any case (stromal TILs & lt;10% in all cases). At an average follow-up of 11 months, there have been no recurrences. Conclusion: This is, to our knowledge, the first series comparing histological findings from immediate and delayed surgery after pre-operative single dose RT. We observed a significant decrease in tumor cellularity with delayed surgery, while no change in cellularity occurred with immediate surgery. The lack of lymphocytic infiltrate does not support immune activation as the mechanism of the ablative effect of 20Gy of radiation. Further follow-up will be needed to determine the prognostic significance of the partial pathological response that was observed in the SPORT-DS cohort. Citation Format: Marie-Hélène Ngo, David Tiberi, Peter Vavassis, David Nguyen, Bernard Fortin, Mai-Kim Gervais, Lucas Sideris, Pierre Dubé, Guy Leblanc, Michel-Pierre Dufresne, Marie-Christine Guilbert, Michael Yassa. Single pre-operative radiation therapy (SPORT) trial for low risk breast cancer: A phase 1 study comparing pathological findings in immediate versus delayed surgery [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P4-12-07.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.SABCS19-P4-12-07
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2020
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  • 6
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    Matrix Metalloproteinase-9 Is Upregulated in Nucleophosmin-Anaplastic Lymphoma Kinase–Positive Anaplastic Lymphomas and Activated at the Cell Surface by the Chaperone Heat Shock Protein 90 to Promote Cell Invasion
    American Association for Cancer Research (AACR) ; 2010
    In:  Cancer Research Vol. 70, No. 17 ( 2010-09-01), p. 6978-6987
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 70, No. 17 ( 2010-09-01), p. 6978-6987
    Abstract: Many anaplastic large cell lymphomas (ALCL) express the chimeric oncogene NPM-ALK, which drives malignant transformation and invasion. In this study, we show that NPM-ALK expression increases matrix metalloproteinase-9 (MMP-9) expression. Accordingly, we found that 100% of a large panel of ALK(+) ALCL biopsies examined were also MMP-9(+), in contrast to only 36.3% of ALK(−) tumors. Mechanistic studies revealed that Rac1 drove MMP-9 secretion. The MMP inhibitor GM6001 and MMP-9 blocking antibodies abolished the invasiveness of NPM-ALK(+) cells. Interestingly, the hyaluronan receptor CD44 acted as a docking surface for MMP-9 and the chaperone heat shock protein 90 on the cell surface, where MMP-9 was cleaved and activated. Membrane-associated MMP-9 was localized to invadopodia, which display a strong gelatinase activity. Taken together, our observations strengthen the concept that chaperones have a major extracellular role in the regulation of protein activation status, and reveal new factors that are crucial for spreading and invasion of ALK(+) ALCL. They also point out new factors crucial for ALK(+) ALCL. Cancer Res; 70(17); 6978–87. ©2010 AACR.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/0008-5472.CAN-10-0861
    RVK:
    XA 36000
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    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2010
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  • 7
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    Abstract A28: Mutational landscape of TP53 in localized prostate cancer
    American Association for Cancer Research (AACR) ; 2017
    In:  Molecular Cancer Research Vol. 15, No. 4_Supplement ( 2017-04-01), p. A28-A28
    Details
    In: Molecular Cancer Research, American Association for Cancer Research (AACR), Vol. 15, No. 4_Supplement ( 2017-04-01), p. A28-A28
    Abstract: Background: We performed a comprehensive interrogation of the mutational landscape of TP53 in the context of localized prostate cancer using a large clinical/molecular-paired dataset from the Canadian Prostate Cancer Gene Network (CPC-GENE). We further test the associations of TP53 mutations with outcomes post-image-guided radiotherapy (IGRT) or radical prostatectomy (RadP). Methods: Copy number status (N = 284), single nucleotide variants (SNV) (N = 123), methylation status (N = 117), and mRNA abundance profiling (N = 115) were assessed using the Affymetrix Oncoscan FFPE express v3.0 assay, whole genome sequencing (up to 100-200x), Illumina 450K methylation array, and Affymetrix HuGene 2.0 array, respectively. Patient cohort comprised of NCCN-defined intermediate-risk prostate cancer who underwent either IGRT (N = 146) or RadP (N = 137). Biochemical-relapse free rate (bRFR) was assessed as the primary clinical end-point. Results: We identified 65 cases (22.9%) with mono-/bi-allelic copy number alteration (CNA) of TP53, and 7 cases (5.7%; 6 non-synonymous and 1 splice variant) with TP53 SNV in our cohort, which was comparable with the TCGA (30% CNA, 7% SNV) and MSKCC (17% CNA, 2.9% SNV) cohorts of low to high-risk localized prostate cancers. Epigenomic profiling revealed specific sites of DNA hypermethylation (β-value & gt;0.7) within the body and 5' UTR gene-regions, while the TSS gene-region was unaffected. Genomic mutations (CNA and/or SNV) of TP53 were associated with global genomic instability (percent genome aberration of 9.5 vs 6.4, p = 0.001) and reduced mRNA levels (mRNA abundance Z-Score: -0.58 vs 0.22, p-value = 0.0011), but methylation status had no consequence on these indices. Neither TP53 genomic mutations (HR = 1.35, 95% CI 0.91-2.00, Wald's p = 0.14) nor mRNA abundance (HR = 1.39, 95% CI 0.71-2.75, Wald's p = 0.34) was associated with bRFR on multivariable analyses. However, stratification by combinatorial genomic and mRNA abundance indices identified an unfavorable subgroup that was associated with poorer bRFR on multivariable analysis (HR = 2.95, 95% CI 1.42-6.12, Wald's p = 0.004). Conclusions: This is the first comprehensive interrogation of the mutational landscape of TP53 in localized prostate cancer. Our findings suggest that functional TP53 loss at both the copy number and transcription level accounts for a subset of non-indolent localized prostate cancer. Citation Format: Osman Mahamud, Melvin L.K Chua, Stephane Supiot, Emilie Lalonde, Alan Dal Pra, Alejandro Berlin, Michèle Orain, Valerie Picard, Helene Hovington, Alain Bergeron, Yves Fradet, Bernard Têtu, Gaetano Zafarana, Alice Meng, Julie Livingstone, Melania Pintilie, Michael Fraser, Theodorus van der Kwast, Paul C. Boutros, Bristow G. Robert. Mutational landscape of TP53 in localized prostate cancer [abstract]. In: Proceedings of the AACR Special Conference on DNA Repair: Tumor Development and Therapeutic Response; 2016 Nov 2-5; Montreal, QC, Canada. Philadelphia (PA): AACR; Mol Cancer Res 2017;15(4_Suppl):Abstract nr A28.
    Type of Medium: Online Resource
    ISSN: 1541-7786 , 1557-3125
    URL: Article
    DOI: 10.1158/1557-3125.DNAREPAIR16-A28
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2017
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  • 8
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    Acquired Initiating Mutations in Early Hematopoietic Cells of CLL Patients
    American Association for Cancer Research (AACR) ; 2014
    In:  Cancer Discovery Vol. 4, No. 9 ( 2014-09-01), p. 1088-1101
    Details
    In: Cancer Discovery, American Association for Cancer Research (AACR), Vol. 4, No. 9 ( 2014-09-01), p. 1088-1101
    Abstract: Appropriate cancer care requires a thorough understanding of the natural history of the disease, including the cell of origin, the pattern of clonal evolution, and the functional consequences of the mutations. Using deep sequencing of flow-sorted cell populations from patients with chronic lymphocytic leukemia (CLL), we established the presence of acquired mutations in multipotent hematopoietic progenitors. Mutations affected known lymphoid oncogenes, including BRAF, NOTCH1, and SF3B1. NFKBIE and EGR2 mutations were observed at unexpectedly high frequencies, 10.7% and 8.3% of 168 advanced-stage patients, respectively. EGR2 mutations were associated with a shorter time to treatment and poor overall survival. Analyses of BRAF and EGR2 mutations suggest that they result in deregulation of B-cell receptor (BCR) intracellular signaling. Our data propose disruption of hematopoietic and early B-cell differentiation through the deregulation of pre-BCR signaling as a phenotypic outcome of CLL mutations and show that CLL develops from a pre-leukemic phase. Significance: The origin and pathogenic mechanisms of CLL are not fully understood. The current work indicates that CLL develops from pre-leukemic multipotent hematopoietic progenitors carrying somatic mutations. It advocates for abnormalities in early B-cell differentiation as a phenotypic convergence of the diverse acquired mutations observed in CLL. Cancer Discov; 4(9); 1088–1101. ©2014 AACR. See related commentary by Jiang and Elemento, p. 995 This article is highlighted in the In This Issue feature, p. 973
    Type of Medium: Online Resource
    ISSN: 2159-8274 , 2159-8290
    URL: Article
    DOI: 10.1158/2159-8290.CD-14-0104
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2014
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  • 9
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    Ontogenic Changes in Hematopoietic Hierarchy Determine Pediatric Specificity and Disease Phenotype in Fusion Oncogene–Driven Myeloid Leukemia
    American Association for Cancer Research (AACR) ; 2019
    In:  Cancer Discovery Vol. 9, No. 12 ( 2019-12-01), p. 1736-1753
    Details
    In: Cancer Discovery, American Association for Cancer Research (AACR), Vol. 9, No. 12 ( 2019-12-01), p. 1736-1753
    Abstract: Fusion oncogenes are prevalent in several pediatric cancers, yet little is known about the specific associations between age and phenotype. We observed that fusion oncogenes, such as ETO2–GLIS2, are associated with acute megakaryoblastic or other myeloid leukemia subtypes in an age-dependent manner. Analysis of a novel inducible transgenic mouse model showed that ETO2–GLIS2 expression in fetal hematopoietic stem cells induced rapid megakaryoblastic leukemia whereas expression in adult bone marrow hematopoietic stem cells resulted in a shift toward myeloid transformation with a strikingly delayed in vivo leukemogenic potential. Chromatin accessibility and single-cell transcriptome analyses indicate ontogeny-dependent intrinsic and ETO2–GLIS2-induced differences in the activities of key transcription factors, including ERG, SPI1, GATA1, and CEBPA. Importantly, switching off the fusion oncogene restored terminal differentiation of the leukemic blasts. Together, these data show that aggressiveness and phenotypes in pediatric acute myeloid leukemia result from an ontogeny-related differential susceptibility to transformation by fusion oncogenes. Significance: This work demonstrates that the clinical phenotype of pediatric acute myeloid leukemia is determined by ontogeny-dependent susceptibility for transformation by oncogenic fusion genes. The phenotype is maintained by potentially reversible alteration of key transcription factors, indicating that targeting of the fusions may overcome the differentiation blockage and revert the leukemic state. See related commentary by Cruz Hernandez and Vyas, p. 1653. This article is highlighted in the In This Issue feature, p. 1631
    Type of Medium: Online Resource
    ISSN: 2159-8274 , 2159-8290
    URL: Article
    DOI: 10.1158/2159-8290.CD-18-1463
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2019
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    Noninvasive Diagnosis of Actionable Mutations by Deep Sequencing of Circulating Free DNA in Lung Cancer from Never-Smokers: A Proof-of-Concept Study from BioCAST/IFCT-1002
    American Association for Cancer Research (AACR) ; 2014
    In:  Clinical Cancer Research Vol. 20, No. 17 ( 2014-09-01), p. 4613-4624
    Details
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 20, No. 17 ( 2014-09-01), p. 4613-4624
    Abstract: Purpose: Tumor somatic mutation analysis is part of the standard management of metastatic lung cancer. However, physicians often have to deal with small biopsies and consequently with challenging mutation testing. Circulating free DNA (cfDNA) is a promising tool for accessing the tumor genome as a liquid biopsy. Here, we evaluated next-generation sequencing (NGS) on cfDNA samples obtained from a consecutive series of patients for the screening of a range of clinically relevant mutations. Experimental Design: A total of 107 plasma samples were collected from the BioCAST/IFCT-1002 lung cancer study (never-smokers cohort). Matched tumor DNA (tDNA) was obtained for 68 cases. Multiplex PCR-based assays were designed to target specific coding regions in EGFR, KRAS, BRAF, ERBB2, and PI3KCA genes, and amplicon sequencing was performed at deep coverage on the cfDNA/tDNA pairs using the NGS IonTorrent Personal Genome Machine Platform. Results: CfDNA concentration in plasma was significantly associated with both stage and number of metastatic sites. In tDNA, 50 mutations (36 EGFR, 5 ERBB2, 4 KRAS, 3 BRAF, and 2 PIK3CA) were identified, of which 26 were detected in cfDNA. Sensitivity of the test was 58% (95% confidence interval, 43%–71%) and the estimated specificity was 87% (62%–96%). Conclusion: These data demonstrate the feasibility and potential utility of mutation screening in cfDNA using IonTorrent NGS for the detection of a range of tumor biomarkers in patients with metastatic lung cancer. Clin Cancer Res; 20(17); 4613–24. ©2014 AACR.
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
    URL: Article
    DOI: 10.1158/1078-0432.CCR-13-3063
    RVK:
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    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2014
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