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  • American Association for Cancer Research (AACR)  (3)
  • Cooke, Susanna L.  (3)
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  • American Association for Cancer Research (AACR)  (3)
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  • 1
    Online Resource
    Online Resource
    Epithelial-to-Mesenchymal Transition Supports Ovarian Carcinosarcoma Tumorigenesis and Confers Sensitivity to Microtubule Targeting with Eribulin
    American Association for Cancer Research (AACR) ; 2022
    In:  Cancer Research Vol. 82, No. 23 ( 2022-12-02), p. 4457-4473
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 82, No. 23 ( 2022-12-02), p. 4457-4473
    Abstract: Ovarian carcinosarcoma (OCS) is an aggressive and rare tumor type with limited treatment options. OCS is hypothesized to develop via the combination theory, with a single progenitor resulting in carcinomatous and sarcomatous components, or alternatively via the conversion theory, with the sarcomatous component developing from the carcinomatous component through epithelial-to-mesenchymal transition (EMT). In this study, we analyzed DNA variants from isolated carcinoma and sarcoma components to show that OCS from 18 women is monoclonal. RNA sequencing indicated that the carcinoma components were more mesenchymal when compared with pure epithelial ovarian carcinomas, supporting the conversion theory and suggesting that EMT is important in the formation of these tumors. Preclinical OCS models were used to test the efficacy of microtubule-targeting drugs, including eribulin, which has previously been shown to reverse EMT characteristics in breast cancers and induce differentiation in sarcomas. Vinorelbine and eribulin more effectively inhibited OCS growth than standard-of-care platinum-based chemotherapy, and treatment with eribulin reduced mesenchymal characteristics and N-MYC expression in OCS patient-derived xenografts. Eribulin treatment resulted in an accumulation of intracellular cholesterol in OCS cells, which triggered a downregulation of the mevalonate pathway and prevented further cholesterol biosynthesis. Finally, eribulin increased expression of genes related to immune activation and increased the intratumoral accumulation of CD8+ T cells, supporting exploration of immunotherapy combinations in the clinic. Together, these data indicate that EMT plays a key role in OCS tumorigenesis and support the conversion theory for OCS histogenesis. Targeting EMT using eribulin could help improve OCS patient outcomes. Significance: Genomic analyses and preclinical models of ovarian carcinosarcoma support the conversion theory for disease development and indicate that microtubule inhibitors could be used to suppress EMT and stimulate antitumor immunity.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/0008-5472.CAN-21-4012
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2022
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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  • 2
    Online Resource
    Online Resource
    Abstract 1176: Leveraging the GENIE dataset to distinguish somatic cancer drivers from passenger events in routine oncology practice
    American Association for Cancer Research (AACR) ; 2022
    In:  Cancer Research Vol. 82, No. 12_Supplement ( 2022-06-15), p. 1176-1176
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 82, No. 12_Supplement ( 2022-06-15), p. 1176-1176
    Abstract: Distinguishing genomic events that drive cancer (drivers) from inconsequential damage (passengers) is key to matching patients with biomarker-associated therapies and clinical trials. Whilst population level genomic analyses can estimate the proportion of driver events within a given gene, they cannot categorize individual variants. Reliable annotation remains a significant barrier to unlocking the full utility of cancer genomics. GENIE (Genomics Evidence Neoplasia Information Exchange) data was used to generate codon recurrence scores (CRS) for known cancer genes. GENIE was parsed to remove duplicates, sequencing artefact (recurrent variants reported by one institution, invariably associated with amplicon-based sequencing) and hypermutated samples ( & gt;15 mutations per megabase). For missense mutations, a codon recurrence of ≥10 was used to classify driver mutations. The table shows proportion of missense mutations classified as drivers by gene and cancer type, comparing population-based non-synonymous to synonymous mutation ratio; dN/dS (Martincorena 2017, PMID 29056346) with assessment of individual variants by CRS. This comparison demonstrates a high degree of concordance. For a few genes, CRS under called driver mutations (ie VHL in renal cancer) likely due to reduced power with small sample numbers. Importantly, CRS is able to assign driver status to individual missense mutations. Comparison with informatic analyses (PMIDs 28115009, 29247016, 30365005, 31034466) showed equivalent or superior performance of the GENIE approach. These findings demonstrate how a large (and expanding) real-world dataset can be used to predict the driver status of somatic missense mutations at the n=1 variant level. This process is amenable to implementation as a rules-based classification process for somatic missense mutations as part of an automated annotation pipeline. +corrected dN/dS ratio not significantly different from one. Pan- cancer Breast cancer Renal cancer Lung adenocarcinoma Gene dN/dS CRS dN/dS CRS dN/dS CRS dN/dS CRS BRAF 91% 76% & lt;50% 34% & lt;50% 33% 88% 74% PIK3CA 94% 89% 97% 95% 65%+ 84% 86% 76% KRAS 97% 98% 90% 95% 80%+ 100% 99% 99% IDH1 96% 81% & lt;50% 16% & lt;50% n/a & lt;50% 47% EGFR 52% 51% & lt;50% 7% & lt;50% 17% 88% 81% TP53 96% 96% 99% 97% 82%+ 89% 96% 95% PTEN 94% 54% 90% 59% & lt;50% 47% 70% 32% VHL 80% 22% & lt;50% 8% 99% 33% & lt;50% 0% CDKN2A 50% 51% & lt;50% 43% & lt;50% n/a & lt;50% 46% APC & lt;50% 1% & lt;50% 1% & lt;50% n/a & lt;50% 1% RB1 & lt;50% 6% & lt;50% 6% & lt;50% 50% & lt;50% 5% ARID1A & lt;50% 3% & lt;50% 2% & lt;50% 6% & lt;50% 2% KMT2C & lt;50% 0% & lt;50% 0% & lt;50% n/a & lt;50% 0% Citation Format: Philip A. Beer, Susanna L. Cooke, Xuan Shirley Li, Andrew V. Biankin. Leveraging the GENIE dataset to distinguish somatic cancer drivers from passenger events in routine oncology practice [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 1176.
    Type of Medium: Online Resource
    ISSN: 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2022-1176
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2022
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
    Location Call Number Limitation Availability
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    Online Resource
  • 3
    Online Resource
    Online Resource
    The Driver Mutational Landscape of Ovarian Squamous Cell Carcinomas Arising in Mature Cystic Teratoma
    American Association for Cancer Research (AACR) ; 2017
    In:  Clinical Cancer Research Vol. 23, No. 24 ( 2017-12-15), p. 7633-7640
    Details
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 23, No. 24 ( 2017-12-15), p. 7633-7640
    Abstract: Purpose: We sought to identify the genomic abnormalities in squamous cell carcinomas (SCC) arising in ovarian mature cystic teratoma (MCT), a rare gynecological malignancy of poor prognosis. Experimental design: We performed copy number, mutational state, and zygosity analysis of 151 genes in SCC arising in MCT (n = 25) using next-generation sequencing. The presence of high-/intermediate-risk HPV genotypes was assessed by quantitative PCR. Genomic events were correlated with clinical features and outcome. Results: MCT had a low mutation burden with a mean of only one mutation per case. Zygosity analyses of MCT indicated four separate patterns, suggesting that MCT can arise from errors at various stages of oogenesis. A total of 244 abnormalities were identified in 79 genes in MCT-associated SCC, and the overall mutational burden was high (mean 10.2 mutations per megabase). No SCC was positive for HPV. The most frequently altered genes in SCC were TP53 (20/25 cases, 80%), PIK3CA (13/25 cases, 52%), and CDKN2A (11/25 cases, 44%). Mutation in TP53 was associated with improved overall survival. In 8 of 20 cases with TP53 mutations, two or more variants were identified, which were bi-allelic. Conclusions: Ovarian SCC arising in MCT has a high mutational burden, with TP53 mutation the most common abnormality. The presence of TP53 mutation is a good prognostic factor. SCC arising in MCT share similar mutation profiles to other SCC. Given their rarity, they should be included in basket studies that recruit patients with SCC of other organs. Clin Cancer Res; 23(24); 7633–40. ©2017 AACR.
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
    URL: Article
    DOI: 10.1158/1078-0432.CCR-17-1789
    RVK:
    XA 36791
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2017
    detail.hit.zdb_id: 1225457-5
    detail.hit.zdb_id: 2036787-9
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