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  • 1
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    Online Resource
    Abstract 3744: Differential Orthopedia Homeobox (OTP) expression in pulmonary carcinoids is associated with changes in DNA methylation
    American Association for Cancer Research (AACR) ; 2022
    In:  Cancer Research Vol. 82, No. 12_Supplement ( 2022-06-15), p. 3744-3744
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 82, No. 12_Supplement ( 2022-06-15), p. 3744-3744
    Abstract: Introduction: Limited number of tumor types have been examined for Orthopedia Homeobox (OTP) expression. In pulmonary carcinoids, loss of expression is a strong indicator of poor prognosis. Here, we investigated OTP expression in 37 different tumor types, and the association between OTP expression and DNA methylation levels in lung neuroendocrine neoplasms. Methods: We analyzed publicly available multi-omics data (whole-exome-, whole-genome-, RNA sequencing, Epic-850K-methylation array) of 58 typical-, 27 atypical carcinoids, 69 large cell neuroendocrine carcinoma and 51 small cell lung cancer patients and TCGA (The Cancer Genome Atlas) data of 33 tumor types. 850K-methylation analysis was cross validated using targeted pyrosequencing on 35 carcinoids. Results: Results showed bimodality of OTP expression in carcinoids (OTPhigh versus OTPlow group, likelihood-ratio test p=1.5x10-2), with the OTPhigh group specific to pulmonary carcinoids while absent from all other cohorts analyzed. Significantly different DNA methylation levels were observed between OTPhigh and OTPlow carcinoids in 12/34 OTP infinium probes (fdr & lt;0.05 & β-value effect size & gt;0.2). Overall, OTPlow carcinoids harbor a high DNA methylation level as compared to OTPhigh carcinoids. OTPlow carcinoids showed a significantly worse overall survival (logrank test p=0.0052). Gene set enrichment analysis for somatically mutated genes associated with hallmarks of cancer showed robust enrichment of three hallmarks in the OTPlow group, i.e., sustaining proliferative signaling, evading growth suppressor, and genome instability and mutation. Conclusion: High OTP expression is a unique feature of pulmonary carcinoids with a favorable prognosis. In poor prognostic patients, OTP expression is lost, most likely due to changes in DNA methylation levels. Citation Format: Laura Moonen, Lise Mangiante, Daphne J. Leunissen, Lisa M. Lap, Aurelie Gabriel, Lisa M. Hillen, Guido M. Roemen, Alexander Koch, Manon van Engeland, Anne-Marie C. Dingemans, Matthieu Foll, Nicolas Alcala, Lynnette Fernandez-Cuesta, Jules L. Derks, Ernst-Jan M. Speel. Differential Orthopedia Homeobox (OTP) expression in pulmonary carcinoids is associated with changes in DNA methylation [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 3744.
    Type of Medium: Online Resource
    ISSN: 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2022-3744
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2022
    detail.hit.zdb_id: 2036785-5
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  • 2
    Online Resource
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    Differential Orthopedia Homeobox expression in pulmonary carcinoids is associated with changes in DNA methylation
    Wiley ; 2022
    In:  International Journal of Cancer Vol. 150, No. 12 ( 2022-06-15), p. 1987-1997
    Details
    In: International Journal of Cancer, Wiley, Vol. 150, No. 12 ( 2022-06-15), p. 1987-1997
    Abstract: Limited number of tumor types have been examined for Orthopedia Homeobox (OTP) expression. In pulmonary carcinoids, loss of expression is a strong indicator of poor prognosis. Here, we investigated OTP expression in 37 different tumor types, and the association between OTP expression and DNA methylation levels in lung neuroendocrine neoplasms. We analyzed publicly available multi‐omics data (whole‐exome‐, whole‐genome‐, RNA sequencing and Epic 850K‐methylation array) of 58 typical carcinoids, 27 atypical carcinoids, 69 large cell neuroendocrine carcinoma and 51 small cell lung cancer patients and TCGA (The Cancer Genome Atlas) data of 33 tumor types. 850K‐methylation analysis was cross‐validated using targeted pyrosequencing on 35 carcinoids. We report bimodality of OTP expression in carcinoids (OTP high vs OTP low group, likelihood‐ratio test P  = 1.5 × 10 −2 ), with the OTP high group specific to pulmonary carcinoids while absent from all other cohorts analyzed. Significantly different DNA methylation levels were observed between OTP high and OTP low carcinoids in 12/34 OTP infinium probes (FDR  〈  0.05 and β ‐value effect size  〉  .2). OTP low carcinoids harbor high DNA methylation levels as compared to OTP high carcinoids. OTP low carcinoids showed a significantly worse overall survival (log‐rank test P  = .0052). Gene set enrichment analysis for somatically mutated genes associated with hallmarks of cancer showed robust enrichment of three hallmarks in the OTP low group, that is, sustaining proliferative signaling, evading growth suppressor and genome instability and mutation. Together our data suggest that high OTP expression is a unique feature of pulmonary carcinoids with a favorable prognosis and that in poor prognostic patients, OTP expression is lost, most likely due to changes in DNA methylation levels.
    Type of Medium: Online Resource
    ISSN: 0020-7136 , 1097-0215
    URL: Issue
    URL: Article
    DOI: 10.1002/ijc.v150.12
    DOI: 10.1002/ijc.33939
    RVK:
    XA 10000
    Language: English
    Publisher: Wiley
    Publication Date: 2022
    detail.hit.zdb_id: 218257-9
    detail.hit.zdb_id: 1474822-8
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  • 3
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    Online Resource
    Abstract 487: A high percentage of LCNEC shows DLL3 expression in association with molecular subtypes and neuroendocrine markers
    American Association for Cancer Research (AACR) ; 2019
    In:  Cancer Research Vol. 79, No. 13_Supplement ( 2019-07-01), p. 487-487
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 79, No. 13_Supplement ( 2019-07-01), p. 487-487
    Abstract: Background Pulmonary large cell neuroendocrine carcinoma (LCNEC) can be subdivided in two types: the co-mutated TP53 and RB1 subtype, and the TP53 and STK11/KEAP1 mutated subtype (Derks et al. Clin Cancer Res 2018; J Thorac Oncol 2018). DLL3 is a member of the Notch ligand family and a possible treatment target for neuroendocrine carcinoma. We investigated DLL3 and NE marker expression in mutational subtypes of metastatic LCNEC. Methods Immunohistochemical (IHC) analysis for DLL3 (clone SC16.65) was performed on 94 pathological reviewed pretreatment stage IV LCNEC. Samples were scored positive if ≥1% tumor cells showed cytoplasmic or dotlike DLL3 immunostaining. Also an H-score was calculated by multiplying intensity by percentage of positive cells. Targeted next generation sequencing (TP53, RB1, STK11, KEAP1) could be performed in 66 patients. Results DLL3 was expressed in 70/94 (75%) LCNEC, 56 of which showed cytoplasmic immunostaining. 37/70 (53%) samples had an H-score & gt;100. DLL3 staining was more often seen in STK11 and/or KEAP1 mutated LCNEC (13/14;93%) than in tumors with wildtype STK11/KEAP1 (36/52;69%) (trend;p=0.093). In addition, DLL3 positivity was associated with expression of ≥2 NE-markers (64/79 LCNEC (81%) vs 3/8 (37%) tumors with & lt;2 NE-markers; p=0.014). Conclusions A high percentage (75%) of stage IV LCNEC shows cytoplasmatic DLL3 epression in association with NE markers, half of which with H-scores & gt;100. Interestingly, DLL3 positivity was observed in almost all STK11/KEAP1 mutated LCNEC, which is in agreement with recent data (George et al. Nat Commun 2018). It thus might be worthwhile to investigate the efficacy of DLL3 targeted therapy in LCNEC. Citation Format: Ernst-Jan M. Speel, Bregtje C. Hermans, Jules L. Derks, Erik Thunnissen, Robert Jan van Suylen, Michael A. den Bakker, Harry J. Groen, Egbert F. Smit, Ronald A. Damhuis, Esther C. van den Broek, Cecile M. Stallinga, Guido M. Roemen, Anne-Marie C. Dingemans. A high percentage of LCNEC shows DLL3 expression in association with molecular subtypes and neuroendocrine markers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 487.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2019-487
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2019
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
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