Differential Orthopedia Homeobox expression in pulmonary carcinoids is associated with changes in DNA methylation

Autor: Laura Moonen, Lise Mangiante, Daphne J. G. Leunissen, Lisa M. V. Lap, Aurelie Gabriel, Lisa M. Hillen, Guido M. Roemen, Alexander Koch, Manon Engeland, Anne‐Marie C. Dingemans, Matthieu Foll, Nicolas Alcala, Lynnette Fernandez‐Cuesta, Jules L. Derks, Ernst‐Jan M. Speel
Přispěvatelé: Pulmonary Medicine, RS: GROW - R2 - Basic and Translational Cancer Biology, Pathologie, MUMC+: DA Pat Pathologie (9), RS: GROW - R3 - Innovative Cancer Diagnostics & Therapy, Pulmonologie, MUMC+: MA Med Staf Spec Longziekten (9), MUMC+: MA Med Staf Artsass Longziekten (9)
Rok vydání: 2022
Předmět:
Zdroj: International Journal of Cancer, 150(12), 1987-1997. Wiley-Liss Inc.
International Journal of Cancer, 150(12), 1987-1997. Wiley
ISSN: 1097-0215
0020-7136
DOI: 10.1002/ijc.33939
Popis: 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 (OTPhigh vs OTPlow group, likelihood-ratio test P = 1.5 × 10−2), 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 < 0.05 and β-value effect size >.2). OTPlow carcinoids harbor high DNA methylation levels as compared to OTPhigh carcinoids. OTPlow 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 OTPlow 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.
Databáze: OpenAIRE
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