Differential Orthopedia Homeobox expression in pulmonary carcinoids is associated with changes in DNA methylation
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 (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.
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BibTeX
@article{moonen2026differential,
title = {{Differential Orthopedia Homeobox expression in pulmonary carcinoids is associated with changes in DNA methylation}},
author = {Laura Moonen and Lise Mangiante and Daphne J G Leunissen and Lisa M V Lap and Aurelie Gabriel and Lisa M Hillen and Guido M Roemen and Alexander Koch and Manon Van Engeland and Anne-Marie C Dingemans and Matthieu Foll and Nicolas Alcala and Lynnette Fernandez-Cuesta and Jules L Derks and Ernst-Jan M Speel},
journal = {International Journal of Cancer},
year = {2026},
month = oct,
doi = {10.1002/ijc.33939},
url = {https://hal.science/hal-05842052v1},
note = {CC BY-NC-ND},
}
RIS
TY - JOUR
TI - Differential Orthopedia Homeobox expression in pulmonary carcinoids is associated with changes in DNA methylation
AU - Laura Moonen
AU - Lise Mangiante
AU - Daphne J G Leunissen
AU - Lisa M V Lap
AU - Aurelie Gabriel
AU - Lisa M Hillen
AU - Guido M Roemen
AU - Alexander Koch
AU - Manon Van Engeland
AU - Anne-Marie C Dingemans
AU - Matthieu Foll
AU - Nicolas Alcala
AU - Lynnette Fernandez-Cuesta
AU - Jules L Derks
AU - Ernst-Jan M Speel
PY - 2026
DA - 2026/10/28
JO - International Journal of Cancer
DO - 10.1002/ijc.33939
UR - https://hal.science/hal-05842052v1
AB - 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.
SN - 0020-7136
SN - 1097-0215
ER -