@article{2e27397cdd824f7bb551d75791a6aee8,
title = "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 x 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 beta-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.",
keywords = "epigenetics, methylation, neuroendocrine, Orthopedia Homeobox, pulmonary carcinoid, LUNG NEUROENDOCRINE TUMORS, SOCIETY EXPERT CONSENSUS, DIAGNOSIS, OTP, HYPERMETHYLATION, GUIDELINES, MANAGEMENT, CD44, MEN1",
author = "L. Moonen and L. Mangiante and D.J.G. Leunissen and L.M.V. Lap and A. Gabriel and L.M. Hillen and G.M. Roemen and A. Koch and {Van Engeland}, M. and A.M.C. Dingemans and M. Foll and N. Alcala and L. Fernandez-Cuesta and J.L. Derks and E.J.M. Speel",
note = "Funding Information: Dr Speel reports personal fees from Amgen, Eli Lilly and Novartis, outside the submitted work. Nonfinancial support from Biocartis and Abbvie and grants from AstraZeneca, Pfizer, Novartis and Bayer, outside the submitted work. Dr Dingemans reports financial conflicts (ad board, paid to institute) of Eli Lilly, Roche, Amgen, Jansen, Pfizer, Astra‐Zeneca, Bayer, Boehringer, Ingelheim, Sanofi, outside the submitted work. Dr van Engeland is co‐founder and shareholder of Epify BV and MLA Diagnostics BV, companies which develop cancer DNA methylation markers. All other authors declare no potential conflicts of interest. Where authors are identified as personnel of the International Agency for Research on Cancer/World Health Organization, the authors alone are responsible for the views expressed in this article and they do not necessarily represent the decisions, policy or views of the International Agency for Research on Cancer/World Health Organization. Funding Information: This work was supported by the Dutch Cancer Foundation [grant number 10956, 2017 to Ernst‐Jan M. Speel], the French National Cancer Institute (INCa, PRT‐K‐17‐047 to Lynnette Fernandez‐Cuesta and Matthieu Foll), the Ligue Nationale Contre le Cancer (LNCC 2016 to Lynnette Fernandez‐Cuesta), and the NeuroendocrineTumor Research Foundation (NETRF, Investigator Award 2019 to Lynnette Fernandez‐Cuesta). Lise Mangiante has a fellowship from the LNCC. The results shown here are in part based upon data generated by the TCGA Research Network ( https://www.cancer.gov/tcga ) and the Rare Cancers Genomics initiative ( http://rarecancersgenomics.com/lungnenomics/ ). Funding Information Publisher Copyright: {\textcopyright} 2022 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.",
year = "2022",
month = jun,
day = "15",
doi = "10.1002/ijc.33939",
language = "English",
volume = "150",
pages = "1987--1997",
journal = "International Journal of Cancer",
issn = "0020-7136",
publisher = "Wiley",
number = "12",
}