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

{"sci_version": "1.2", "schema": "https://corpus.bntrg.co.uk/sci/1.0/sci.schema.json", "id": "pmid:35076935", "kind": "science-record", "revision": 5, "content_hash": "sha256:58b3d87a82f1697e63b94b70e601279a0b0bbdc0504d44fa7ccedfb36aba0a3c", "created_at": "2026-11-01T17:36:48Z", "updated_at": "2026-11-01T22:05:40Z", "generator": {"name": "corpus-assay-engine", "run_id": "reading-sci-2026-11-01"}, "paper": {"state": "complete", "title": "Differential Orthopedia Homeobox expression in pulmonary carcinoids is associated with changes in DNA methylation.", "doi": "10.1002/ijc.33939", "pmid": "35076935", "authors": ["Laura Moonen", "Lise Mangiante", "Daphne J G Leunissen", "Lisa M V 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"], "journal": "International journal of cancer", "year": 2022, "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.", "claims": [{"id": "claim-method", "statement": "Differential DNA methylation was tested using the Wilcoxon rank‐sum test on β values, to allow comparisons between the nonnormally distributed distributions of β values.", "kind": "methodological", "target": null, "evidence": [{"asset": "source:pmid:35076935", "locator": "sections[8] \"Methylome analyses\" paragraph 2", "quote": "Differential DNA methylation was tested using the Wilcoxon rank‐sum test on β values, to allow comparisons between the nonnormally distributed distributions of β values."}], "state": "complete"}, {"id": "claim-data-access", "statement": "Data sources and handling of the publicly available datasets used in our study are described in the Materials and Methods. Further details and other data that support the findings of our study are available from the corresponding author upon request.", "kind": "methodological", "target": null, "evidence": [{"asset": "source:pmid:35076935", "locator": "sections[24] \"DATA AVAILABILITY STATEMENT\" paragraph 2", "quote": "Data sources and handling of the publicly available datasets used in our study are described in the Materials and Methods. Further details and other data that support the findings of our study are available from the corresponding author upon request."}], "state": "complete"}, {"id": "claim-target-result", "statement": "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).", "kind": "qualitative", "target": null, "evidence": [{"asset": "source:pmid:35076935", "locator": "sections[0] \"Abstract\" paragraph 1", "quote": "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)."}], "state": "complete"}], "gaps": []}, "experiment": {"state": "partial", "objective": "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).", "steps": [{"id": "read_published_estimate", "order": 1, "name": "Read the published estimate from the source", "kind": "other", "state": "complete", "blocked_on": null, "description": "The claim, method and evidence span published with the source article.", "duration_hours": null, "parameters": {}, "inputs": ["source:pmid:35076935"], "outputs": ["the published estimate and its evidence"], "instruments": [], "reagents": []}, {"id": "obtain_source_data", "order": 2, "name": "Obtain the source data from the named repository", "kind": "data-preparation", "state": "complete", "blocked_on": null, "description": "The GEO series accession resolves and its sample accessions are listed. 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