{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,14]],"date-time":"2026-09-14T14:21:07Z","timestamp":1789395667762,"version":"build-2803163510"},"reference-count":21,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T00:00:00Z","timestamp":1788998400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Curr. Issues Mol. Biol.","CIMB"],"abstract":"<jats:p>Adhesion G protein-coupled receptor D1 (ADGRD1), formerly known as GPR133, has been implicated in tumor-associated signaling; however, its histology-specific clinicopathologic and prognostic significance in non-small cell lung cancer (NSCLC) remains incompletely characterized. Clinical and survival data from The Cancer Genome Atlas lung adenocarcinoma (TCGA-LUAD) and lung squamous cell carcinoma (TCGA-LUSC) cohorts were integrated with harmonized gene-expression data obtained from the Genomic Data Commons (GDC). ADGRD1 expression was dichotomized using a cohort-specific median cutoff and additionally analyzed as a continuous standardized variable. Clinicopathologic associations, Pearson correlations with prespecified subtype-associated genes, Kaplan\u2013Meier survival analyses, and univariate and multivariable Cox proportional hazards regression analyses were performed. Benjamini\u2013Hochberg false-discovery-rate correction was applied to molecular correlation analyses. Independent validation was performed using GSE30219 and GSE50081, followed by random-effects meta-analysis and proportional hazards sensitivity analyses. High ADGRD1 expression was associated with favorable overall survival (OS) in LUAD in both univariate (HR = 0.542, 95% CI = 0.400\u20130.734, p &lt; 0.001) and clinically adjusted Cox analyses (HR = 0.543, 95% CI = 0.398\u20130.740, p &lt; 0.001). Continuous-expression analyses showed concordant results, and the association remained significant in an additional LUAD model incorporating EGFR mutation status (HR = 0.611, 95% CI = 0.391\u20130.956, p = 0.031). High ADGRD1 expression was also associated with favorable recurrence-free survival (RFS) in LUAD. In contrast, high ADGRD1 expression was associated with adverse OS in LUSC in both univariate (HR = 1.444, 95% CI = 1.099\u20131.898, p = 0.008) and clinically adjusted analyses (HR = 1.501, 95% CI = 1.137\u20131.982, p = 0.004), whereas RFS was not significantly different. After false-discovery-rate correction, ADGRD1 correlated positively with TP53 expression in LUAD and inversely with CDKN2A, SOX2, and PIK3CA in LUSC. Independent GEO validation supported the favorable LUAD association (pooled HR = 0.675, 95% CI = 0.538\u20130.847, p &lt; 0.001), whereas the adverse LUSC association was not independently reproduced (pooled HR = 0.909, 95% CI = 0.686\u20131.204, p = 0.504). ADGRD1 shows histology-dependent prognostic associations in NSCLC. Its favorable association with survival in LUAD was robust across dichotomized and continuous analyses, multivariable adjustment, EGFR-mutation sensitivity analysis, and independent GEO cohorts. In contrast, the adverse association observed in TCGA-LUSC was not reproduced externally. These findings support further evaluation of ADGRD1 as a subtype-specific prognostic marker, particularly in LUAD.<\/jats:p>","DOI":"10.3390\/cimb48090927","type":"journal-article","created":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T14:11:22Z","timestamp":1789049482000},"page":"927","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Subtype-Specific Prognostic and Molecular Significance of ADGRD1 in Lung Adenocarcinoma and Lung Squamous Cell Carcinoma"],"prefix":"10.3390","volume":"48","author":[{"given":"Su-Min","family":"Ryu","sequence":"first","affiliation":[{"name":"Medical Course, School of Medicine, Keimyung University, Daegu 42601, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"conceptualization","vocabulary":"credit"},{"role":"validation","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"},{"role":"writing-original-draft","vocabulary":"credit"}]},{"given":"Guen-Hye","family":"Kim","sequence":"additional","affiliation":[{"name":"Medical Course, School of Medicine, Keimyung University, Daegu 42601, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"formal-analysis","vocabulary":"credit"},{"role":"writing-original-draft","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"},{"role":"resources","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-6124-6740","authenticated-orcid":false,"given":"Yunah","family":"Nam","sequence":"additional","affiliation":[{"name":"Medical Course, School of Medicine, Keimyung University, Daegu 42601, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"investigation","vocabulary":"credit"},{"role":"software","vocabulary":"credit"},{"role":"resources","vocabulary":"credit"},{"role":"writing-original-draft","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-9437-5749","authenticated-orcid":false,"given":"Jun-Chae","family":"Lee","sequence":"additional","affiliation":[{"name":"Medical Course, School of Medicine, Keimyung University, Daegu 42601, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"investigation","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"},{"role":"data-curation","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5562-0720","authenticated-orcid":false,"given":"Jae-Ho","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Anatomy, School of Medicine, Keimyung University, Daegu 42601, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"conceptualization","vocabulary":"credit"},{"role":"project-administration","vocabulary":"credit"},{"role":"writing-original-draft","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3272-7859","authenticated-orcid":false,"given":"Hyowon","family":"Hong","sequence":"additional","affiliation":[{"name":"Department of Anatomy, School of Medicine, Keimyung University, Daegu 42601, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"conceptualization","vocabulary":"credit"},{"role":"writing-original-draft","vocabulary":"credit"},{"role":"project-administration","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"},{"role":"funding-acquisition","vocabulary":"credit"}]}],"member":"1968","published-online":{"date-parts":[[2026,9,10]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"446","DOI":"10.1038\/nature25183","article-title":"The biology and management of non-small cell lung cancer","volume":"553","author":"Herbst","year":"2018","journal-title":"Nature"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"535","DOI":"10.1016\/S0140-6736(21)00312-3","article-title":"Lung cancer","volume":"398","author":"Thai","year":"2021","journal-title":"Lancet"},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"The Cancer Genome Atlas Research Network (2014). 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