{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,27]],"date-time":"2026-08-27T09:19:54Z","timestamp":1787822394841,"version":"build-2784847793"},"reference-count":26,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2026,8,27]],"date-time":"2026-08-27T00:00:00Z","timestamp":1787788800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Medicina"],"abstract":"<jats:p>Background and Objectives: Non-small cell lung cancer (NSCLC) comprises biologically distinct histologic subtypes, including lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC). We evaluated whether the prognostic association of cyclin-dependent kinase-like 2 (CDKL2) differs by histology. Materials and Methods: TCGA CDKL2 expression was linked to harmonized clinical data. The primary analysis used a pooled multivariable Cox model with continuous standardized CDKL2 expression, histology, and a CDKL2 \u00d7 histology interaction, adjusted for age, sex, pathologic stage, and smoking. Additional analyses assessed model assumptions, tumor purity, tumor-versus-normal expression, KEGG pathways, the tumor microenvironment, and single-cell RNA sequencing. External evaluation used GSE30219. Results: The primary TCGA cohort included 943 patients (471 LUAD, 472 LUSC; 375 deaths). Higher CDKL2 expression was associated with lower mortality in LUAD (HR per 1 pooled SD = 0.721, 95% CI 0.603\u20130.862, p &lt; 0.001) but higher mortality in LUSC (HR = 1.237, 95% CI 1.011\u20131.515, p = 0.039), with a significant interaction (HR = 1.717, p &lt; 0.001) persisting after tumor-purity adjustment. CDKL2-low tumors were enriched for cell-cycle, DNA-replication, proteasome, and DNA-repair programs. Single-cell analyses showed predominant epithelial detection and greater malignant-cell CDKL2 detection in LUAD. In GSE30219, the favorable LUAD association was supported in a median-split-adjusted analysis of 207073_at (HR = 0.473, 95% CI 0.250\u20130.897, p = 0.022), whereas the corresponding continuous estimate was directionally favorable but nonsignificant; 236331_at was nonsignificant in both models; neither probe supported the adverse LUSC association or histology interaction. Conclusions: Higher CDKL2 expression showed a favorable prognostic association in LUAD, with consistent TCGA sensitivity analyses and limited but suggestive independent-cohort support. The adverse LUSC association remains preliminary, and CDKL2 should be regarded as a candidate prognostically associated marker rather than an established clinical biomarker.<\/jats:p>","DOI":"10.3390\/medicina62091638","type":"journal-article","created":{"date-parts":[[2026,8,27]],"date-time":"2026-08-27T08:02:27Z","timestamp":1787817747000},"page":"1638","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Prognostic Significance of CDKL2 in Non-Small Cell Lung Cancer: A Favorable Association in Lung Adenocarcinoma"],"prefix":"10.3390","volume":"62","author":[{"ORCID":"https:\/\/orcid.org\/0009-0007-4034-4835","authenticated-orcid":false,"given":"Minji","family":"Song","sequence":"first","affiliation":[{"name":"Medical Course, School of Medicine, Keimyung University, Daegu 42601, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-6704-2203","authenticated-orcid":false,"given":"Yunha","family":"Lee","sequence":"additional","affiliation":[{"name":"Medical Course, School of Medicine, Keimyung University, Daegu 42601, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"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"}]},{"given":"An-Na","family":"Bae","sequence":"additional","affiliation":[{"name":"Department of Molecular Biology, Pusan National University, Busan 46241, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"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"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,27]]},"reference":[{"key":"ref_1","first-page":"229","article-title":"Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries","volume":"74","author":"Bray","year":"2024","journal-title":"CA Cancer J. 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