{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,15]],"date-time":"2026-09-15T10:02:46Z","timestamp":1789466566572,"version":"build-2803163510"},"reference-count":19,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2026,9,15]],"date-time":"2026-09-15T00:00:00Z","timestamp":1789430400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Background\/Objectives: Retinoic acid receptor \u03b3 (RAR\u03b3), encoded by RARG, is increasingly recognized as a cancer-associated regulator through aberrant expression in multiple solid tumors and recurrent gene rearrangements in acute myeloid leukemia. While the oncogenic relevance of RAR\u03b3 is well established, the potential involvement of its N-terminal activation function-1 (AF1) domain in human cancer remains poorly characterized. Previous biochemical studies demonstrated that phosphorylation of Ser66 and Ser68 in RAR\u03b32, corresponding to Ser77 and Ser79 in canonical RAR\u03b31, is required for ligand-dependent receptor activation, ubiquitination, and proteasome-mediated degradation. Methods: To determine whether this experimentally validated phosphoregulatory region is altered in human cancer, we interrogated the Catalogue of Somatic Mutations in Cancer (COSMIC v104, GRCh38) at single-residue resolution. Mutation data were integrated with clinical and pathological information obtained from the corresponding primary publications and public annotation resources. Results: Rare somatic mutations affecting the AF1 phosphoregulatory region were identified, including the missense variants p.S77L and p.S79L, the nonsense variant p.S79*, and the in-frame insertion p.S77_P78insLQ. These alterations occurred in independent epithelial malignancies, including cervical neuroendocrine carcinoma, head and neck squamous cell carcinoma, lung adenocarcinoma, bladder carcinoma, and gastric neuroendocrine carcinoma. Notably, the truncating p.S79* mutation was detected in five spatially distinct regions of a single EGFR-mutant lung adenocarcinoma, consistent with an early clonal event during tumor evolution. Rare cancer-associated mutations affect a previously characterized AF1 phosphoregulatory module of RAR\u03b3. These findings extend established RAR\u03b3 regulatory biology into the context of human malignancy and broaden the spectrum of reported cancer-associated RARG alterations. While the functional consequences of these rare variants remain unknown, their occurrence within residues known to regulate receptor activation and turnover highlights the AF1 phosphoregulatory region as a candidate for future mechanistic investigation.<\/jats:p>","DOI":"10.3390\/genes17091119","type":"journal-article","created":{"date-parts":[[2026,9,15]],"date-time":"2026-09-15T08:16:48Z","timestamp":1789460208000},"page":"1119","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Rare Cancer-Associated Mutations May Affect the AF1 Phosphoregulatory Domain of RAR\u03b3"],"prefix":"10.3390","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0009-0001-5315-0649","authenticated-orcid":false,"given":"Eliezer","family":"Kopf","sequence":"first","affiliation":[{"name":"Safety Unit, Weizmann Institute of Science, P.O. Box 26, Rehovot 7610001, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,9,15]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Brown, G., and Petrie, K. (2021). The RAR\u03b3 oncogene: An Achilles heel for some cancers. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22073632"},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Brown, G. (2025). The emerging oncogenic role of RAR\u03b3: From stem cell regulation to a potential cancer therapy. Int. J. Mol. Sci., 26.","DOI":"10.3390\/ijms26094357"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"493","DOI":"10.1007\/s12672-026-04706-w","article-title":"The role of RARG in solid tumor progression and therapeutic potential","volume":"17","author":"Guo","year":"2026","journal-title":"Discov. 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