{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,20]],"date-time":"2026-04-20T05:53:23Z","timestamp":1776664403611,"version":"3.51.2"},"reference-count":30,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,4,20]],"date-time":"2026-04-20T00:00:00Z","timestamp":1776643200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Cell Dev. Biol."],"abstract":"<jats:p>\n                    Clear cell renal cell carcinoma (ccRCC) can transition from indolent, low-grade lesions to high-grade, lethal disease through a layered cascade of genomic, epigenomic, metabolic, and immune remodeling. The initiating event in \u223c90% of ccRCC is loss of chromosome 3p, enabling biallelic inactivation of VHL and frequent co-loss of chromatin regulators PBRM1, BAP1, and SETD2. The order and combination of genetic alterations shape distinct evolutionary trajectories in ccRCC. PBRM1 loss, observed in approximately 55% of cases, is linked to angiogenic, initially low-grade tumors that may later progress to higher-grade disease. In contrast, BAP1 loss (\u223c15%) drives early high-grade, inflammatory, immune-enriched phenotypes associated with aggressive behavior and worse prognosis. Progression is further shaped by structural and copy-number events including, chromothripsis coupling 3p loss with 5q gain, and recurrent 9p and 14q losses and 8q gain further promote cell-cycle dysregulation, genomic instability, and metastatic competence. Functionally, VHL loss stabilizes HIF-2\u03b1, driving VEGF signaling and Carbonic Anhydrase IX (CA9) expression and coupling pseudohypoxia to metabolic reprogramming and redox protection (glutathione\/SLC7A11). Proteogenomic and metabolomic studies further highlight nutrient addiction with GLUT1\/ASCT2 upregulation and a stress-resistant metabolic shield linked to grade and therapy resistance. Single-cell and spatial atlases place these programs in anatomic setting. They show that invasive fronts with high epithelial\u2013mesenchymal transition (EMT) activity co-localize with myeloid and regulatory T-cell niches dominated by IL-1\u03b2, NF-\u03baB, IL-10, STAT3, and TGF-\u03b2, along with exhausted CD8\n                    <jats:sup>+<\/jats:sup>\n                    T cells, thereby promoting immune escape and invasion. Integrating these layers yields mechanism-based biomarkers and therapeutic nodes for risk-adapted precision treatment.\n                  <\/jats:p>","DOI":"10.3389\/fcell.2026.1815377","type":"journal-article","created":{"date-parts":[[2026,4,20]],"date-time":"2026-04-20T05:24:22Z","timestamp":1776662662000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Multi-omics insights into tumor grade progression in clear cell renal cell carcinoma: from molecular mechanisms to precision therapeutics"],"prefix":"10.3389","volume":"14","author":[{"given":"Rajat Subhra","family":"Jena","sequence":"first","affiliation":[{"name":"Computational Oncology Laboratory, Department of Life Sciences, National Institute of Technology Rourkela","place":["Sundargarh, Odisha, India"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Akhilesh","family":"Mishra","sequence":"additional","affiliation":[{"name":"Computational Oncology Laboratory, Department of Life Sciences, National Institute of Technology Rourkela","place":["Sundargarh, Odisha, India"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2026,4,20]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"5852","DOI":"10.1007\/s00261-025-04982-0","article-title":"MRI-based radiomics for differentiating high-grade from low-grade clear cell renal cell carcinoma: a systematic review and meta-analysis","volume":"50","author":"Broomand Lomer","year":"2025","journal-title":"Abdom. 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