{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,25]],"date-time":"2026-03-25T15:22:58Z","timestamp":1774452178050,"version":"3.50.1"},"reference-count":34,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2026,3,25]],"date-time":"2026-03-25T00:00:00Z","timestamp":1774396800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Capital\u2019s Funds for Health Improvement and Research","award":["2024-2-4078"],"award-info":[{"award-number":["2024-2-4078"]}]},{"name":"Scientific and Technological Achievements Transformation Incubation Guidance Funding Project of Peking University First Hospital\n\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t\t              https:\/\/ror.org\/02z1vqm45","award":["2022CX10"],"award-info":[{"award-number":["2022CX10"]}]},{"name":"Wuxi \u201cTaihu Talents Program\u201d Medical and Health High-level Talents Project"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Diagnostics"],"abstract":"<jats:p>Background\/Objectives: Traditional histopathologic grading of renal cell carcinoma (RCC) is subjective, is poorly reproducible, and fails to predict responses to modern targeted agents or immunotherapies. In the era of precision oncology, molecular pathology offers objective tools for individualized management. We aimed to characterize genomic alterations in clear-cell RCC (ccRCC) with venous tumor thrombus and to develop pathology-driven panels for personalized prognostic stratification, with exploratory assessment of their potential to predict therapeutic response. Methods: Formalin-fixed paraffin-embedded pT1 ccRCC samples with and without thrombus underwent whole-exome sequencing. Distinct somatic mutations and copy number variations were incorporated into multigene panels. External assessment was performed in TCGA and PAWG cohorts, assessing survival outcomes and therapeutic biomarkers including homologous recombination deficiency (HRD), tumor mutational burden (TMB), and microsatellite instability (MSI). Results: Thrombus cases showed unique genomic heterogeneity compared with matched controls. Three multigene panels were constructed. Across external datasets, including a 354-patient TCGA-KIRC ccRCC cohort, the panels provided consistent molecular stratification signals for overall, disease-specific, and progression-free survival, complementing established pathological risk factors. They were significantly associated with established therapy-related genomic biomarkers, including HRD, TMB, and MSI, showing high sensitivity and negative predictive value in identifying patients unlikely to harbor these biomarker-positive profiles. These findings support the panels\u2019 prognostic utility, with exploratory evidence for their potential in therapy response prediction. Conclusions: Small ccRCC with thrombus harbors distinct molecular pathological features. The proposed pathology-driven panels, compatible with FFPE tissue, represent pathology-compatible genomic tools that may support modern precision pathology by improving molecular risk stratification and informing exploratory therapeutic biomarker assessment.<\/jats:p>","DOI":"10.3390\/diagnostics16070989","type":"journal-article","created":{"date-parts":[[2026,3,25]],"date-time":"2026-03-25T13:57:34Z","timestamp":1774447054000},"page":"989","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Pathology-Driven Genomic Panels for Personalized Prognostic Stratification and Exploratory Therapeutic Prediction in Clear-Cell Renal Cell Carcinoma with Tumor Thrombus"],"prefix":"10.3390","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0009-0005-4209-8936","authenticated-orcid":false,"given":"Chenghao","family":"Tan","sequence":"first","affiliation":[{"name":"Department of Urology, Peking University First Hospital, Beijing 100034, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shiming","family":"He","sequence":"additional","affiliation":[{"name":"Department of Urology, Peking University First Hospital, Beijing 100034, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sainan","family":"Zhu","sequence":"additional","affiliation":[{"name":"Department of Biostatistics, Peking University First Hospital, Beijing 100034, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Qun","family":"He","sequence":"additional","affiliation":[{"name":"Department of Urological Pathology, Peking University First Hospital, Beijing 100034, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhisong","family":"He","sequence":"additional","affiliation":[{"name":"Department of Urology, Peking University First Hospital, Beijing 100034, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Liqun","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of Urology, Peking University First Hospital, Beijing 100034, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gengyan","family":"Xiong","sequence":"additional","affiliation":[{"name":"Department of Urology, Peking University First Hospital, Beijing 100034, China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2026,3,25]]},"reference":[{"key":"ref_1","first-page":"10","article-title":"Cancer statistics, 2025","volume":"75","author":"Siegel","year":"2025","journal-title":"CA Cancer J. Clin."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1007\/BF02524349","article-title":"Effect of papillary and chromophobe cell type on disease-free survival after nephrectomy for renal cell carcinoma","volume":"11","author":"Beck","year":"2004","journal-title":"Ann. Surg. Oncol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1496","DOI":"10.1111\/j.1464-410X.2008.08259.x","article-title":"A critical assessment of the prognostic value of clear cell, papillary and chromophobe histological subtypes in renal cell carcinoma: A population-based study","volume":"103","author":"Capitanio","year":"2009","journal-title":"BJU Int."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"391","DOI":"10.1016\/j.juro.2012.04.006","article-title":"Histopathology of surgically treated renal cell carcinoma: Survival differences by subtype and stage","volume":"188","author":"Keegan","year":"2012","journal-title":"J. Urol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"655","DOI":"10.1097\/00000478-198210000-00007","article-title":"Prognostic significance of morphologic parameters in renal cell carcinoma","volume":"6","author":"Fuhrman","year":"1982","journal-title":"Am. J. Surg. Pathol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"625","DOI":"10.1002\/cncr.20812","article-title":"Multicenter determination of optimal interobserver agreement using the Fuhrman grading system for renal cell carcinoma: Assessment of 241 patients with >15-year follow-up","volume":"103","author":"Lang","year":"2005","journal-title":"Cancer"},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Chen, Z., Yang, F., Ge, L., Qiu, M., Liu, Z., Liu, C., Tian, X., Zhang, S., and Ma, L. (2021). Outcomes of renal cell carcinoma with associated venous tumor thrombus: Experience from a large cohort and short time span in a single center. BMC Cancer, 21.","DOI":"10.1186\/s12885-021-08508-x"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"163423","DOI":"10.1155\/2015\/163423","article-title":"Prognostic Outcomes and Risk Factors for Patients with Renal Cell Carcinoma and Venous Tumor Thrombus after Radical Nephrectomy and Thrombectomy: The Prognostic Significance of Venous Tumor Thrombus Level","volume":"2015","author":"Tang","year":"2015","journal-title":"Biomed. Res. Int."},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Sobin, L.H., Gospodarowicz, M.K., Wittekind, C., and International Union Against Cancer (2009). TNM Classification of Malignant Tumours, Wiley-Blackwell.","DOI":"10.1002\/9780471420194.tnmc26.pub2"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"641","DOI":"10.1016\/j.juro.2017.09.087","article-title":"Growth Kinetics of Small Renal Masses on Active Surveillance: Variability and Results from the DISSRM Registry","volume":"199","author":"Uzosike","year":"2018","journal-title":"J. Urol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"400","DOI":"10.1016\/j.cell.2018.02.052","article-title":"An Integrated TCGA Pan-Cancer Clinical Data Resource to Drive High-Quality Survival Outcome Analytics","volume":"173","author":"Liu","year":"2018","journal-title":"Cell"},{"key":"ref_12","unstructured":"The ICGC\/TCGA Pan-Cancer Analysis of Whole Genomes Consortium (2020). Pan-cancer analysis of whole genomes. Nature, 578, 82\u201393."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"894","DOI":"10.1038\/s41467-018-03276-y","article-title":"Whole-exome sequencing reveals the origin and evolution of hepato-cholangiocarcinoma","volume":"9","author":"Wang","year":"2018","journal-title":"Nat. Commun."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1056\/NEJMoa060655","article-title":"Sorafenib in advanced clear-cell renal-cell carcinoma","volume":"356","author":"Escudier","year":"2007","journal-title":"N. Engl. J. Med."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1056\/NEJMoa065044","article-title":"Sunitinib versus interferon alfa in metastatic renal-cell carcinoma","volume":"356","author":"Motzer","year":"2007","journal-title":"N. Engl. J. Med."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"2271","DOI":"10.1056\/NEJMoa066838","article-title":"Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma","volume":"356","author":"Hudes","year":"2007","journal-title":"N. Engl. J. Med."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"401","DOI":"10.1158\/2159-8290.CD-12-0095","article-title":"The cBio cancer genomics portal: An open platform for exploring multidimensional cancer genomics data","volume":"2","author":"Cerami","year":"2012","journal-title":"Cancer Discov."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"pl1","DOI":"10.1126\/scisignal.2004088","article-title":"Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal","volume":"6","author":"Gao","year":"2013","journal-title":"Sci. Signal"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"102","DOI":"10.1016\/j.eururo.2008.11.033","article-title":"External validation of the Mayo Clinic stage, size, grade, and necrosis (SSIGN) score for clear-cell renal cell carcinoma in a single European centre applying routine pathology","volume":"57","author":"Zigeuner","year":"2010","journal-title":"Eur. Urol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"2391","DOI":"10.1056\/NEJMoa1910962","article-title":"Niraparib in Patients with Newly Diagnosed Advanced Ovarian Cancer","volume":"381","author":"Pothuri","year":"2019","journal-title":"N. Engl. J. Med."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1115","DOI":"10.1016\/j.annonc.2020.07.002","article-title":"The FDA approval of pembrolizumab for adult and pediatric patients with tumor mutational burden (TMB) >\/=10: A decision centered on empowering patients and their physicians","volume":"31","author":"Subbiah","year":"2020","journal-title":"Ann. Oncol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"471","DOI":"10.1001\/jamaoncol.2018.5801","article-title":"Analysis of the Prevalence of Microsatellite Instability in Prostate Cancer and Response to Immune Checkpoint Blockade","volume":"5","author":"Abida","year":"2019","journal-title":"JAMA Oncol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"286","DOI":"10.1200\/JCO.18.00283","article-title":"Microsatellite Instability Is Associated With the Presence of Lynch Syndrome Pan-Cancer","volume":"37","author":"Latham","year":"2019","journal-title":"J. Clin. Oncol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"675","DOI":"10.1038\/s41587-020-0546-8","article-title":"Visualizing and interpreting cancer genomics data via the Xena platform","volume":"38","author":"Goldman","year":"2020","journal-title":"Nat. Biotechnol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"739","DOI":"10.1038\/s41467-020-14601-9","article-title":"Integrative genomic study of Chinese clear cell renal cell carcinoma reveals features associated with thrombus","volume":"11","author":"Wang","year":"2020","journal-title":"Nat. Commun."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"7477","DOI":"10.1038\/s41598-018-25544-z","article-title":"Genomic features of renal cell carcinoma with venous tumor thrombus","volume":"8","author":"Warsow","year":"2018","journal-title":"Sci. Rep."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Niu, S., Liu, K., Xu, Y., Peng, C., Yu, Y., Huang, Q., Wu, S., Cui, B., Huang, Y., and Ma, X. (2021). Genomic Landscape of Chinese Clear Cell Renal Cell Carcinoma Patients with Venous Tumor Thrombus Identifies Chromosome 9 and 14 Deletions and Related Immunosuppressive Microenvironment. Front. Oncol., 11.","DOI":"10.3389\/fonc.2021.646338"},{"key":"ref_28","unstructured":"Xiong, G., He, S., He, Z., and Zhou, L. (2022). A Gene Panel for Grading Human Tumors and Its Applications. (ZL 2021 1 0762353.5), Chinese Patent."},{"key":"ref_29","unstructured":"Xiong, G., He, S., He, Z., and Zhou, L. (2025). Gene Combinations for Classification of Human Tumors and Their Use. (JP 7,667,865 B2), Japanese Patent."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"D777","DOI":"10.1093\/nar\/gkw1121","article-title":"COSMIC: Somatic cancer genetics at high-resolution","volume":"45","author":"Forbes","year":"2017","journal-title":"Nucleic Acids Res."},{"key":"ref_31","first-page":"PO.17.00011","article-title":"OncoKB: A Precision Oncology Knowledge Base","volume":"2017","author":"Chakravarty","year":"2017","journal-title":"JCO Precis. Oncol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"696","DOI":"10.1038\/s41568-018-0060-1","article-title":"The COSMIC Cancer Gene Census: Describing genetic dysfunction across all human cancers","volume":"18","author":"Sondka","year":"2018","journal-title":"Nat. Rev. Cancer"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"302","DOI":"10.1038\/nature12981","article-title":"Realizing the promise of cancer predisposition genes","volume":"505","author":"Rahman","year":"2014","journal-title":"Nature"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"355","DOI":"10.1016\/j.cell.2018.03.039","article-title":"Pathogenic germline variants in 10,389 adult cancers","volume":"173","author":"Huang","year":"2018","journal-title":"Cell"}],"container-title":["Diagnostics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2075-4418\/16\/7\/989\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,3,25]],"date-time":"2026-03-25T14:20:11Z","timestamp":1774448411000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2075-4418\/16\/7\/989"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,3,25]]},"references-count":34,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2026,4]]}},"alternative-id":["diagnostics16070989"],"URL":"https:\/\/doi.org\/10.3390\/diagnostics16070989","relation":{},"ISSN":["2075-4418"],"issn-type":[{"value":"2075-4418","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,3,25]]}}}