Pathway-integrated genomic analysis of papillary renal cell carcinoma in the WHO 2022 era: cell cycle pathway alterations as an independent adverse prognostic marker-a dual-cohort study
Year: 2026
Type: article
Abstract: Aims: The 2022 WHO Classification of Renal Tumors introduced molecularly defined entities within papillary renal cell carcinoma (pRCC), removing the historical type 1/type 2 distinction. The independent prognostic significance of these entities and pathway-level alterations in this revised framework remains incompletely characterized. We aimed to (i) characterize the genomic landscape of pRCC according to the 2022 WHO classification using a dual-cohort approach, (ii) evaluate the independent prognostic significance of molecularly defined entities, and (iii) assess pathway-level genomic alterations as candidate prognostic biomarkers.Methods: We analyzed 370 pRCC patients from two publicly available cohorts (TCGA-KIRP, n=283; MSK-IMPACT, n=87) accessed through cBioPortal. A 28-gene panel was used to classify tumors into WHO 2022 molecularly defined entities (FHdeficient, TFE3/TFEB-rearranged, ALK-rearranged, SDH-deficient, ELOC-mutated, SMARCB1-deficient) and to define pathway-level alterations: cell cycle (TP53/RB1/CDKN2A), chromatin remodeling (SETD2/BAP1/PBRM1/KMT2C/KDM6A/ARID1A), DNA damage repair, and NRF2 axis. Survival analysis used Kaplan-Meier estimation and multivariable Cox proportional hazards regression, stratified by sample type (primary/metastasis) and cohort.Results: Molecularly defined entities accounted for 11.4% (42/370) of cases, with FH-deficient (n=15), SMARCB1-deficient (n=9), and TFE3-rearranged (n=8) being most frequent. Molecularly defined status was not independently associated with overall survival in the combined cohort (adjusted HR 0.99, 95% CI 0.36-2.67, p=0.978). Conversely, cell cycle pathway alterations (8.9% prevalence) were associated with markedly worse survival (median OS 21 vs not reached, log-rank p
Authors: Elif Sertesen Çamöz, Cengiz Karaçin
Institution: Ankara Eğitim ve Araştırma Hastanesi
Language: English
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
OpenAlex ID: W7213636125