AI Summary & Key Takeaways
AI InsightMolecularly 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).
📌 3 Key Takeaways
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<0.001) and remained independently prognostic after adjustment for age, gender, and cohort/sample type stratification (adjusted HR 4.98, 95% CI 2.17-11.41, p<0.001). The cell cycle pathway effect was consistent across early-stage (log-rank p=0.018) and advanced-stage (p=0.037) subgroups in TCGA-KIRP. Cell cycle alterations co-occurred significantly with chromatin remodeling alterations (OR 2.51, p=0.022). Advanced tumor stage remained the dominant prognostic factor (HR 6.58, 95% CI 3.49-12.40, p<0.001). Conclusion: In this dual-cohort analysis spanning the WHO 2022 classification era, cell cycle pathway alterations emerged as an independent adverse prognostic marker in pRCC, while molecularly defined entity status did not independently predict survival. These findings suggest that aggregated molecularly defined status did not provide independent prognostic information in the present dataset, while supporting pathway-level genomic assessment as a complement to anatomic staging in pRCC risk stratification; entity-specific prognostic relevance cannot be excluded.