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

Elif Sertesen Çamöz; Cengiz Karaçin

doi:10.38053/acmj.1946804

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

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.

Keywords

Supporting Institution

None

Ethical Statement

Ethics Approval Statement This study did not require institutional ethics committee approval as it analyzed exclusively publicly available, de-identified genomic and clinical data from the cBioPortal for Cancer Genomics platform (https://www.cbioportal.org). Per the policy of Dr. Abdurrahman Yurtaslan Ankara Oncology Training and Research Hospital and consistent with international standards (ICMJE recommendations and the Declaration of Helsinki), secondary analyses of publicly available de-identified data do not constitute research on identifiable human subjects and do not require additional institutional review board approval or patient informed consent. The original primary data collection was performed under institutional ethics committee approval at the source institutions, as detailed in the respective source publications: (i) The Cancer Genome Atlas Kidney Renal Papillary Cell Carcinoma cohort (study ID: kirp_tcga_pan_can_atlas_2018); and (ii) the MSK-IMPACT clinical sequencing cohort (study ID: msk_impact_2017; Zehir et al., Nat Med 2017). Original informed consent was obtained from all participants by the primary investigators of each source cohort. Informed Consent Not applicable. This study analyzed only publicly available de-identified data; original informed consent was obtained by the primary investigators of each source cohort. Data Availability All genomic and clinical data analyzed in this study are publicly available through the cBioPortal for Cancer Genomics (https://www.cbioportal.org) under study identifiers "kirp_tcga_pan_can_atlas_2018" (TCGA-KIRP) and "msk_impact_2017" (MSK-IMPACT, filtered for papillary renal cell carcinoma). Analysis scripts are available from the corresponding author upon reasonable request. Compliance with Ethical Standards This study was conducted in accordance with the Declaration of Helsinki and applicable Turkish national regulations governing research with publicly available de-identified data. The authors declare no conflicts of interest relevant to this work. No external funding was received for this study.

Thanks

We thank the investigators of TCGA-KIRP and MSK-IMPACT for making these data publicly available, and the cBioPortal team for maintaining the platform that enabled this analysis.

References

Chawla NS, Sayegh N, Prajapati S, Chan E, Pal SK, Chehrazi-Raffle A. An update on the treatment of papillary renal cell carcinoma. Cancers (Basel). 2023;15(3):565. doi:10.3390/cancers15030565
Pal SK, Tangen C, Thompson IM Jr, et al. A comparison of sunitinib with cabozantinib, crizotinib, and savolitinib for treatment of advanced papillary renal cell carcinoma: a randomised, open-label, phase 2 trial. Lancet. 2021;397(10275):695-703. doi:10.1016/S0140-6736(21)00152-5
Moch H, Amin MB, Berney DM, et al. The 2022 World Health Organization classification of tumours of the urinary system and male genital organs-part A: renal, penile, and testicular tumours. Eur Urol. 2022;82(5):458-468. doi:10.1016/j.eururo.2022.06.016
Lobo J, Ohashi R, Amin MB, et al. WHO 2022 landscape of papillary and chromophobe renal cell carcinoma. Histopathology. 2022;81(4):426-438. doi:10.1111/his.14700
Trpkov K, Hes O, Williamson SR, et al. New developments in existing WHO entities and evolving molecular concepts: the Genitourinary Pathology Society (GUPS) update on renal neoplasia. Mod Pathol. 2021; 34(7):1392-1424. doi:10.1038/s41379-021-00779-w
Shuch B, Amin A, Armstrong AJ, et al. Understanding pathologic variants of renal cell carcinoma: distilling therapeutic opportunities from biologic complexity. Eur Urol. 2015;67(1):85-97. doi:10.1016/j.eururo.2014.04.029
Carlo MI, Mukherjee S, Mandelker D, et al. Prevalence of germline mutations in cancer susceptibility genes in patients with advanced renal cell carcinoma. JAMA Oncol. 2018;4(9):1228-1235. doi:10.1001/jamaoncol.2018.1986
Choueiri TK, Bauer TM, Papadopoulos KP, et al. Inhibition of hypoxia-inducible factor-2α in renal cell carcinoma with belzutifan: a phase 1 trial and biomarker analysis. Nat Med. 2021;27(5):802-805. doi:10.1038/s41591-021-01324-7

Gleeson JP, Nikolovski I, Dinatale R, et al. Comprehensive molecular characterization and response to therapy in fumarate hydratase-deficient renal cell carcinoma. Clin Cancer Res. 2021;27(10):2910-2919. doi:10.1158/1078-0432.CCR-20-4367
Attalla K, DiNatale RG, Rappold PM, et al. Prevalence and landscape of actionable genomic alterations in renal cell carcinoma. Clin Cancer Res. 2021;27(20):5595-5606. doi:10.1158/1078-0432.CCR-20-4058
Cancer Genome Atlas Research Network, Linehan WM, Spellman PT, et al. Comprehensive molecular characterization of papillary renal-cell carcinoma. N Engl J Med. 2016;374(2):135-145. doi:10.1056/NEJMoa1505917
Ricketts CJ, De Cubas AA, Fan H, et al. The Cancer Genome Atlas comprehensive molecular characterization of renal cell carcinoma. Cell Rep. 2018;23(1):313-326.e5. doi:10.1016/j.celrep.2018.03.075
Kovac M, Navas C, Horswell S, et al. Recurrent chromosomal gains and heterogeneous driver mutations characterise papillary renal cancer evolution. Nat Commun. 2015;6:6336. doi:10.1038/ncomms7336
Murugan P, Jia L, Dinatale RG, et al. Papillary renal cell carcinoma: a single institutional study of 199 cases addressing classification, clinicopathologic and molecular features, and treatment outcome. Mod Pathol. 2022;35(6):825-835. doi:10.1038/s41379-021-00990-9
Sanchez-Vega F, Mina M, Armenia J, et al. Oncogenic signaling pathways in The Cancer Genome Atlas. Cell. 2018;173(2):321-337.e10. doi:10.1016/j.cell.2018.03.035
Zehir A, Benayed R, Shah RH, et al. Mutational landscape of metastatic cancer revealed from prospective clinical sequencing of 10,000 patients. Nat Med. 2017;23(6):703-713. doi:10.1038/nm.4333
Cerami E, Gao J, Dogrusoz U, et al. The cBio cancer genomics portal: an open platform for exploring multidimensional cancer genomics data. Cancer Discov. 2012;2(5):401-404. doi:10.1158/2159-8290.CD-12-0095
Gao J, Aksoy BA, Dogrusoz U, et al. Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal. Sci Signal. 2013;6(269):pl1. doi:10.1126/scisignal.2004088
Hakimi AA, Tickoo SK, Jacobsen A, et al. TCEB1-mutated renal cell carcinoma: a distinct genomic and morphological subtype. Mod Pathol. 2015;28(6):845-853. doi:10.1038/modpathol.2015.6
Calderaro J, Masliah-Planchon J, Richer W, et al. Balanced translocations disrupting SMARCB1 are hallmark recurrent genetic alterations in renal medullary carcinomas. Eur Urol. 2016;69(6):1055-1061. doi:10.1016/j.eururo.2015.09.027

Details

Primary Language

English

Subjects

Clinical Oncology

Journal Section

Research Article

Authors

Elif Sertesen Çamöz ^*
0000-0002-1991-6620
Türkiye

Cengiz Karaçin
0000-0002-7310-9328
Türkiye

Publication Date

September 11, 2026

Submission Date

May 7, 2026

Acceptance Date

August 3, 2026

Published in Issue

Year 2026 Volume: 8 Number: 5

DOI

https://doi.org/10.38053/acmj.1946804

IZ

https://izlik.org/JA44GZ46NF

Cite

RIS / Bibtex

APA

Sertesen Çamöz, E., & Karaçin, C. (2026). 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. Anatolian Current Medical Journal, 8(5), 986-993. https://doi.org/10.38053/acmj.1946804

AMA

1.Sertesen Çamöz E, Karaçin C. 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. Anatolian Curr Med J / ACMJ / acmj. 2026;8(5):986-993. doi:10.38053/acmj.1946804

Chicago

Sertesen Çamöz, Elif, and Cengiz Karaçin. 2026. “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”. Anatolian Current Medical Journal 8 (5): 986-93. https://doi.org/10.38053/acmj.1946804.

EndNote

Sertesen Çamöz E, Karaçin C (September 1, 2026) 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. Anatolian Current Medical Journal 8 5 986–993.

IEEE

[1]E. Sertesen Çamöz and C. Karaçin, “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”, Anatolian Curr Med J / ACMJ / acmj, vol. 8, no. 5, pp. 986–993, Sept. 2026, doi: 10.38053/acmj.1946804.

ISNAD

Sertesen Çamöz, Elif - Karaçin, Cengiz. “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”. Anatolian Current Medical Journal 8/5 (September 1, 2026): 986-993. https://doi.org/10.38053/acmj.1946804.

JAMA

1.Sertesen Çamöz E, Karaçin C. 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. Anatolian Curr Med J / ACMJ / acmj. 2026;8:986–993.

MLA

Sertesen Çamöz, Elif, and Cengiz Karaçin. “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”. Anatolian Current Medical Journal, vol. 8, no. 5, Sept. 2026, pp. 986-93, doi:10.38053/acmj.1946804.

Vancouver

1.Elif Sertesen Çamöz, Cengiz Karaçin. 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. Anatolian Curr Med J / ACMJ / acmj. 2026 Sep. 1;8(5):986-93. doi:10.38053/acmj.1946804