Renal cell carcinoma (RCC) is a heterogeneous disease comprising histologically defined subtypes. For therapy selection, precise subtype identification and individualized prognosis are mandatory, but currently limited. Our aim was to refine subtyping and outcome prediction across main subtypes, assuming that a tumor is composed of molecular features present in distinct pathological subtypes.
Individual RCC samples were modeled as linear combination of the main subtypes (clear cell (ccRCC), papillary (pRCC), chromophobe (chRCC)) using computational gene expression deconvolution. The new molecular subtyping was compared with histological classification of RCC using the Cancer Genome Atlas (TCGA) cohort (n = 864; ccRCC: 512; pRCC: 287; chRCC: 65) as well as 92 independent histopathologically well-characterized RCC. Predicted continuous subtypes were correlated to cancer-specific survival (CSS) in the TCGA cohort and validated in 242 independent RCC. Association with treatment-related progression-free survival (PFS) was studied in the JAVELIN Renal 101 (n = 726) and IMmotion151 trials (n = 823). CSS and PFS were analyzed using the Kaplan-Meier and Cox regression analysis.
One hundred seventy-four signature genes enabled reference-free molecular classification of individual RCC. We unambiguously assign tumors to either ccRCC, pRCC, or chRCC and uncover molecularly heterogeneous tumors (e.g., with ccRCC and pRCC features), which are at risk of worse outcome. Assigned proportions of molecular subtype-features significantly correlated with CSS (ccRCC (P = 4.1E - 10), pRCC (P = 6.5E - 10), chRCC (P = 8.6E - 06)) in TCGA. Translation into a numerical RCC-R(isk) score enabled prognosis in TCGA (P = 9.5E - 11). Survival modeling based on the RCC-R score compared to pathological categories was significantly improved (P = 3.6E - 11). The RCC-R score was validated in univariate (P = 3.2E - 05; HR = 3.02, 95% CI: 1.8-5.08) and multivariate analyses including clinicopathological factors (P = 0.018; HR = 2.14, 95% CI: 1.14-4.04). Heterogeneous PD-L1-positive RCC determined by molecular subtyping showed increased PFS with checkpoint inhibition versus sunitinib in the JAVELIN Renal 101 (P = 3.3E - 04; HR = 0.52, 95% CI: 0.36 - 0.75) and IMmotion151 trials (P = 0.047; HR = 0.69, 95% CI: 0.48 - 1). The prediction of PFS significantly benefits from classification into heterogeneous and unambiguous subtypes in both cohorts (P = 0.013 and P = 0.032).
Switching from categorical to continuous subtype classification across most frequent RCC subtypes enables outcome prediction and fosters personalized treatment strategies.
Genome medicine. 2022 Sep 15*** epublish ***
Florian A Büttner, Stefan Winter, Viktoria Stühler, Steffen Rausch, Jörg Hennenlotter, Susanne Füssel, Stefan Zastrow, Matthias Meinhardt, Marieta Toma, Carmen Jerónimo, Rui Henrique, Vera Miranda-Gonçalves, Nils Kröger, Silvia Ribback, Arndt Hartmann, Abbas Agaimy, Christine Stöhr, Iris Polifka, Falko Fend, Marcus Scharpf, Eva Comperat, Gabriel Wasinger, Holger Moch, Arnulf Stenzl, Marco Gerlinger, Jens Bedke, Matthias Schwab, Elke Schaeffeler
Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Auerbachstrasse 112, 70376, Stuttgart, Germany., Department of Urology, University Hospital Tuebingen, Tuebingen, Germany., Department of Urology, University Hospital and Faculty of Medicine, Technische Universität Dresden, Dresden, Germany., Institute of Pathology, University Hospital and Faculty of Medicine, Technische Universität Dresden, Dresden, Germany., Cancer Biology & Epigenetics Group-Research Center, Portuguese Oncology Institute of Porto (CI-IPOP, IPO Porto), Porto, Portugal., Department of Urology, University of Greifswald, Greifswald, Germany., Institute of Pathology, University Medicine Greifswald, Greifswald, Germany., Institute of Pathology, Friedrich-Alexander-University Erlangen-Nürnberg (FAU), University Hospital, Erlangen, Germany., Institute of Pathology and Neuropathology, University Hospital Tuebingen, Tuebingen, Germany., Department of Pathology, Medical University of Vienna, Vienna, Austria., Department of Pathology and Molecular Pathology, University Hospital Zuerich, University of Zuerich, Zuerich, Switzerland., Translational cancer immunotherapy and genomics lab, Barts Cancer Institute, Queen Mary University of London, London, UK., Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Auerbachstrasse 112, 70376, Stuttgart, Germany. .