Renal cell carcinoma histologic subtypes exhibit distinct transcriptional profiles

Abstract

Molecular profiling of clear cell renal cell carcinoma (ccRCC) tumors of patients in a clinical trial has identified distinct transcriptomic signatures with predictive value, yet data in non-clear cell variants (nccRCC) are lacking. We examined the transcriptional profiles of RCC tumors representing key molecular pathways, from a multi-institutional, real-world patient cohort, including ccRCC and centrally reviewed nccRCC samples. ccRCC had increased angiogenesis signature scores compared with the heterogeneous group of nccRCC tumors, while cell cycle, fatty acid oxidation/AMPK signaling, and fatty acid synthesis/pentose phosphate signature scores were increased in one or more nccRCC subtypes. Among both ccRCC and nccRCC tumors, T effector scores statistically correlated with increased immune cell infiltration and were more commonly associated with immunotherapy-related markers (PD-L1+/TMBhi/MSIhi). In conclusion, this study provides evidence of differential gene transcriptional profiles among ccRCC versus nccRCC tumors, providing insights for optimizing personalized and histology-specific therapeutic strategies for patients with advanced RCC.

Keywords: Cancer; Genetics; Molecular genetics; Oncology; Urology.

Figure 1. Consort diagram of study inclusion process.

Figure 2. RCC subtypes exhibit distinct gene expression profiles.

(A) Differential expression of 10 gene sets representing key molecular pathways by RCC subtype. (B) Radial plots of the median gene signature expression level by RCC subtype. Mann-Whitney U test, *P < 0.05, **P < 0.01, ***P < 0.001 when compared with ccRCC.

Figure 3. Genomic alterations associated with gene signatures across RCC histologies.

Oncoprint of the most commonly altered genes, with heatmap indicating the difference in gene signature score differences between biomarker⁺ (i.e., mutated) and biomarker^– tumors in (A) clear cell, (B) chromophobe, (C) collecting duct, (D) papillary, and (E) mixed tumors. Note: genes with less than 2 altered samples were excluded. *P < 0.05, Mann-Whitney U test.

Figure 4. Association of gene scores with unique tumor microenvironments.

(A) Heatmap of immuno-oncology–related (IO-related) biomarkers, relative abundance of immune and stromal cell population estimated from RNA expression, and expression of key immune checkpoint genes across all RCC samples, with adjacent heatmap indicating the Spearman’s correlation strength with gene scores. (B) Radial plot of the median relative abundance of cell types by RCC subtype. (C) Prevalence of IO-related biomarkers by RCC subtype. *P < 0.05, **P < 0.01 when compared with ccRCC, χ² or Fisher’s exact test, where appropriate.

Figure 5. Sarcomatoid/rhabdoid features are associated with distinct expression profiles.

Radial plot of the median gene signature expression level by subgroups.