Unique Transcriptomic Profile of Collecting Duct Carcinomas Relative to Upper Tract Urothelial Carcinomas and other Kidney Carcinomas

Abstract

Collecting duct carcinoma (CDC) is a kidney cancer subtype that is thought to arise from principal cells in distal parts of the collecting ducts. Some studies suggested an overlap of CDC with upper tract urothelial carcinoma (UTUC), making the pathological diagnosis challenging. Herein, we performed for the first time transcriptome sequencing of CDC and compared them to UTUC and renal cell carcinoma subtypes. We discovered that CDC displays a unique transcriptomic signature among kidney cancer subtypes, with a putative cell of origin in the distal convoluted tubules. Hierarchical unsupervised clustering reveals that the CDC signature is closer to that of other RCC subtypes than to UTUC, which is similar to that of bladder carcinoma. CDC is characterized by a metabolic shift, with impairment of oxidoreductase activity, pyruvate metabolism and the tricarboxlyic acid cycle, as well as an immunogenic response consistent with increased tumor infiltrating lymphocytes, particularly within metastatic cases. In addition, pathways differentially altered between CDC and UTUC point to a basal-like phenotype of CDC in contrast to the luminal-like signature of UTUC. We conclude that CDC harbors a pathognomonic transcriptomic signature characterized by immunogenic and a metabolic aberrations, indicating that targeting these processes might provide therapeutic options for patients.

Figure 1. Unsupervised clustering for the most differentially expressed mRNA.

(A) CDC forms a unique cluster compared to muscle-invasive UTUC and normal kidney tissue. (B) CDC compose a unique cluster compared to urothelial tumor (bladder carcinoma and UTUC) and other renal cell carcinoma subtypes, clear-cell RCC (KIRC), papillary RCC (KIRP), translocation RCC (Xp11RCC) and chromophobe RCC (KICH).

Figure 2. Association of CDC expression patterns with those of specific regions of the nephron.

(A) The 8 kidney nephron regions evaluated: Glom, glomerulus; S1 and S3, the proximal tubule; mTAL, medullary thick ascending limb of Henle’s loop; cTAL, cortical thick ascending limb of Henle’s loop; DCT, distal convoluted tubule; CCD, cortical collecting duct; OMCD, outer medullary collecting duct. (B) Heat maps showing inter-sample correlations (red, positive) between mRNA profiles of RCC (columns) and mRNA profiles of nephron anatomical sites (rows). CDC, collecting duct carcinomas; KIRC, TCGA clear-cell RCC cases; KIRP, TCGA papillary RCC cases; Xp11RCC, TCGA translocation RCC cases; KICH, TCGA chromophobe RCC cases.

Figure 3

(A,B) Functional enrichment analysis of the genes differentially expressed between CDC and normal kidney tissue; (A) overexpressed in CDC; (B) underexpressed in CDC. (C) Gene set enrichment analysis showing impairment of pyruvate metabolism and tricarboxylic acid cycle in CDC. (D) Schematic of differential expression patterns of CDC versus clear-cell RCC in metabolism-related pathways, with a focus on gene expression patterns previously associated with Warburg-like effects in kidney cancer. P-values calculated by a t-test.

Figure 4. CDC and the immune system.

(A,B) Gene set enrichment analysis showing enrichment for positive regulation of T cell proliferation pathways, with the corresponding heatmap of differentially expressed genes. (C) Percentage of CD3 tumor infiltrating lymphocytes in all CDC cases and in metastatic versus non-metastatic cases. (D) Percentage of tumor infiltrating CD8 lymphocytes in all CDC cases and in metastatic versus non-metastatic cases. P-values calculated by a t-test.

Figure 5

(A,B) Functional enrichment analysis of the genes differentially expressed between CDC and UTUC; (A) overexpressed in CDC; (B) underexpressed in CDC. (C) Gene set enrichment analysis showing enrichment of luminal-like breast cancer signature versus mesenchymal signature in CDC compared to UTUC. (D) Box-plots of the expression of 10 genes previously reported as differentially expressed between luminal-like and basal-like breast cancer tumors.