ASCO 2017: Integrative analysis of sarcomatoid clear-cell renal cell carcinomas reveals an immune subgroup

Chicago, IL ( Integrative analysis of clear-cell renal cell carcinomas (ccRCC) has revealed that there are four transcriptomic subgroups associated with distinct patients outcomes. Integrative analysis of sarcomatoid ccRCC, which represent the most aggressive form of ccRCC, remains unknown. 

Dr. Malouf presented a study where integrative analysis of sarcomatoid ccRCC was performed for (n = 28 patients) and Fuhrman grade IV ccRCC (n = 9) cases using whole-exome sequencing (n = 37), RNA-sequencing (n = 32), and DNA methylation profiling by Infinium 450K arrays (n = 31). Additionally, correlation with clinico-pathlogical tumor features and patients’ outcomes were undertaken.  Fresh frozen primary ccRCC and matched normal tissues were included from patients who underwent nephrectomy. 

The most frequent somatic mutations in sarcomatoid ccRCC were VHL (74%), PBRM1 (48%), SETD2 (18%), BAP1 (11%), and TP53 (11%). The mutational load was significantly inferior to the TCGA dataset (p=0.0102). Hierarchical unsupervised clustering of gene expression revealed two transcriptomic subgroups C1 and C2 which do not differ in term of clinical features, presence of sarcomatoid dedifferentiation and patient’s outcomes. Furthermore, these clusters do not differ in their genomic features (VHL, PBRM1 and SETD2 mutations) or their mutational loads. Strikingly, C1 cluster was highly enriched for genes related to T cell receptor signaling pathway (p = 2.6x10-6) and adaptive immunity (p = 8.5x10-5); in addition, the C1 « immune » subgroup was characterized by up-regulation of genes related to cell cycle. Conversely, C2 cluster revealed down-regulation of metabolic pathways (p = 7. 5x10-5). At the epigenetic level, methylome clustering revealed two distinct epi-clusters, epi-C1 (n = 10) and epi-C2 (n = 21); patients with tumors belonging to C2 epi-cluster displayed 9p loss and harbored inferior progression-free survival as compared to those in C1 epi-cluster (11 months versus NR ; P = 0.02). Importantly, this was independent of clinico-pathological tumor features and transcriptomic classification. 

In conclusion, this study suggests that genetic and epigenetic landscapes of sarcomatoid ccRCC might not differ from grade IV ccRCC. In addition, the authors discovered an immune sarcomatoid ccRCC cluster. This new discovery provides a rationale for future use of immune checkpoint inhibitors in sarcomatoid ccRCC.

Presented By: Gabriel G. Malouf, Pitié-Salpêtrière Hospital, Paris, France

Written By: Hanan Goldberg, MD, Urologic Oncology Fellow (SUO), University of Toronto, Princess Margaret Cancer Centre
Twitter: @GoldbergHanan

at the 2017 ASCO Annual Meeting - June 2 - 6, 2017 - Chicago, Illinois, USA