Molecular subtypes and prognosis in RCC

including growing cancer incidence in an aging population, and increasing costs of new anti-cancer drugs. A better understanding of tumor biology and heterogeneity should lead to the development of new predictive biomarkers allowing to tailor therapies in order to increase therapeutic efficacy and more rationally use the health care budget. Since 2005, anti-vascular endothelial growth factor receptor targeted tyrosine kinase inhibitors (anti-VEGFR-TKIs) such as sunitinib and pazopanib have significantly improved the prognosis of metastatic clear-cell renal cell carcinoma (m-ccRCC)-patients. Nevertheless, selecting patients who might benefit from these therapies remains a challenge since no reliable biomarkers of sunitinib sensitivity or primary/secondary resistance have been identified [1]. Recently, through an unsupervised transcriptome analysis, we discovered a molecular classification of ccRCC with four robust subgroups (ccrcc1 to 4) related to previous molecular classifications [2, 3] and associated with outcome on sunitinib [4]. Non-responders (progressive disease as best response) were enriched in ccrcc1 (22%) and ccrcc4 (27%) versus 3% in ccrcc2 and 0% in ccrcc3. In contrast, partial or complete responses were over-represented in ccrcc2 (53%) and ccrcc3 (70%) compared to 41% and 21% in ccrcc1 and ccrcc4, respectively (p=0.005). Accordingly, ccrcc1 and ccrcc4-tumors when compared to ccrcc2 and ccrcc3-tumors showed a poorer median progression-free survival (mPFS) (13, 8 versus 19 and 24 months, respectively; p=0.0003) and median overall survival (mOS) (24, 14 versus 35 and 50 months, respectively; p=0.001). Classification of the tumors belonging to ccrcc1&4 versus ccrcc2&3 subgroups was the most significant covariate in univariate cox analysis with a poorer mPFS (p=0.017) and mOS (p=0.006). We further characterized these four molecular subgroups. Whereas mutations in VHL and PBRM1 were rarely found in ccrcc4-tumors, they were frequent in ccrcc1-and ccrcc2-tumors but without relationship with sunitinib response. ccrcc1/ccrcc4-tumors were characterized by a stem-cell polycomb signature and CpG hypermethylation. ccrcc4-tumors exhibited frequent sarcomatoid differentiation with a strong inflammatory, Th1-oriented but suppressive immune Editorial microenvironment, with high expression of PDCD1 (PD-1) and its ligands PD-L1 and PD-L2. ccrcc4-tumors showed several characteristic copy number aberrations, the most significant being 2p12-, 2p22.3-and 8q21.13-amplifications. Both ccrcc1-and ccrcc4-subtypes over-expressed MYC-targets. The expression and methylation profile of ccrcc3-samples was similar to that of normal kidney tissue concerning metabolic pathways and transporter activities. The ccrcc2-subtype was not characterized by specific pathways; it always showed an intermediate expression signature, comprised between ccrcc3 and (ccrcc1/ccrcc4) related profiles. ccrcc2-tumors showed the highest mutation rate for VHL. In ccrcc2-tumors, the " cellular response to hypoxia " …