Molecular subtypes of clear cell renal cell carcinoma are associated with sunitinib response in the metastatic setting.

Content Provider	Semantic Scholar
Author	Beuselinck, B. Job, Sylvie Becht, Etienne Karadimou, Alexandra Verkarre, Virginie Couchy, Gabrielle Giraldo, Nicolás A. Rioux-Leclercq, Nathalie Molinié, Vincent Sibony, Mathilde Elaidi, Réza Teghom, Corinne Patard, Jean-Jacques Méjean, Arnaud Fridman, Wolf Herman Sautès-Fridman, Catherine Reyniès, Aurélien De Oudard, Stephane Marie Zucman-Rossi, Jessica
Copyright Year	2015
Abstract	PURPOSE Selecting patients with metastatic clear-cell renal cell carcinoma (m-ccRCC) who might benefit from treatment with targeted tyrosine kinase inhibitors (TKI) is a challenge. Our aim was to identify molecular markers associated with outcome in patients with m-ccRCC treated with sunitinib. EXPERIMENTAL DESIGN We performed global transcriptome analyses on 53 primary resected ccRCC tumors from patients who developed metastatic disease and were treated with first-line sunitinib. We also determined chromosome copy-number aberrations, methylation status, and gene mutations in von Hippel-Lindau and PBRM1. Molecular data were analyzed in relation with response rate (RR), progression-free survival (PFS), and overall survival (OS). Validation was performed in 47 additional ccRCC samples treated in first-line metastatic setting with sunitinib. RESULTS Unsupervised transcriptome analysis identified 4 robust ccRCC subtypes (ccrcc1 to 4) related to previous molecular classifications that were associated with different responses to sunitinib treatment. ccrcc1/ccrcc4 tumors had a lower RR (P = 0.005) and a shorter PFS and OS than ccrcc2/ccrcc3 tumors (P = 0.001 and 0.0003, respectively). These subtypes were the only significant covariate in the multivariate Cox model for PFS and OS (P = 0.017 and 0.006, respectively). ccrcc1/ccrcc4 tumors were characterized by a stem-cell polycomb signature and CpG hypermethylation, whereas ccrcc3 tumors, sensitive to sunitinib, did not exhibit cellular response to hypoxia. Moreover, ccrcc4 tumors exhibited sarcomatoid differentiation with a strong inflammatory, Th1-oriented but suppressive immune microenvironment, with high expression of PDCD1 (PD-1) and its ligands. CONCLUSIONS ccRCC molecular subtypes are predictive of sunitinib response in metastatic patients, and could be used for personalized mRCC treatment with TKIs, demethylating or immunomodulatory drugs.
File Format	PDF HTM / HTML
DOI	10.1158/1078-0432.CCR-14-1128
Alternate Webpage(s)	http://clincancerres.aacrjournals.org/content/clincanres/21/6/1329.full.pdf
Alternate Webpage(s)	http://clincancerres.aacrjournals.org/content/clincanres/early/2015/01/10/1078-0432.CCR-14-1128.full.pdf
PubMed reference number	25583177
Alternate Webpage(s)	https://doi.org/10.1158/1078-0432.CCR-14-1128
Journal	Medline
Volume Number	21
Issue Number	6
Journal	Clinical cancer research : an official journal of the American Association for Cancer Research
Language	English
Access Restriction	Open
Content Type	Text
Resource Type	Article