Molecular Subtypes of Clear Cell Renal Cell Carcinoma Are Associated with Sunitinib Response in the Metastatic Setting

被引：266

作者：

Beuselinck, Benoit ^{[1
,2
,3
,5
]}

Job, Sylvie ^{[6
]}

Becht, Etienne ^{[2
,4
]}

Karadimou, Alexandra ^{[1
,2
,3
]}

Verkarre, Virginie ^{[2
,7
]}

Couchy, Gabrielle ^{[1
,2
,3
]}

Giraldo, Nicolas ^{[2
,4
]}

Rioux-Leclercq, Nathalie ^{[8
]}

Molinie, Vincent ^{[9
]}

Sibony, Mathilde ^{[2
,10
]}

Elaidi, Reza ^{[5
]}

Teghom, Corinne ^{[5
]}

Patard, Jean-Jacques ^{[11
]}

Mejean, Arnaud ^{[2
,5
]}

Fridman, Wolf Herman ^{[2
,3
,4
]}

Sautes-Fridman, Catherine ^{[2
,3
,4
]}

de Reynies, Aurelien ^{[6
]}

Oudard, Stephane ^{[2
,5
]}

Zucman-Rossi, Jessica ^{[1
,2
,3
,5
]}

机构：

[1] INSERM, UMR 1162, Genom Fonct Tumeurs Solides, F-75010 Paris, France

[2] Univ Paris 05, Sorbonne Paris Cite, Fac Med, Paris, France

[3] Labex Immuno oncol, Paris, France

[4] Ctr Rech Cordeliers, UMR S1138, Paris, France

[5] Hop Europeen Georges Pompidou, AP HP, Dept Oncol, Paris, France

[6] Ligue Natl Canc, Programme Cartes Ident Tumeurs, Paris, France

[7] Hop Necker Enfants Malad, AP HP, Dept Pathol, Paris, France

[8] CHU Rennes, Dept Pathol, Rennes, France

[9] Clin St Joseph, Dept Pathol, Paris, France

[10] Hop Cochin, AP HP, Dept Pathol, F-75674 Paris, France

[11] Hop Bicetre, Dept Urol, Le Kremlin Bicetre, France

来源：

CLINICAL CANCER RESEARCH | 2015年 / 21卷 / 06期

关键词：

C-REACTIVE PROTEIN; INTERFERON-ALPHA; TARGETED THERAPY; POOR SURVIVAL; CANCER; EXPRESSION; DYNAMICS; DEFINES; GAP;

D O I：

10.1158/1078-0432.CCR-14-1128

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 [肿瘤学];

摘要：

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. (C)2015 AACR.

引用

页码：1329 / 1339

页数：11

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