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Burnichon N.,French Institute of Health and Medical Research | Burnichon N.,University of Paris Pantheon Sorbonne | Vescovo L.,Programme Cartes dIdentitedes Tumeurs | Amar L.,French Institute of Health and Medical Research | And 22 more authors.
Human Molecular Genetics | Year: 2011

Pheochromocytomas and paragangliomas are neuroendocrine tumors that occur in the context of inherited cancer syndromes in ~30% of cases and are linked to germline mutations in the VHL, RET, NF1, SDHA, SDHB, SDHC, SDHD, SDHAF2 and TMEM127 genes. Although genome-wide expression studies have revealed some of the mechanisms likely to be involved in pheochromocytoma/paraganglioma tumorigenesis, the complete molecular distinction of all subtypes of hereditary tumors has not been solved and the genetic events involved in the generation of sporadic tumors are unknown. With these purposes in mind, we investigated 202 pheochromocytomas/paragangliomas, including 75 hereditary tumors, using expression profiling, BAC array comparative genomic hybridization and somatic mutation screening. Gene expression signatures defined the hereditary tumors according to their genotype and notably, led to a complete subseparation between SDHx- and VHL-related tumors. In tumor tissues, the systematic characterization of somatic genetic events associated with germline mutations in tumor suppressor genes revealed loss of heterozygosity (LOH) in a majority of cases, but also detected point mutations and copy-neutral LOH. Finally, guided by transcriptome classifications and LOH profiles, somatic mutations in VHL or RET genes were identified in 14% of sporadic pheochromocytomas/paragangliomas. Overall, we found a germline or somatic genetic alteration in 45.5% (92/202) of the tumors in this large series of pheochromocytomas/paragangliomas. Regarding mutated genes, specific molecular pathways involved in tumorigenesis mechanisms are identified. Altogether, these new findings suggest that somatic mutation analysis is likely to yield important clues for personalizing molecular targeted therapies. © The Author 2011. Published by Oxford University Press. All rights reserved.

Beuselinck B.,French Institute of Health and Medical Research | Beuselinck B.,University of Paris Descartes | Beuselinck B.,University Hospitals Leuven | Jean-Baptiste J.,French Institute of Health and Medical Research | And 20 more authors.
British Journal of Cancer | Year: 2015

Background:Bone metastases (BMs) are associated with poor outcome in metastatic clear-cell renal carcinoma (m-ccRCC) treated with anti-vascular endothelial growth factor tyrosine kinase inhibitors (anti-VEGFR-TKIs). We aimed to investigate whether expression in the primary tumour of genes involved in the development of BM is associated with outcome in m-ccRCC patients treated with anti-VEGFR-TKIs.Methods:Metastatic clear-cell renal cell carcinoma patients with available fresh-frozen tumour and treated with anti-VEGFR-TKIs. Quantitative real-time PCR (qRT-PCR) for receptor activator of NF-kB (RANK), RANK-ligand (RANKL), osteoprotegerin (OPG), the proto-oncogene SRC and DKK1 (Dickkopf WNT signalling pathway inhibitor-1). Time-to-event analysis by Kaplan-Meier estimates and Cox regression.Results:We included 129 m-ccRCC patients treated between 2005 and 2013. An elevated RANK/OPG ratio was associated with shorter median time to metastasis (HR 0.50 (95% CI 0.29-0.87); P=0.014), shorter time to BM (HR 0.54 (95% CI 0.31-0.97); P=0.037), shorter median overall survival (mOS) since initial diagnosis (HR 2.27 (95% CI 1.44-3.60); P=0.0001), shorter median progression-free survival (HR 0.44 (95% CI 0.28-0.71); P=0.001) and mOS (HR 0.31 (95% CI 0.19-0.52); P<0.0001) on first-line anti-VEGFR-TKIs in the metastatic setting. Higher RANK expression was associated with shorter mOS on first-line anti-VEGFR-TKIs (HR 0.46 (95% CI 0.29-0.73); P=0.001).Conclusions:RANK/OPG ratio of expression in primary ccRCC is associated with BM and prognosis in patients treated with anti-VEGFR-TKIs. Prospective validation is warranted. © 2015 Cancer Research UK. All rights reserved.

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