MET Is a Potential Target across All Papillary Renal Cell Carcinomas: Result from a Large Molecular Study of pRCC with CGH Array and Matching Gene Expression Array

• Published in: Clinical cancer research Vol. 20; no. 13; pp. 3411 - 3421
• Main Authors: ALBIGES, Laurence, GUEGAN, Justine, ALLORY, Yves, OREAR, Cedric, COUVE, Sophie, GAD, Sophie, PATARD, Jean-Jacques, ESCUDIER, Bernard, LE FORMAL, Audrey, VERKARRE, Virginie, RIOUX-LECLERCQ, Nathalie, SIBONY, Mathilde, BERNHARD, Jean-Christophe, CAMPARO, Philippe, MERABET, Zahira, MOLINIE, Vincent
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 01.07.2014
• Subjects: Adult; Aged; Aged, 80 and over; Antineoplastic agents; Biological and medical sciences; Carcinoma, Papillary - genetics; Carcinoma, Papillary - pathology; Carrier Proteins - genetics; Cluster Analysis; Comparative Genomic Hybridization; Computational Biology; DNA Copy Number Variations; Exons; Female; Gene Expression; Gene Expression Profiling; General aspects; Genetics; Humans; Kidney Neoplasms - genetics; Kidney Neoplasms - pathology; Kidneys; Life Sciences; Male; Medical sciences; Middle Aged; Mutation; Neoplasm Grading; Neoplasm Staging; Nephrology. Urinary tract diseases; Pharmacology. Drug treatments; Protein Binding; Proto-Oncogene Proteins c-met - genetics; Sequence Analysis, DNA; Tumors of the urinary system; Kidney disease; Urinary system disease; Targeting; DNA chip; Malignant tumor; Gene expression; Target; Comparative genomic hybridization; Papillary renal cell carcinoma; C-Onc gene; Inhibitor; Protooncogene; Cancer
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-13-2173

Papillary renal cell carcinomas (pRCC) are the most common nonclear cell RCC subtype. Germline mutations of the MET oncogene at 7q31 have been detected in patients with hereditary type I pRCC and in 13% of sporadic type I pRCC. Recent report of MET inhibition strengthened the role of c-Met inhibition across pRCC. We collected 220 frozen samples of sporadic pRCC through the French RCC Network and quality controlled for percentage of malignant cells >70%. Gene expression was assessed on 98 pRCC using human whole-genome Agilent 8 × 60K arrays. Copy number alterations were analyzed using Agilent Human 2 × 400K and 4× 180K array for type II pRCC and comparative genomic microarray analysis method for type I pRCC. MET gene sequencing was performed on type I pRCC. MET expression level was high across all pRCC. We identified copy number alterations (gain) in 46% of type II pRCC and in 81% of type I pRCC. Correlation between DNA copy number alterations and mRNA expression level was highly significant. Eleven somatic mutations of MET gene were identified amongst 51 type I pRCC (21.6%), including 4 new mutations. We validated LRRK2 cokinase as highly correlated to MET expression. The present report expands the role of MET activation as a potential target across all pRCC subtypes. These data support investigating MET inhibitors in pRCC in correlation with MET activation status.