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

Abstract

Purpose: 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.Experimental Design: 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 Â 60K arrays. Copy number alterations were analyzed using Agilent Human 2 Â 400K and 4Â 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.Results: 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 MET Inhibitor AZD6094 (Savolitinib, HMPL-504) Induces Regression in Papillary Renal Cell Carcinoma Patient–Derived Xenograft Models

“…In addition, one displays increased HGF expression levels suggesting presence of a putative autocrine/paracrine activation loop. Together, these data suggest that these models may be representative of a subset of PRCC patients and may therefore represent models that can better predict clinical efficacy (9).…”

“…Of note, although no samples were identified as amplified (defined as over 5 copies), MET copy number gain was observed in both of the distinct pathologic subtypes of PRCC (81% of type I and 46% of type II PRCC; ref. 9). Together, these data suggest an oncogenic role for MET in PRCC.…”

MET exon 14 juxtamembrane splicing mutations: clinical and therapeutical perspectives for cancer therapy

“…The majority of missense mutations were located in the tyrosine kinase domain (exons 16-21) of the MET gene, both in patients affected by hereditary papillary RCC and in a small subgroup of patients with sporadic papillary RCC (67,68). Moreover, the duplication of chromosome 7 represents an alternative mechanism enhancing the MET signaling in most of sporadic papillary RCC cases (69).…”

Cabozantinib inhibits tumor growth and metastasis of a patient-derived xenograft model of papillary renal cell carcinoma with MET mutation

“…4 Activating mutations in the kinase domain of MET are found in the majority of hereditary pRCC cases, as well as in 5-13% of sporadic pRCC cases. 5,6 Elevated MET gene expression was observed in large molecular studies of pRCC and correlated with adverse clinical features, [7][8][9] indicating a pivotal role of MET in pRCC.…”