CSF1R copy number changes, point mutations, and RNA and protein overexpression in renal cell carcinomas

Abstract

Renal cell carcinomas comprise a heterogeneous group of tumors. Of these, 80% are clear cell renal cell carcinomas, which are characterized by loss of 3p, often with concomitant gain of 5q22qter. Although VHL is considered the main target gene of the 3p deletions, none has been identified as the relevant target gene for the 5q gain. We have studied 75 consecutive kidney tumors and paired normal kidney samples to evaluate at the genomic and expression levels the tyrosine kinase genes CSF1R and PDGFRB as potential targets in this region. Our findings show that RNA expression of CSF1R, but not of PDGFRB, was significantly higher in clear cell renal cell carcinomas than in normal tissue samples, something that was corroborated at the protein level by immunohistochemistry. The CSF1R staining pattern in clear cell renal cell carcinomas was clearly different from that observed in other renal cell carcinomas, suggesting its potential usefulness in differential diagnosis. FISH analysis demonstrated whole chromosomal gain and relative CSF1R/PDGFRB copy number gain in clear cell renal cell carcinomas, which might contribute to CSF1R overexpression. Finally, one polymorphism and two novel mutations were identified in CSF1R in clear cell renal cell carcinoma patients. Our data allow us to conclude that CSF1R plays a relevant role in clear cell renal cell carcinoma carcinogenesis and raise the possibility that CSF1R may represent a future valuable therapeutic target in these patients. Keywords: renal cell carcinoma; CSF1R oncogene; mutation; overexpression Renal cell carcinomas comprise a heterogeneous group of tumors that represent about 3% of all malignancies in adults in the Western countries. 1 Clear cell renal cell carcinomas, which represent about 80% of all kidney tumors, are characterized by the loss of the short arm of chromosome 3 (3p), often with a concomitant gain of 5q22qter as the result of an unbalanced 3p;5q translocation. 2 Several genes have been presented as the targets of the 3p deletions seen in this tumor type, with emphasis for VHL (3p25Bp26). In fact, germline mutations of VHL underlie the von Hippel-Lindau syndrome (which includes clear cell renal cell carcinoma as one of its features), whereas somatic inactivation of this gene has been demonstrated in the great majority of sporadic clear cell renal cell carcinomas. 3,4 On the other hand, no target genes have been identified for the 5q22qter gain, the second most common copy number change in clear cell renal cell carcinomas. 2,5 The colony-stimulating factor-1 receptor (CSF1R) gene located in 5q33 is a potential target for this chromosomal gain in clear cell renal cell carcinomas. CSF1R is a transmembrane tyrosine kinase receptor and the CSF1R/CSF1 receptor/ligand complex has essential physiological functions in monocyte and macrophage differentiation, embryonic implantation, placental development, and lactogenic differentiation of the human breast. 6 Codons 301 and 969 located in CSF1R exons 7 and 22, respectively, have been shown to be mutated in he...

Multilevel Whole-Genome Analysis Reveals Candidate Biomarkers in Clear Cell Renal Cell Carcinoma

“…We also identified a peak gain of 5q32, containing 5 genes including the known oncogenes CSF1R and PDGFRB, which is consistent with a recent study reporting CSF1R/PDGFRB copy number gain and overexpression of CSF1R at the transcriptomic and proteomic levels in ccRCCs (32). Moreover, 2 mutations and 1 polymorphism were previously identified in the CSF1R gene in ccRCCs, further showing this region to be a target of 5q CNAs (32).…”

“…Moreover, 2 mutations and 1 polymorphism were previously identified in the CSF1R gene in ccRCCs, further showing this region to be a target of 5q CNAs (32). The distal region of 5q (5q34-q35.3) showed significant copy number gain as well, consistent with previous studies reporting similar boundaries of 5q distal gain in ccRCCs (8)(9)(10).…”

CSF1Rmosaicism in a family with hereditary diffuse leukoencephalopathy with spheroids

“…While introduction of cells with wild-type CSF1R by HSCT may compensate for partial loss of CSF1R function, the alternative of over-expression of CSF1R beyond normal levels in individual cells, by gene therapy for example, may carry risks. An increase in CSF1R copy number and point mutations leading to constitutive activation of the CSF1R receptor has been associated with tumour development, including haematological malignancies and renal cell carcinomas (Ridge et al, 1990;Soares et al, 2009).…”

Elevated PDGFRB gene copy number gain is prognostic for improved survival outcomes in resected malignant pleural mesothelioma

“…PDGFRB gene copy number was evaluated by three ways: a) gene amplification, defined as presence of loose or tight gene cluster or PDGFRB gene to centromeric probe 5 radio ≥2; b) copy number gain (CNG) defined at 2 levels: ≥ 4 copies in > 10% cells and in > 40% of cells as previously published. 19,20 …”