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Identification of anaplastic lymphoma kinase fusions in clear cell renal cell carcinoma.

ABSTRACT: As one of the most common types of renal cancer, clear cell renal cell carcinoma (ccRCC) in advanced stages constitutes a continued major challenge for uro?oncologists, as the identification of novel driver mutations and the development of novel targeted therapies against them remain an unmet need. Aberrations in anaplastic lymphoma kinase (ALK), a rational therapeutic target, as verified in lung cancer with ALK rearrangement, have been implicated in the pathogenesis of multiple human cancers. In the present study, we screened ALK expression in 87 pathologically defined ccRCCs via immunohistochemistry (IHC) using a newly developed rabbit anti?human ALK monoclonal antibody (clone D5F3). Four patients tested positive for ALK expression, as confirmed by IHC. Among them, 2 patients were further confirmed with fluorescence in situ hybridization (FISH) assay with the use of the Vysis LSI ALK dual color break?apart probe. Furthermore, we detected the existence of the echinoderm microtubule?associated protein?like 4/anaplastic lymphoma kinase (EML4?ALK) (E13:A20, variant 1) fusion gene in tumors from these two patients by using rapid amplification of cDNA ends (RACE)?coupled PCR sequencing and RT?PCR. Notably, we first showed that enforced EML4?ALK expression could significantly promote in vitro proliferation, clonogenic colony formation and apoptosis resistance in HK2 immortalized normal renal tubal epithelial cells and their in vivo outgrowth when injected into immunocompromised nude mice. Importantly, this pro?tumorigenic effect was completely abolished by the ALK?specific inhibitor crizotinib, indicating the potential effectiveness of ALK?specific inhibitors in treating ALK?rearranged ccRCC patients. Our data revealed that ALK fusions exist in adult ccRCC, providing a rationale for ALK inhibitor therapy in selected patients with ccRCC.

SUBMITTER: Chen W

PROVIDER: S-EPMC7041106 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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Identification of anaplastic lymphoma kinase fusions in clear cell renal cell carcinoma.

Chen Wei W Li Wei W Bai Bing B Wei Huafeng H

Oncology reports 20200114 3

As one of the most common types of renal cancer, clear cell renal cell carcinoma (ccRCC) in advanced stages constitutes a continued major challenge for uro‑oncologists, as the identification of novel driver mutations and the development of novel targeted therapies against them remain an unmet need. Aberrations in anaplastic lymphoma kinase (ALK), a rational therapeutic target, as verified in lung cancer with ALK rearrangement, have been implicated in the pathogenesis of multiple human cancers. I ...[more]

PMID: 32020234

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Project description:The purpose of the present study was to screen potential pathogenic biomarkers of clear cell renal cell carcinoma (ccRCC) via microarray analysis. The mRNA and microRNA (miRNA) expression profiles of GSE96574 and GSE71302 were downloaded from the Gene Expression Omnibus (GEO) database, as well as the methylation profile of GSE61441. A total of 5 ccRCC tissue samples and 5 normal kidney tissue samples were contained in each profile of GSE96574 and GSE71302, and 46 ccRCC tissue samples and 46 normal kidney tissue samples were involved in GSE61441. The differentially expressed genes (DEGs) and the differentially expressed miRNAs (DEMs) were obtained via limma package in ccRCC tissues compared with normal kidney tissues. The Two Sample t-test and the Beta distribution test were used to identify the differentially methylated sites (DMSs). The Database for Annotation, Visualization and Integrated Discovery (DAVID) was used to perform the Gene Ontology (GO) term and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses of the DEGs. The targets of the DEMs were screened with the miRWalk database, and the further combination analyses of DEGs, DEMs and DMSs were conducted. Additionally, reverse transcription PCR (RT-PCR) and methylation-specific PCR (MS-PCR) were performed to detect the mRNA level and methylation status of HAPLN1. The mRNA levels of hsa-miR-204 and hsa-miR-218 were tested by RT-PCR. A total of 2,172 DEGs, 202 DEMs and 2,172 DMSs were identified in RCC samples compared with normal samples. The DEGs were enriched in 1,015 GO terms and 69 KEGG pathways. A total of 10,601 miRNA-gene pairs were identified in at least 5 algorithms of the miRWalk database. A total of 143 overlaps were identified between the DEGs and the differentially methylated genes. Furthermore, the DEGs were involved in 851 miRNA-gene pairs, including 127 pairs in which the target genes were negatively associated with their corresponding DEMs and DMSs. HAPLN1 was lowly expressed and highly methylated in ccRCC tissues, while hsa-miR-204 and hsa-miR-218 were highly expressed. The results of the present study indicated that HAPLN1, hsa-miR-204 and hsa-miR-218 may be involved in the pathogenesis of ccRCC.

Dataset Information

Identification of anaplastic lymphoma kinase fusions in clear cell renal cell carcinoma.

Publications

Identification of anaplastic lymphoma kinase fusions in clear cell renal cell carcinoma.

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