Renal cell carcinoma development in the rat independent of alterations at the VHL gene locus

Our plain-English summary of Renal cell carcinoma development in the rat independent of alterations at the VHL gene locus, by C. Walker, Y.T. Ahn, J. Everitt, et al (Molecular Carcinogenesis, 1996).

The study

• Authors: C. Walker, Y.T. Ahn, J. Everitt, X. Yuan
• Journal: Molecular Carcinogenesis
• Published: 1996;15(2):154-61
• Cited by: 19 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Germline alterations of the human von Hippel-Lindau (VHL) tumor suppressor gene predispose to renal cell carcinoma and a constellation of other tumor types found in VHL disease. This gene is also mutated or deleted in a high proportion of sporadic nonpapillary renal cell carcinomas. In the Eker rat model, spontaneous renal cell carcinoma develops with a high frequency. We therefore investigated the role of this tumor suppressor gene in the development of these hereditary rat tumors. By using reverse transcriptase (RT)-polymerase chain reaction (PCR) analysis, the sequence of the rat VHL gene was determined over the portion of the gene homologous to regions where most mutations in the human VHL gene occur. The sequence homology was 90% and the amino-acid identity 99% between the rat and human genes. A developmental and tumor-specific pattern of expression for the VHL gene was found; a ubiquitous 3.2-kb transcript was expressed in all rat tissues examined (neonatal kidney, lung, liver, brain, heart, kidney, spleen, testis, and stomach), and an additional 4.5-kb transcript was expressed in neonatal kidney and cell lines derived from Eker rat renal cell carcinomas (ERC cell lines). To determine whether mutations in the VHL gene were involved in tumor development in the Eker model, RT-PCR, single-strand conformation polymorphism (SSCP) analysis, and direct sequencing were used to search for alterations in this gene in the ERC cell lines. Alterations in the VHL gene were not detected by SSCP, and these data were confirmed by direct sequencing. Transformed rat kidney epithelial cell lines derived from Fisher rats also expressed the VHL gene but like the ERC cell lines did not contain mutations in the VHL gene. These data indicate that in the rat, transformation of kidney epithelial cells and the development of solid, nonpapillary renal cell carcinoma can occur via pathways that are independent of alterations at the VHL gene locus.

In plain English

This laboratory study looked at kidney cancer in rats, not asbestos. The authors examined the rat version of the VHL gene, which is often altered in human kidney cancer. They used eight cell lines grown from kidney tumors in Eker rats, which carry an inherited mutation in the tuberous sclerosis gene. They also used six lines of Fisher rat kidney cells that had been chemically transformed in the laboratory. Over the region they sequenced, the rat gene was 90% alike in sequence to the human gene and more than 99% alike at the protein level. All rat tissues examined made one form of the gene's message, and the tumor lines also made a second form seen in newborn kidney. No VHL mutations were found in any cell line by screening (none of eight tumor lines, none of six chemically transformed lines) or by sequencing five tumor lines. The authors concluded that rat kidney cancer can develop without changes in this gene. They noted that mutations outside the region examined, or rare mutations, could have been missed.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Laboratory (molecular genetic) study of rat cell lines and tissues: gene sequencing, measurement of gene messages (northern analysis), and mutation screening by SSCP with direct sequencing
• Who was studied: Eight renal cell carcinoma cell lines from independent tumors in Eker rats; six kidney epithelial cell lines from Fisher rats transformed in vitro; normal rat tissues (neonatal kidney, lung, liver, brain, heart, adult kidney, spleen, testis, stomach). Human cell lines were used as test controls: renal carcinoma line A-498 as a positive control and mesothelioma line GATES as a negative control.
• Exposure: No asbestos exposure was studied. The tumor lines came from rats with the inherited Eker mutation in the tuberous sclerosis gene. The TRKE lines were transformed by the chemical N-methyl-N'-nitro-N-nitrosoguanidine.
• Main results:
  • Over the region sequenced, the rat VHL gene was 90% homologous to the human gene and 96% homologous to the mouse gene at the nucleotide level, with more than 99% identity at the amino-acid level.
  • A 3.2-kb VHL transcript was expressed in all normal rat tissues examined. An additional 4.5-kb transcript was expressed by neonatal rat kidney but not by adult tissues.
  • All eight Eker rat tumor cell lines expressed both transcripts. All six TRKE cell lines also expressed both (data not shown).
  • All eight ERC lines and all six TRKE lines expressed the normal splice form of the gene.
  • No VHL mutations were detected by SSCP in the Eker rat tumor cell lines (none of eight) or the TRKE lines (none of six). Direct sequencing found none in five Eker tumor lines.
• The authors' conclusion: The authors concluded that the lack of VHL alterations in the Eker rat tumors and in the laboratory-transformed rat kidney cells supports the idea that kidney tumor development can proceed by pathways independent of VHL mutations. They also suggested that the Eker rat model may be useful for studying such alternative pathways.
• Limitations the authors state:
  • Only part of the rat VHL gene was sequenced, so mutations outside exons 1 to 3 could have been missed.
  • Very infrequent mutations of the VHL gene could have been missed.

Topics

Medical terms in this study, explained in our Lexicon: Carcinoma, Tumor Suppressor Gene.

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