Nucleic Acids Research

The von Hippel-Lindau disease is a dominantly inherited familial cancer syndrome, with an incidence of 1 in 36 000, predisposing to the development of retinal, cerebellar and spinal hæmangioblastomas, pancreatic cysts and carcinoma and RCC (1,2). RCC, the most frequent malignancy in the adult kidney, is usually sporadic and its phenotype is extremely heterogeneous. Both sporadic and familial RCC bear relation as clear cells subtype accounts for most tumors. It has been postulated that these tumors have a common carcinogenic pathway and that at least one gene should be altered in both forms. This hypothesis has been confirmed with the cloning of the VHL gene and the identification of germline and somatic mutations of this gene in VHL patients and sporadic RCC. The human VHL gene encodes a 213 amino acid (aa) protein expressed in all tissues (3). To understand its functions, different groups have identified and characterized proteins which interacts with pVHL. Three groups have shown that pVHL stably associates with the two regulatory subunits B and C of the transcription elongation factor, elongin (4-6). Duan et al. showed that pVHL can inhibit transcriptional elongation by elongation factor sIII (4). Pause and colleagues showed that the trimeric pVHL-elongin B-C specifically associates with the Hs-CUL-2, a member of the Cdc53 family of proteins (7). Tsuchiya et al. have shown that a novel protein, VBP1, can form a complex with pVHL in vivo (8) but its role remains unknown. Concurrently, investigations were performed on identified mutations of this gene. Today, 314 mutations have been described in VHL families (3,9-18), 143 reported in sporadic RCC (17,19-24) and 49 in cell lines (3,17,22,25). If most germline VHL mutations are missense alterations, most of the sporadic mutations result in truncated protein. The collection of a large number of mutations is then necessary to understand this discrepancy, to identify key residues in the biological function of the protein and to establish correlations between the localization of the mutation and specific phenotypes.

To handle the flow of all known VHL mutations and study genotype/phenotype relations, we adapted the `universal mutation database' software to this gene (26-28).

DATABASE AND SOFTWARE

The database of VHL mutations was developed using the `Universal Mutation Database' tool (26-28). It contains all mutations localized in the coding region of the VHL gene. In an attempt to standardize the numbering system used to describe VHL mutations, all mutations which have been previously reported using the numbering scheme of Latif et al. (3) have been renumbered. Amino acid positions are derived from the numbering system used in Kuzmin et al. (29) who identified the VHL gene promotor and defined the initiation codon at position +71 from the original sequence described by Latif et al. (3). The current version of the database contains 507 entries. When the same mutation was reported in more than one article, only the first report was taken into account. For each mutation, information is provided at several levels: at the gene level (exon and codon number, wild type and mutant codon, mutational event, mutation name), at the protein level (wild type and mutant amino acid), at the clinical level (angioma, hemangioblastoma, pheochromocytoma, RCC), at the molecular level (LOH of the second allele) and at the histological level (Robson stage).

Table 1. A section of the database in Excel spreadsheet format

Each line represents a single VHL mutation. The columns contain the following information and abbreviations:
Column A: file number.
Column B: exon number at which the mutation is located. Exons are numbered with respect to the translational initiation site given by Kuzmin et al. (29).
Column C: nucleotide position at which the mutation is located, numbered as above.
Column D: codon number at which the mutation is located, numbered as above. If the mutation spans more than one codon, e.g., there is a deletion of several bases, only the first (5[prime]) codon is entered.
Column E: normal base sequence of the codon in which the mutation occurred.
Column F: mutated base sequence of the codon in which the mutation occurred. If the mutation is a base pair deletion or insertion this is indicated by `del' or `ins' followed by the number of bases deleted or inserted and the position of this deletion or insertion in the codon (a, b or c). The nucleotide position is the first that is deleted or the one following the insertions. For example, `del66b' is a deletion of 66 bases including the second base of the codon; `ins4b' is an insertion of 4 bases occurring between the first and the second base of the codon.
Column G: concerns base substitutions. It gives the base change, by convention, read from the coding strand. If the mutation predicts a premature protein-termination, the novel stop codon position is given, e.g., `Stop at 115'.
Column H: mutational event (transition/transversion or frameshift).
Column I: indicates if the mutation is a transition occurring at a CpG dinucleotide.
Column J: name of the tumor/patient/cell line as given by the authors.
Column K: wild type amino acid.
Column L: mutant amino acid. Deletion and insertion mutations which result in frameshift are designated by `Fr'.
Column M: cancer.
Column N: origin of the mutation (tumor, cell line, xenograft or germline).
Column O: LOH, if available. 2, two alleles remaining; 1, only one allele remaining; ?, no information available or non-informative.
Columns P-S: clinical information if available. P, angioma; Q; hemangioblastoma; R, pheochromocytoma; S, RCC. For each clinical location, the number of affected patients/number of patients carrying the mutation is indicated.
Column T: tumor stage according to Robson staging system.
Column U: reference number indicating the publication in which the mutation is described. Full citations (authors, year, title, volume, pages) are provided with the database. If the same mutation has been reported for the same patient in different papers only one entry is made. If the same mutation has been reported for unrelated patients, a separate entry is made for each patient.

The software package contains routines for the analysis of the VHL database that were developed with the 4^th dimension[prime][prime] (4D) package from ACI. The use of the 4D SGDB gives access to optimized multicriteria research and sorting tools to select records from any field. Moreover, all routines already developed for other databases were added to the VHL package: (i) `Position' studies the distribution of mutations at the nucleotide level to identify preferential mutation sites; (ii) `Mutational events' is comparable to (i) but also indicates the type of mutational event. The result can either be displayed as a table or in a graphic representation; (iii) `Frequency of mutations' allows one to study the relative distribution of mutations at all sites and to sort them according to their frequency. A graphic representation is also available and displays a cumulative chart of mutation distributions; (iv) `Frequency of events' is similar to (iii) but also indicates if mutations are localized in a CpG dinucleotide; (v) `Distribution of mutations' and `Binary comparison' are two graphical routines which allow one to compare the distribution of mutations in up to eight groups of records and display the result either in one or two graphics; (vi) `Stat exons' studies the distribution of mutations in the different exons. It enables detection of a statistically significant difference between observed and expected mutations; (vii) `Insertions and deletions analysis' searches for repeated sequences surrounding the mutation and possibly involved in the mutational mechanism.

Subsequently, the software will be expanded as the database grows and according to the requirements of its users. New functions could be implemented. Table 1 describes a section of the database.

AVAILABILITY

The current database and subsequent updated versions are (will be) available on request to C.B. on floppy disc either Apple or PC formatted. Notification of omissions and errors in the current version as well as specific phenotypic data would be gratefully received by the corresponding author. If you use this database, please cite the present article as reference. The software package is available on a collaborative basis.

The current database and the analysis software will be accessible via the internet and world wide web interface in January 1998 at the URL: http://www.umd.necker.fr

ACKNOWLEDGEMENTS

This work was supported by the Ligue Nationale contre le Cancer and the Association pour la Recherche sur le Cancer (ARC).

REFERENCES

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*To whom correspondence should be addressed at: INSERM UR 383, Hôpital Necker-Enfants Malades, 149-161, rue de Sèvres, 75745 Paris Cedex 15, France. Tel: +33 1 44 49 44 84; Fax: +33 1 47 83 32 06; Email: beroud@necker.fr

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