ABSTRACT
A large number of different mutations in the APC and p53 tumor suppressor genes
have been identified in various types of cancer. This substantial increase
since our previous reports can enable analyses which were not previously
possible. In order to capture all these new data, the software permitting
analysis has been improved. This report describes the various improvements
since the second release of the database.
We have previously described a generic software which allows the entry and
analysis of mutations in any gene of interest. This software was used for the
creation and the analysis of mutation databases for the p53 gene (
1
), the APC gene (
2
), the fibrilin gene (
3
) and the VHL gene (C. Béroud, unpublished data).
Since the last release in 1995, each database has been updated and several
improvements have been included in the software that is now freely available
through the use of a runtime that does not require any royalties to ACI. The
p53 database (6000 mutations, September 1996) and the APC database (1000
mutations, September 1996) can be used for molecular epidemiology in order to
draw some precise link between carcinogen exposure and specific mutational
events.
Although the p53 gene is usually inactivated by missens mutations, 10% of the
mutations are small frameshift mutations (insertions or deletions). An
exhaustive analysis of these frameshift mutations has been performed recently (
4
). Most of them do not occur at random position as they are found at specific
DNA sequences which are known to be associated with DNA polymerase infidelity:
monotonic base runs, adjacent or nonadjacent repeats of short tandem sequences,
palindromes or homocopolymer runs.
The huge increase of p53 mutations which have been included in the database now
allows more precise evaluation of the pattern of p53 mutations. For a given
cancer type such as breast or lung cancer, analysis can be performed for
distinct histologic group or for patients from different geographical areas.
When available, these new criteria have been added in the p53 database.
In the APC gene, an inverse situation is observed with >95% of the alterations
corresponding either to frameshift or to nonsense mutations. Huang
et al
. have investigated the influence of the replication error phenotype (RER) on
the pattern of APC mutations (
5
). Although the frequency of APC mutations is similar in RER and non-RER tumors, there is a significant excess of frameshift mutations in the
RER cases. This observation suggests first that the mechanism involved in APC
mutation is different in these two tumor types. Second, the genetic instability
associated with the RER phenotype is directly involved in APC mutation and has
a direct role in tumor formation. Recent studies have confirmed that some
clinical feature such as ophthalmic or dental lesions (
6
,
7
).
The program was developed with the 4thDimension (4D) package from ACI (version
5.5.1). This version generates a compiled program which can be used either on
MAC (680xx or PowerMac) or IBM computer (486 or Pentium). Furthermore, the
compilation integrates the runtime of 4thDimension that alleviate the need of
any other software. This standalone software has a size of 4 Mo. The p53
database and the APC database have a size of 10 Mo and 3 Mo, respectively. The
software and the databases are now freely available. They can be obtained from
T. Soussi (100721.1244@Compuserve.com). Ten formatted floppy disks are
necessary for sending the full version of the database and the software. Solid
support such as Syquest cartridge (44 Mo, 88 Mo or 200 Mo) or Jaz cartridge (1
Go) can also be handled. Both databases are also available as Microsoft Excel
files (two formatted floppy disks are necessary). The software and the
databases will be available on the web during mid-1997.
This work was supported by grants from the Association de Recherche sur le
Cancer, Ligue Nationale contre le Cancer (Comité de Paris), Ligue Nationale contre le Cancer (Comité National) and MGEN.
REFERENCES
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