BIOINFORMATICS APPLICATIONS NOTE
Vol. 21 no. 7 2005, pages 1282–1283 doi:10.1093/bioinformatics/bti146
Genetics and population analysis
CyDAS: a cytogenetic data analysis system Bernhard Hiller1 , Jutta Bradtke1 , Harald Balz1 and Harald Rieder1,2,∗ 1 Institut
für Klinische Genetik der Phillipps-Universität Marburg, Bahnhofstrasse 7, 35037 Marburg, Germany and 2 Institut für Humangenetik und Anthropologie, Universitätsklinikum Düsseldorf, Universitätsstrasse 1, 40225 Düsseldorf, Germany Received on October 20, 2004; revised and accepted on November 8, 2004 Advance Access publication November 16, 2004
Metaphase chromosome analysis is a well-established tool for the investigation of the genetic changes in tumors. It provides an overview of the genomic alterations on a single cell level and is, therefore, unexcelled for the detection of cell clones carrying different chromosome changes in tumor tissues. In tumors, which display chromosomally distinct cell populations, the sequence of occurrence of chromosome aberrations can be investigated. The time point of the occurrence of particular chromosome aberrations during tumor progression can also be estimated by the correlation of the frequency of the respective chromosomal change in a cohort of tumors with the number of alterations of the karyotypes (Hoglund et al., 2001, 2002). Both approaches provide clues to the chromosomal pathways of the tumor progression. The identification of recurring chromosome breakpoints and/or the delineation of minimal regions of chromosome gains or losses may point to the chromosomal localization of genes which are important for the development of the tumor, in focus of the investigation (Cooper, 1996). The chromosomal aberrations are inferred from banding patterns and written down using the International System for Human Cytogenetic Nomenclature (ISCN, 1995). The text strings of the ISCN karyotypes display the chromosome changes as single aberration events. In karyotypes, which contain unbalanced translocations or complexly rearranged chromosomes, the chromosomal gains and/or losses are not directly deducible from the respective ISCN string. This information becomes evident only if the entire karyotype is considered and, therefore, represents metainformation. Owing to technical reasons, the resolution of the chromosome banding and the accurateness of the chromosome changes may differ between different tumor samples. To improve the access to the karyotype metainformation and to normalize the chromosome banding ∗ To
whom correspondence should be addressed.
resolution for statistical evaluations, a simplified computer readable cytogenetic nomenclature (SCCN) was developed. Using SCCN, qualitative and quantitative aberrations are written separately and explicitly and, thus, can be easily used as an input for computer programs (Bradtke et al., 2003). However, no automated procedure for the translation of ISCN karyotypes into SCCN strings has been available, as yet. Only a few approaches have been undertaken to develop programs for an automated analysis of ISCN karyotypes. In the 1980s, a computer program was presented which determined the types of aberrations and breakpoints as well as gains and losses of whole chromosomes (Kamada et al., 1983; Hashimoto et al., 1989). The extraction of the metainformation from the ISCN formula, i.e. the gains and losses of chromosomal fragments implied by the aberrations, was not possible. Recently, two Internet applications were launched which address the conversion of ISCN karyotypes into computer accessible data formats. The KaryoReader calculates a list of gains, losses and structural aberrations per chromosome band (Liang, 2004, http://falcon.roswellpark.org/KR/). The Karyotype Cytoband Table Converter draws bars according to the cumulative gains and losses next to ideograms. A table containing the data on chromosome band level is available (Baudis, 2004, http://www.progenetix.de/felixtest.html). Complex chromosome aberrations are not adequately processed, which may lead to erroneous results. Neither program seems to be intended for integration into desktop applications. Here we describe a new application, which analyses single aberrations, single karyotypes and large sets of karyotype data. It can be accessed online via the Internet, and a desktop version— which is available for download—that runs on common Windows computers. The business logic is packed in a class library (dot net assembly). Its major entrance point is the Karyotype class, which analyzes a single karyotype. The analysis of the aberration elements is delegated to the Aberration class, with one Aberration object for each aberration element. The Aberration object calculates the structural aberrations and gains and losses for the aberration. The QuantitativeAberrations and QualitativeAberrations objects returned from the Aberration objects are summed up by the Karyotype object. Such QuantitativeAberrations and QualitativeAberrations objects can be summed up for several karyotypes. From them, an object showing gains, losses and structural aberrations per chromosomal band can be calculated. The CyDASGraphics class uses such an object as input for generating bitmaps representing these data. From these
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ABSTRACT For statistical analyses in cancer cytogenetics, the genomic changes encoded by the karyotype must be translated into numerical codes. We developed a program, which extracts chromosomal gains and losses as well as breakpoints from the karyotype. The changes are compiled in tables according to the chromosome bands involved and/or depicted in projection to the respective chromosome ideogram. The data are ready to be integrated into further statistical analyses. The program may be run as desktop or Internet application. Availability: http://www.cydas.org/ Contact: [email protected]
CyDAS: a cytogenetic data analysis system
figures, recurring aberrations—both structural and numeric—and chromosomal imbalances can be seen easily. Since information on human chromosomal structure is placed into an XML file, karyotypes of other species whose cytogenetic nomenclature is compatible with human nomenclature can be analyzed when that file is replaced. On the CyDAS website, three programs showing useful examples of the employment of the class library for typical cytogenetic tasks can be accessed online.
• Drawing aberrant chromosomes draws ideograms for derivative chromosomes. After entering the description of the aberrant chromosome in ISCN style, the desired banding resolution is selected. Distinct colors for each chromosomal origin are used. With such ideograms the cytogenetic descriptions of aberrant chromosomes can be visually checked. • Analyzing Mitelman Data graphically analyses large datasets downloaded from the Mitelman database of chromosome aberrations in cancer (Mitelman et al., 2004, http://cgap.nci.nih.gov/Chromosomes/Mitelman). A text file is uploaded which contains the chromosome data retrieved by a database query. Several parameters can be selected, which, e.g. define the way of processing of uncertainties of chromosome findings, the level of banding resolution and the settings for the graphical visualization. The program calculates the amount of aberrations and of gains and losses per chromosomal band. The results are displayed as columns projecting to the respective chromosome ideograms and are also available as a table, which can be used in data-mining approaches. Furthermore, a
Desktop versions of these programs can also be downloaded. They run on common computers with current versions of Microsoft Windows and the Dot Net framework. An integration into common Microsoft Access databases is possible. For people interested in writing their own programs, a large set of documentation and how-to document is available online.
ACKNOWLEDGEMENTS This work was supported by a grant of the Deutsche Forschungsgemeinschaft, RI 1123/2-1 (DFG).
REFERENCES Baudis,M. (2004) Karyotype cytoband table converter. Bradtke,J., Balz,H., Fonatsch,C., Heinze,B., Jauch,A., Mohr,B., Schoch,C. and Rieder,H. (2003) Computer aided analysis of additional chromosome aberrations in Philadelphia chromosome positive acute lymphoblastic leukaemia using a simplified computer readable cytogenetic notation. BMC Bioinformatics, 4, 4. Cooper,C.S. (1996) Translocations in solid tumours. Curr. Opin. Genet. Dev., 6, 71–75. Hashimoto,T., Kamada,N., Yamamoto,H. and Munaka,M. (1989) A computer program for analysis of chromosome abnormalities. Nippon Ketsueki Gakkai Zasshi, 52, 38–48. Hiller,B., Bradtke,J., Balz,H. and Rieder,H. (2004) ISCNAnalyzer easily detects karyotype errors in cytogenetic databases. Eur. J. Hum. Genet., 12(Suppl. 1), 128–129. Hoglund,M., Sall,T., Heim,S., Mitelman,F., Mandahl,N. and Fadl-Elmula,I. (2001) Identification of cytogenetic subgroups and karyotypic pathways in transitional cell carcinoma. Cancer Res., 61, 8241–8246. Hoglund,M., Gisselsson,D., Sall,T. and Mitelman,F. (2002) Coping with complexity multivariate analysis of tumor karyotypes. Cancer Genet. Cytogenet., 135, 103–109. ISCN (1995) An International System for Human Cytogenetic Nomenclature. In Mitelman,F. (ed.), S Karger, Basel. Kamada,N., Yamamoto,H., Tanaka,K., Ohtaki,M., Ueoka,H., Munaka,M. and Kuramoto,A. (1983) Analysis and rearrangement of human karyotypes by computer. Cancer Genet. Cytogenet., 10, 17–22. Liang,P. (2004) KaryoReader. Mitelman,F., Johansson,B. and Mertens,F. (Eds) (2004) Mitelman Database of Chromosome Aberrations in Cancer.
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• ISCN Analysis analyzes a single karyotype. It shows virtually all information, which can be extracted from an ISCN formula. In case of an error, the program will show the first erroneous element and a description of the error. This feature is useful for quality management of the cytogenetic data: ∼10% of the entries in the Mitelman database—which is based on published data only—contain errors (Hiller et al., 2004).
commented list of the errors is presented which were found in the karyotypes.