SelTarbase, a database of human mononucleotide-microsatellite mutations and their potential impact to tumorigenesis and immunology

Nucleic Acids Research, Jan 2010

About 15% of human colorectal cancers and, at varying degrees, other tumor entities as well as nearly all tumors related to Lynch syndrome are hallmarked by microsatellite instability (MSI) as a result of a defective mismatch repair system. The functional impact of resulting mutations depends on their genomic localization. Alterations within coding mononucleotide repeat tracts (MNRs) can lead to protein truncation and formation of neopeptides, whereas alterations within untranslated MNRs can alter transcription level or transcript stability. These mutations may provide selective advantage or disadvantage to affected cells. They may further concern the biology of microsatellite unstable cells, e.g. by generating immunogenic peptides induced by frameshifts mutations. The Selective Targets database (http://www.seltarbase.org) is a curated database of a growing number of public MNR mutation data in microsatellite unstable human tumors. Regression calculations for various MSI–H tumor entities indicating statistically deviant mutation frequencies predict TGFBR2, BAX, ACVR2A and others that are shown or highly suspected to be involved in MSI tumorigenesis. Many useful tools for further analyzing genomic DNA, derived wild-type and mutated cDNAs and peptides are integrated. A comprehensive database of all human coding, untranslated, non-coding RNA- and intronic MNRs (MNR_ensembl) is also included. Herewith, SelTarbase presents as a plenty instrument for MSI-carcinogenesis-related research, diagnostics and therapy.

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SelTarbase, a database of human mononucleotide-microsatellite mutations and their potential impact to tumorigenesis and immunology

Stefan M. Woerner 1 2 Yan P. Yuan 0 Axel Benner 3 Sebastian Korff 1 Magnus von Knebel Doeberitz 1 Peer Bork 0 0 Structural and Computational Biology Unit, European Molecular Biology Laboratory , Meyerhofstr. 1, D-69117 Heidelberg 1 Applied Tumorbiology, Institute of Pathology, University Hospital Heidelberg , Im Neuenheimer Feld 220/221, D-69120 Heidelberg 2 Institute for Clinical Chemistry, Medical Faculty of Mannheim of the University of Heidelberg , Theodor-Kutzer-Ufer 1-3, D-68167 Mannheim 3 Central Unit Biostatistics, German Cancer Research Center , Im Neuenheimer Feld 280, D-69120 Heidelberg, Germany - About 15% of human colorectal cancers and, at varying degrees, other tumor entities as well as nearly all tumors related to Lynch syndrome are hallmarked by microsatellite instability (MSI) as a result of a defective mismatch repair system. The functional impact of resulting mutations depends on their genomic localization. Alterations within coding mononucleotide repeat tracts (MNRs) can lead to protein truncation and formation of neopeptides, whereas alterations within untranslated MNRs can alter transcription level or transcript stability. These mutations may provide selective advantage or disadvantage to affected cells. They may further concern the biology of microsatellite unstable cells, e.g. by generating immunogenic peptides induced by frameshifts mutations. The Selective Targets database (http://www.seltarbase.org) is a curated database of a growing number of public MNR mutation data in microsatellite unstable human tumors. Regression calculations for various MSIH tumor entities indicating statistically deviant mutation frequencies predict TGFBR2, BAX, ACVR2A and others that are shown or highly suspected to be involved in MSI tumorigenesis. Many useful tools for further analyzing genomic DNA, derived wildtype and mutated cDNAs and peptides are integrated. A comprehensive database of all human coding, untranslated, non-coding RNA- and intronic MNRs (MNR_ensembl) is also included. Herewith, SelTarbase presents as a plenty instrument for MSI-carcinogenesis-related research, diagnostics and therapy. The completion of the human genome project in 2003 provided the data basis for genome-wide analyses (1). Now it became within reach to systematically investigate the whole human genome for sequence motifs or structures by computer assisted investigation to clarify the association of genome variation or mutation with certain human diseases using the human genome draft as a consensus. Currently, there are more than 22 000 known protein-coding genes annotated within the 3 G of base pairs within Human Ensembl (rel. 55.37, http://www .ensembl.org/Homo_sapiens/) leading to more than 100 000 transcripts. Sequence motifs of special interest comprise single nucleotide polymorphisms (SNPs), splice site recognition patterns or promoter motifs, regulatory motifs and binding sites. The human genome sequence also facilitated the systematic search for human microsatellites that had been started earlier based on EMBL DNA and mRNA data (2). Microsatellites are especially prone to deletion and insertion mutations during DNA replication with a strong dependency of mutability from their length (3). They are distributed non-randomly throughout the whole human genome within non-coding and coding regions (4). Their function, however, is nearly unknown. Mononucleotide repeats (MNRs) seem to represent the most interesting kind of microsatellites. The length of coding MNRs (cMNRs) is conserved (5). Length alterations of cMNRs of 1 or 2 nucleotides lead to frameshift mutations. The length of non-coding MNRs however can vary highly from individual to individual. However, there are also a number of so-called quasimonomorphic MNRs of higher length (2040 bp) within non-coding regions that show a significantly restricted length variation within the human population which may indicate the possibility of functional relevance of these non-coding MNRs. It is well known, that alterations in polypyrimidine MNRs in the 50 local neighborhood of splice donor sites can lead to exon skipping (6,7), which will result in a frameshift situation in two-thirds (8). In addition, shortening or elongation of MNRs within 50 UTRs can have an impact on the transcription level, of those in the 30 UTR on transcript stability of the respective mRNA (9). Microsatellite alterations are corrected by the DNA mismatch repair system (MMR). The functional inactivation of the MMR system results in the manifestation of microsatellite mutations which is termed microsatellite instability (MSI). The MSI phenotype is found in >90% of tumors developing in MMR germline mutation carriers among hereditary non-polyposis colorectal cancer (HNPCC) or Lynch syndrome patients and 15% of sporadic cancers (10). Colorectal MSIH tumors are characterized by certain clinico-histopathological properties such as a better prognosis compared to tumors of the CIN phenotype (1113). (...truncated)


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Stefan M. Woerner, Yan P. Yuan, Axel Benner, Sebastian Korff, Magnus von Knebel Doeberitz, Peer Bork. SelTarbase, a database of human mononucleotide-microsatellite mutations and their potential impact to tumorigenesis and immunology, Nucleic Acids Research, 2010, pp. D682-D689, 38/suppl 1, DOI: 10.1093/nar/gkp839