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

Abstract

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.

Figure 1.

Graph of sigmoid regression analysis. Result of colorectal cancer mutation data: ncMNRs (non-coding i.e. untranslated, intronic and pseudogene MNRs, open diamonds), cMNRs (amino acid coding MNRs, grey filled circles), and nMNRs (intergenic MNRs, open squares). Red marked MNRs changed since previous release, respectively represent new data. Regression analysis was performed combined for all MNR types. The fitted regression line is drawn as solid black line, the upper and lower prediction lines as bold dashed grey lines. If the pointing device is moved over data points that reside above the upper respectively below the lower prediction line, a popup will appear, showing the name of the gene and the mutation frequency as well as the number of analyzed tumor samples. If the pointing device is moved over the fitted regression line (solid black line), a popup will appear, showing the length × with the corresponding mean mutation frequency as well as the lower and upper prediction thresholds for the length ×.

Figure 2.

The MNR detail information page. Most details are mentioned within the 2nd paragraph of section Web Interface. Using the buttons ‘MNR’ or ‘Reference’ several filters can be defined for scrolling from MNR to MNR, either restricting to MNRs of one contributing reference and/or regarding coding status and MNR length. Filters can be used in combination. If the pointing device is moved over cell line names, a popup will appear, showing additional information regarding this cell line including links to publications from which this information is drawn (Supplementary references of SelTarbase).

Figure 3.

Transcription and translation information page: transcripts/peptides are scrollable from 5′ to 3′ using different units of 10–500 bp (default 50 bp). When the page is loaded all MNR containing transcripts are aligned according to MNR position showing the MNR at the left border of the sequence window. Transcripts that do not contain the MNR are greyed, and no frameshift information is calculated. More information about this function is provided within the 2nd paragraph of section Web Interface.

Figure 4.

MNR_ensembl query form: searching for human coding, untranslated, other non-coding and intronic MNRs: results can be reported for single categories or in combination. Ensembl accession numbers (ENSG), the hugoID or gene description key words can be searched for. Ordering is possible by genomic position or by MNR length in descending order. Results can be restricted to certain minimum and maximum MNR lengths with an absolute minimum of 4 nt. Due to alternative splicing of genes or several transcripts MNRs can be reported several times as cMNR(s), uMNR(s) and/or iMNR(s). Using the option unique positions, a complete MNR list of a gene can be generated listing each MNR at a given genomic position only once. The annotation hierarchy in this case is cMNRs > uMNRs > iMNRs, what means that an MNR once reported as cMNR will not be able to be reported as uMNR or iMNR using that option. All cMNRs will be listed as they would be transcribed within one large transcript including all annotated exons of that gene. Additionally, the search can further be limited to only those transcripts (genes) which are related to a specific subcellular localization according to the GO term(s) used in the LOCATE database (http://locate.imb.uq.edu.au). Additionally, a somewhat elder version of all mouse MNRs is also available (mouse rel. 45.36f).