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.

Identification and Selective Degradation of Neopeptide-Containing Truncated Mutant Proteins in the Tumors with High Microsatellite Instability

“…When 1-or 2-bp deletions/insertions were detected in the cMNR region, genes that acquired abnormal stop codons distal to a site 50 to 55 nt from the last exon junction complex were selected. 12). Most of the abnormal stop codons were PTCs; however, abnormal stop codons after normal stop codons (readthrough) were also found in some genes with cMNR mutations.…”

“…The length alterations in microsatellites of the coding region [coding mononucleotide repeats (cMNRs)] result in frameshift mutations in the affected genes, and these mutations are believed to contribute to tumor development and progression (10). Although many reports indicated that numerous genes are frequently mutated in their cMNRs in MSI-H cancers, few of these genes have been reported to express their mutant gene products in MSI-H cancers (11)(12)(13). We searched for genes containing cMNRs in the last exon and analyzed the frequency of mutations in these genes.…”

Deficiency of SATB1 expression in Sézary cells causes apoptosis resistance by regulating FasL/CD95L transcription

“…Several previously reported up-regulated genes in Sézary cells, such as DNM3, 11 PLS3, 15 NEDD4L, 11 and TWIST1, 11,23 and down-regulated genes (STAT4 and BCL11A 23 ) were also found in this gene list (supplemental Table 3). The genes differentially up-regulated in Sézary cells include genes regulating cell proliferation, cell adhesion, cytoskeleton organization, and signal transduction, as well as several oncogenes identified in other malignancies, such as ACVR2A (breast cancer 24 ), CDH1 (hepatocellular cancer 25 ), KLF8 (ovarian cancer 5 ), and PDGFA (papillary thyroid carcinoma 26 ). Genes differentially down-regulated in Sézary cells are involved in regulation of apoptosis, cell proliferation, and T-cell differentiation.…”

Coding Microsatellite Frameshift Mutations Accumulate in Atherosclerotic Carotid Artery Lesions: Evaluation of 26 Cases and Literature Review

“…We hypothesized that a lesion-promoting functional significance of a certain microsatellite mutation would be reflected by an accelerated outgrowth of the affected cell, which should result in a higher likelihood of the mutation to be detectable in the resulting lesion. Accordingly, we hypothesized that an increased frequency of a certain microsatellite mutation may suggest functional relevance during plaque development, according to models that have convincingly demonstrated associations in cancers with MMR deficiency (10)(11)(12)(13)(14).…”