Polarity of mutations in tumor-associated microsatellite instability

Abstract

Many factors have been implicated in influencing the rate of microsatellite mutations, including the length and base composition of the repeat motif, number of repeats, base composition of flanking sequences and, perhaps most importantly, degree of perfection of the repeats. The latter is of clinical relevance, since in both spino-cerebellar ataxia and fragile X syndrome, alleles with imperfect repeats appear to be much more stable than perfect ones. As yet, the relative importance of increased replication slippage and decreased mismatch repair efficiency in the preference of mutations to occur within perfect repeats has not been fully determined. D13S308E is an asymmetric trinucleotide repeat microsatellite with the sequence (CAT)3CAC(CAT)CAC(CAT)2CAC(CAT)CAC(CAT)15, thus containing two parts: an 11-repeat imperfect portion (underlined above) and a 15-repeat perfect one (bold). We sequenced eight new mutant alleles of D13S308E from three human gastric tumors with instability in this and other microsatellites. In all mutations the size variation occurred exclusively in the perfect part of the microsatellite. These results constitute direct evidence that the molecular basis of microsatellite alterations seen in normal cells is similar to those that occur in human tumors with extensive microsatellite instability. The investigation of mechanisms involved in microsatellite mutations has been handicapped by the fact that they are rare events. The microsatellite instability observed in malignant tumors provides us with a useful general system to study these mechanisms.

Correlation Between the Allelic Distribution of STRs in a Finnish Population and Phenotypically Different Gastrointestinal Tumours: A Study Using Four X‐Chromosomal Markers (DXS7423, DXS8377, ARA, DXS101)

“…Analysis of BAT-26 confirmed the MSI-H status of the tumours as detected by the autosomal STRs. The new alleles of the X-STR loci observed in tumours were all within the size range seen in the Finnish population of 103 individuals, which is in agreement with data from previous studies on cancers (HoffOlsen et al 1998;Sturzeneker et al 1998;Di Rienzo et al 1998;Sturzeneker et al 2000). Alterations at at least one X-STR locus were found in 100%, 60% and 25.6% of the MSI-H, MSI-L and MSS phenotypes, respectively.…”

“…Low-frequency MSI (MSI-L) cancers exhibit sporadic new alleles in up to one third of loci examined. Microsatellite instability in tumours has been suggested as a way of studying STR mutations in addition to family trio and population studies (Hoff-Olsen et al 1998;Sturzeneker et al 1998;Di Rienzo et al 1998;Sturzeneker et al 2000). The autosomal loci with the greatest allelic diversity at the population level also show the greatest instability in tumours (Sturzeneker et al 1998).…”

Molecular characterization of allelic variants of (GATA)n microsatellite loci in parthenogenetic lizards Darevskia unisexualis (Lacertidae)

“…First, the variations are polar, occurring at one end of the microsatellite cluster. Polar mutations have previously been described in human minisatellite and microsatellite loci, suggesting the existence of cis-acting elements near the arrays that are involved in complex processes of gene conversion (Jeffreys et al, 1995(Jeffreys et al, , 1997Sturzeneker et al, 1998). Second, the variability of the imperfect 3′-end regions of the Du281 microsatellite cluster was limited to only two types (GATGA-TATA and GATATA) among the 24 alleles sequenced.…”

A genome-wide investigation of microsatellite mismatches and the association with body mass among bird species

“…It has been found that genomes possess a relatively small but significant number of imperfect microsatellites ( Brinkmann et al, 1998 ). Mismatch variation of imperfect microsatellites is critical for their maintenance in the genome and imperfect microsatellites are more stable compared to perfect microsatellites since the former is less prone to slippage mutation ( Sturzeneker et al, 1998 ). Several previous studies have already revealed the genome-wide motif imperfection pattern among species (e.g., Behura & Severson, 2015 ).…”