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Variation in mutation rate and direction between tetranucleotide STR loci in human colorectal carcinomas
P Hoff-Olsen1, G I Meling, B Olaisen
1Institute of Forensic Medicine, University of Oslo, Rikshospitalet, Norway. per.hoff-olsen@labmed.uio.no
Abstract:
Replication error (RER) is defined as mutation events in repetitive DNA segments. To investigate further the RER phenomenon and reveal any differences in mutation outcome between different short tandem repeat (STR) loci, we have investigated the somatic mutation rate and the size distribution of new tumour alleles in four tetranucleotide STRs in a large material of unselected colorectal adenocarcinomas. DNA was extracted from the blood and carcinomas of 217 patients. All blood/tumour pairs were analysed using the STRs HUMTHO1, HUMFES/FPS, HUMVWA31/A and HUMF13A1. Mutations are detected at all four loci. There are substantial differences in mutation rate and mutation direction (i.e. expansion versus contraction) between different STR loci. In all four STRs, the majority of events represent gain or loss of a single repeat. Almost all new tumour alleles correspond to known alleles in a population database, indicating that these are also composed of integers of the four base pair repeat. There is no statistically significant size bias in the mutating alleles as compared to the allelic distribution in the population database.
Insights
Replication error (RER) mutations in short tandem repeat (STR) loci differ significantly in colorectal cancers. Most new tumor alleles involve single repeat changes, with no significant size bias observed across STRs.
Area of Science:
- Genetics
- Cancer Research
- Molecular Biology
Background:
- Replication error (RER) involves mutation events within repetitive DNA segments.
- Understanding RER is crucial for cancer research, particularly in colorectal adenocarcinomas.
- Investigating differences in mutation outcomes across various short tandem repeat (STR) loci is essential.
Purpose of the Study:
- To investigate the somatic mutation rate and new tumor allele size distribution in four tetranucleotide STRs.
- To reveal differences in mutation outcomes between distinct STR loci.
- To analyze RER in a large cohort of unselected colorectal adenocarcinomas.
Main Methods:
- DNA extraction from blood and tumor samples of 217 colorectal adenocarcinoma patients.
- Analysis of four tetranucleotide STR loci: HUMTHO1, HUMFES/FPS, HUMVWA31/A, and HUMF13A1.
- Comparison of mutation rates and allele size distributions between blood and tumor DNA.
Main Results:
- Mutations were detected at all four analyzed STR loci.
- Substantial differences in mutation rates and directions (expansion vs. contraction) were observed between STR loci.
- The majority of RER events involved the gain or loss of a single repeat unit.
- New tumor alleles predominantly corresponded to known population alleles, composed of integer repeat units.
- No statistically significant size bias was found in mutating alleles compared to population allele distribution.
Conclusions:
- Significant locus-specific variations exist in somatic mutation rates and outcomes for STRs during colorectal carcinogenesis.
- RER in colorectal adenocarcinomas primarily results in minor alterations (single repeat changes) at STR loci.
- The observed RER patterns do not introduce significant size bias in tumor alleles relative to the general population.