Comprehensive analysis of indels in whole-genome microsatellite regions and microsatellite instability across 21 cancer types

Fujimoto, Akihiro; Fujita, Masashi; Hasegawa, Takanori; Wong, Jing Hao; Maejima, Kazuhiro; Oku-Sasaki, Aya; Nakano, Kaoru; Shiraishi, Yuichi; Miyano, Satoru; Yamamoto, Go; Akagi, Kiwamu; Imoto, Seiya; Nakagawa, Hidewaki

doi:10.1101/gr.255026.119

Cited by 67 publications

(56 citation statements)

References 57 publications

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“…In accordance with previous large-scale sequencing efforts in CRC, MSI was evident in our WGS data as the MSI tumors harbored the most indels in repeat regions (Supplementary Table 3). [8][9][10]12,28,29,31,33,34,41,43,44 Instability of tetranucleotide repeats was observed in all 18 MSI CRCs as anticipated (Figure 1A). 14,20,23 Indels in CRCs exhibiting MSI have been reported to occur most prominently in mononucleotide repeats, but also in other short repeats.…”

Section: Discussionsupporting

confidence: 79%

“…Largescale sequencing studies on CRC have confirmed MSI CRCs to be a distinct subset of CRC with a large number of mutations, especially indels in their short tandem repeats. [8][9][10]12,28,29,31,33,34,41 To our knowledge, however, EMAST has not been studied on the genomewide level before. Hence, in order to gain a comprehensive picture of tetranucleotide repeat instability in CRC, we utilized WGS data from 227 MSS CRCs, 18 MSI CRCs, 3 POLE-mutated CRCs, and their respective normal samples.…”

Section: Discussionmentioning

confidence: 99%

“…[8][9][10]12,[28][29][30][31][32][33][34][35][36][37][38][39][40][41] These studies have confirmed MSI CRCs as a clearly distinct subset of CRCs, especially in terms of the number of indels in short repeated regions. [8][9][10]12,28,29,31,33,34,41 However, none of these large-scale studies have had a particular focus on tetranucleotide repeats. In order to comprehensively characterize tetranucleotide repeat instability on a genome-wide level, we utilized whole genome sequencing (WGS) data from 227 MSS CRCs, 18 MSI CRCs, 3 POLEmutated CRCs, and their respective normal samples.…”

Section: Introductionmentioning

confidence: 95%

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No evidence of EMAST in whole genome sequencing data from 248 colorectal cancers

Kondelin

Martin

Katainen

et al. 2021

Genes Chromosomes & Cancer

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Microsatellite instability (MSI) is caused by defective DNA mismatch repair (MMR), and manifests as accumulation of small insertions and deletions (indels) in short tandem repeats of the genome. Another form of repeat instability, elevated microsatellite alterations at selected tetranucleotide repeats (EMAST), has been suggested to occur in 50% to 60% of colorectal cancer (CRC), of which approximately one quarter are accounted for by MSI. Unlike for MSI, the criteria for defining EMAST is not consensual. EMAST CRCs have been suggested to form a distinct subset of CRCs that has been linked to a higher tumor stage, chronic inflammation, and poor prognosis. EMAST CRCs not exhibiting MSI have been proposed to show instability of di‐ and trinucleotide repeats in addition to tetranucleotide repeats, but lack instability of mononucleotide repeats. However, previous studies on EMAST have been based on targeted analysis of small sets of marker repeats, often in relatively few samples. To gain insight into tetranucleotide instability on a genome‐wide level, we utilized whole genome sequencing data from 227 microsatellite stable (MSS) CRCs, 18 MSI CRCs, 3 POLE‐mutated CRCs, and their corresponding normal samples. As expected, we observed tetranucleotide instability in all MSI CRCs, accompanied by instability of mono‐, di‐, and trinucleotide repeats. Among MSS CRCs, some tumors displayed more microsatellite mutations than others as a continuum, and no distinct subset of tumors with the previously proposed molecular characters of EMAST could be observed. Our results suggest that tetranucleotide repeat mutations in non‐MSI CRCs represent stochastic mutation events rather than define a distinct CRC subclass.

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Section: Discussionsupporting

confidence: 79%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 95%

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No evidence of EMAST in whole genome sequencing data from 248 colorectal cancers

Kondelin

Martin

Katainen

et al. 2021

Genes Chromosomes & Cancer

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“…Meanwhile, however, researchers have yet to account for simple sequence repeats with repeated units of dinucleotides (SRs), which are somewhat similar to HPs and are frequently observed in longer barcodes (e.g., 8–12 mer). In this reason, SR is another possible source of errors in PCR amplification and sequencing steps as previously reported [ 24 ].…”

Section: Introductionmentioning

confidence: 84%

Development of a program for in silico optimized selection of oligonucleotide-based molecular barcodes

et al. 2021

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Short DNA oligonucleotides (~4 mer) have been used to index samples from different sources, such as in multiplex sequencing. Presently, longer oligonucleotides (8–12 mer) are being used as molecular barcodes with which to distinguish among raw DNA molecules in many high-tech sequence analyses, including low-frequent mutation detection, quantitative transcriptome analysis, and single-cell sequencing. Despite some advantages of using molecular barcodes with random sequences, such an approach, however, makes it impossible to know the exact sequences used in an experiment and can lead to inaccurate interpretation due to misclustering of barcodes arising from the occurrence of unexpected mutations in the barcodes. The present study introduces a tool developed for selecting an optimal barcode subset during molecular barcoding. The program considers five barcode factors: GC content, homopolymers, simple sequence repeats with repeated units of dinucleotides, Hamming distance, and complementarity between barcodes. To evaluate a selected barcode set, penalty scores for the factors are defined based on their distributions observed in random barcodes. The algorithm employed in the program comprises two steps: i) random generation of an initial set and ii) optimal barcode selection via iterative replacement. Users can execute the program by inputting barcode length and the number of barcodes to be generated. Furthermore, the program accepts a user’s own values for other parameters, including penalty scores, for advanced use, allowing it to be applied in various conditions. In many test runs to obtain 100000 barcodes with lengths of 12 nucleotides, the program showed fast performance, efficient enough to generate optimal barcode sequences with merely the use of a desktop PC. We also showed that VFOS has comparable performance, flexibility in program running, consideration of simple sequence repeats, and fast computation time in comparison with other two tools (DNABarcodes and FreeBarcodes). Owing to the versatility and fast performance of the program, we expect that many researchers will opt to apply it for selecting optimal barcode sets during their experiments, including next-generation sequencing.

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“…Annotation of UTRs was performed using ANNOVAR (Wang et al 2010). We also annotated insertions for micro-satellites using an in-house comprehensive list of microsatellites (Fujimoto et al 2020). For ltering out insertions which were possibly false positives due to misalignments of short reads, we applied a ltering strategy similar to the one used in our previous study (Wong et al 2019).…”

Section: Filtering Insertion Candidates Based On Their Annotationsmentioning

confidence: 99%

Characterization of intermediate-sized insertions using whole genome sequencing data and analysis of their functional impacts on gene expression

Ashouri

Wong

Nakagawa

et al. 2021

Preprint

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Intermediate-sized insertions are one of the structural variants contributing to genome diversity. However, due to technical difficulties in identifying them, their importance in disease pathogenicity and gene expression regulation remains unclear. We used whole-genome sequencing data of 174 Japanese samples to characterize intermediate-sized insertions using a highly-accurate insertion calling method (IMSindel software and joint-call recovery) and obtained a catalogue of 4,254 insertions. We constructed an imputation panel comprising of insertions and SNVs from all samples, and conducted imputation of intermediate-sized insertions for 82 publicly-available Japanese samples. Imputation accuracy, evaluated using Nanopore long-read sequencing data, was 97%. Subsequent eQTL analysis predicted 128 (~ 3.0%) insertions as causative for gene expression level changes. Enrichment analysis of causal insertions for genome regulatory elements showed significant associations with CTCF-binding sites, super-enhancers, and promoters. Among 17 causal insertions found in the same causal set with GWAS hits, there were insertions associated with changes in expression of cancer-related genes such as BRCA1, ZNF222, and ABCB10. Analysis of insertions sequences revealed that 461 insertions were short tandem duplications frequently found in early replicating regions of genome. Furthermore, comparison of functional importance of intermediate-sized insertions with that of intermediate-sized deletions detected in the same sample set in our previous study showed that insertions were more frequent in genic regions, and proportion of functional candidates was smaller in insertions. Here, we characterize a high-confidence set of intermediate-sized insertions and indicate their importance in gene expression regulation. Our results emphasize the importance of considering intermediate-sized insertions in trait association studies.

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Comprehensive analysis of indels in whole-genome microsatellite regions and microsatellite instability across 21 cancer types

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Cited by 67 publications

References 57 publications

No evidence of EMAST in whole genome sequencing data from 248 colorectal cancers

No evidence of EMAST in whole genome sequencing data from 248 colorectal cancers

Development of a program for in silico optimized selection of oligonucleotide-based molecular barcodes

Characterization of intermediate-sized insertions using whole genome sequencing data and analysis of their functional impacts on gene expression

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