SomaticSignatures: inferring mutational signatures from single-nucleotide variants: Fig. 1.

Mutational signatures are patterns in the occurrence of somatic single nucleotide variants (SNVs) that can reflect underlying mutational processes. The SomaticSignatures package provides flexible, interoperable, and easy-to-use tools that identify such signatures in cancer sequencing data. It facilitates large-scale, cross-dataset estimation of mutational signatures, implements existing methods for pattern decomposition, supports extension through user-defined methods and integrates with Bioconductor workflows. The R package SomaticSignatures is available as part of the Bioconductor project (R Core Team, 2014; Gentleman et al., 2004). Its documentation provides additional details on the methodology and demonstrates applications to biological datasets.

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Transcription-coupled repair in Drosophila melanogaster is independent of the mismatch repair pathway

10.1101/2020.04.07.029033 ◽

2020 ◽

Cited By ~ 1

Author(s):

Lauri Törmä ◽

Claire Burny ◽

Viola Nolte ◽

Kirsten-André Senti ◽

Christian Schlötterer

Keyword(s):

Drosophila Melanogaster ◽

Mismatch Repair ◽

Repair Pathway ◽

Single Nucleotide Variants ◽

Mutational Signatures ◽

Data Set ◽

Single Nucleotide ◽

Additional Exon ◽

Recent Demonstration ◽

Transcription Coupled Repair

AbstractTranscription-coupled repair (TCR) removes base damage on the transcribed strand of a gene to ensure a quick resumption of transcription. Based on the absence of key enzymes for TCR and empirical evidence, TCR was thought to be missing in Drosophila melanogaster. The recent demonstration of TCR in S2 cells raises the question about the involved genes. Since the mismatch repair (MMR) pathway serves a central role in TCR, at least in Escherichia coli, we studied the mutational signatures in flies with a deletion of the MMR gene spellchecker1 (spel1), a MutS homolog. Whole-genome sequencing of mutation accumulation (MA) lines obtained 7,345 new single nucleotide variants (SNVs) and 5,672 short indel mutations, the largest data set from an MA study in D. melanogaster. Based on the observed mutational strand-asymmetries, we conclude that TCR is still active without spel1. The operation of TCR is further confirmed by a negative association between mutation rate and gene expression. Surprisingly, the TCR signatures are detected for introns, but not for exons. We propose that an additional exon-specific repair pathway is masking the signature of TCR. This study presents the first step towards understanding the molecular basis of TCR in Drosophila melanogaster.

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Variant profiling of colorectal adenomas from three patients of two families with MSH3-related adenomatous polyposis

PLoS ONE ◽

10.1371/journal.pone.0259185 ◽

2021 ◽

Vol 16 (11) ◽

pp. e0259185

Author(s):

Claudia Perne ◽

Sophia Peters ◽

Maria Cartolano ◽

Sukanya Horpaopan ◽

Christina Grimm ◽

...

Keyword(s):

Colorectal Adenomas ◽

Colorectal Carcinogenesis ◽

Adenomatous Polyposis ◽

Single Nucleotide Variants ◽

Sequence Context ◽

Mutational Signatures ◽

Driver Genes ◽

Single Nucleotide ◽

Whole Exome ◽

Mutational Pattern

The spectrum of somatic genetic variation in colorectal adenomas caused by biallelic pathogenic germline variants in the MSH3 gene, was comprehensively analysed to characterise mutational signatures and identify potential driver genes and pathways of MSH3-related tumourigenesis. Three patients from two families with MSH3-associated polyposis were included. Whole exome sequencing of nine adenomas and matched normal tissue was performed. The amount of somatic variants in the MSH3-deficient adenomas and the pattern of single nucleotide variants (SNVs) was similar to sporadic adenomas, whereas the fraction of small insertions/deletions (indels) (21–42% of all small variants) was significantly higher. Interestingly, pathogenic somatic APC variants were found in all but one adenoma. The vast majority (12/13) of these were di-, tetra-, or penta-base pair (bp) deletions. The fraction of APC indels was significantly higher than that reported in patients with familial adenomatous polyposis (FAP) (p < 0.01) or in sporadic adenomas (p < 0.0001). In MSH3-deficient adenomas, the occurrence of APC indels in a repetitive sequence context was significantly higher than in FAP patients (p < 0.01). In addition, the MSH3-deficient adenomas harboured one to five (recurrent) somatic variants in 13 established or candidate driver genes for early colorectal carcinogenesis, including ACVR2A and ARID genes. Our data suggest that MSH3-related colorectal carcinogenesis seems to follow the classical APC-driven pathway. In line with the specific function of MSH3 in the mismatch repair (MMR) system, we identified a characteristic APC mutational pattern in MSH3-deficient adenomas, and confirmed further driver genes for colorectal tumourigenesis.

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Discovery of Cancer Driver Long Noncoding RNAs across 1112 Tumour Genomes: New Candidates and Distinguishing Features

10.1101/065805 ◽

2016 ◽

Cited By ~ 2

Author(s):

Andrés Lanzós ◽

Joana Carlevaro-Fita ◽

Loris Mularoni ◽

Ferran Reverter ◽

Emilio Palumbo ◽

...

Keyword(s):

Noncoding Rnas ◽

Long Noncoding Rnas ◽

Single Nucleotide Variants ◽

Mutational Signatures ◽

Single Nucleotide ◽

Cancer Driver ◽

Cancer Types ◽

Distinguishing Features ◽

Genome Projects ◽

Excess Load

AbstractLong noncoding RNAs (lncRNAs) represent a vast unexplored genetic space that may hold missing drivers of tumourigenesis, but few such “driver lncRNAs” are known. Until now, they have been discovered through changes in expression, leading to problems in distinguishing between causative roles and passenger effects. We here present a different approach for driver lncRNA discovery using mutational patterns in tumour DNA. Our pipeline, ExInAtor, identifies genes with excess load of somatic single nucleotide variants (SNVs) across panels of tumour genomes. Heterogeneity in mutational signatures between cancer types and individuals is accounted for using a simple local trinucleotide background model, which yields high precision and low computational demands. We use ExInAtor to predict drivers from the GENCODE annotation across 1112 entire genomes from 23 cancer types. Using a stratified approach, we identify 15 high-confidence candidates: 9 novel and 6 known cancer-related genes, including MALAT1, NEAT1 and SAMMSON. Both known and novel driver lncRNAs are distinguished by elevated gene length, evolutionary conservation and expression. We have presented a first catalogue of mutated lncRNA genes driving cancer, which will grow and improve with the application of ExInAtor to future tumour genome projects.

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Faculty Opinions recommendation of Phylogenetic and physicochemical analyses enhance the classification of rare nonsynonymous single nucleotide variants in type 1 and 2 long-QT syndrome.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.717960422.793463950 ◽

2012 ◽

Author(s):

Jeffrey Noebels ◽

Tara Klassen

Keyword(s):

Long Qt Syndrome ◽

Single Nucleotide Variants ◽

Long Qt ◽

Single Nucleotide ◽

Qt Syndrome

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Single-Nucleotide Variants in microRNAs Sequences or in their Target Genes Might Influence the Risk of Epilepsy: A Review

Cellular and Molecular Neurobiology ◽

10.1007/s10571-021-01058-7 ◽

2021 ◽

Author(s):

Renata Parissi Buainain ◽

Matheus Negri Boschiero ◽

Bruno Camporeze ◽

Paulo Henrique Pires de Aguiar ◽

Fernando Augusto Lima Marson ◽

...

Keyword(s):

Target Genes ◽

Single Nucleotide Variants ◽

Single Nucleotide

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Combination of Genome-Wide Polymorphisms and Copy Number Variations of Pharmacogenes in Koreans

Journal of Personalized Medicine ◽

10.3390/jpm11010033 ◽

2021 ◽

Vol 11 (1) ◽

pp. 33

Author(s):

Nayoung Han ◽

Jung Mi Oh ◽

In-Wha Kim

Keyword(s):

Copy Number ◽

Genome Wide Association Study ◽

Copy Number Gain ◽

Copy Number Variations ◽

Gene Gain ◽

Single Nucleotide Variants ◽

Single Nucleotide ◽

Haplotype Blocks ◽

Genome Wide ◽

Control And Prevention

For predicting phenotypes and executing precision medicine, combination analysis of single nucleotide variants (SNVs) genotyping with copy number variations (CNVs) is required. The aim of this study was to discover SNVs or common copy CNVs and examine the combined frequencies of SNVs and CNVs in pharmacogenes using the Korean genome and epidemiology study (KoGES), a consortium project. The genotypes (N = 72,299) and CNV data (N = 1000) were provided by the Korean National Institute of Health, Korea Centers for Disease Control and Prevention. The allele frequencies of SNVs, CNVs, and combined SNVs with CNVs were calculated and haplotype analysis was performed. CYP2D6 rs1065852 (c.100C>T, p.P34S) was the most common variant allele (48.23%). A total of 8454 haplotype blocks in 18 pharmacogenes were estimated. DMD ranked the highest in frequency for gene gain (64.52%), while TPMT ranked the highest in frequency for gene loss (51.80%). Copy number gain of CYP4F2 was observed in 22 subjects; 13 of those subjects were carriers with CYP4F2*3 gain. In the case of TPMT, approximately one-half of the participants (N = 308) had loss of the TPMT*1*1 diplotype. The frequencies of SNVs and CNVs in pharmacogenes were determined using the Korean cohort-based genome-wide association study.

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Unsuspected somatic mosaicism for FBN1 gene contributes to Marfan syndrome

Genetics in Medicine ◽

10.1038/s41436-020-01078-6 ◽

2021 ◽

Author(s):

Pauline Arnaud ◽

Hélène Morel ◽

Olivier Milleron ◽

Laurent Gouya ◽

Christine Francannet ◽

...

Keyword(s):

Marfan Syndrome ◽

Somatic Mosaicism ◽

Variant Calling ◽

Copy Number Variations ◽

Pathogenic Variant ◽

Single Nucleotide Variants ◽

Bioinformatics Analyses ◽

Single Nucleotide ◽

Fbn1 Gene ◽

Pathogenic Variants

Abstract Purpose Individuals with mosaic pathogenic variants in the FBN1 gene are mainly described in the course of familial screening. In the literature, almost all these mosaic individuals are asymptomatic. In this study, we report the experience of our team on more than 5,000 Marfan syndrome (MFS) probands. Methods Next-generation sequencing (NGS) capture technology allowed us to identify five cases of MFS probands who harbored a mosaic pathogenic variant in the FBN1 gene. Results These five sporadic mosaic probands displayed classical features usually seen in Marfan syndrome. Combined with the results of the literature, these rare findings concerned both single-nucleotide variants and copy-number variations. Conclusion This underestimated finding should not be overlooked in the molecular diagnosis of MFS patients and warrants an adaptation of the parameters used in bioinformatics analyses. The five present cases of symptomatic MFS probands harboring a mosaic FBN1 pathogenic variant reinforce the fact that apparently asymptomatic mosaic parents should have a complete clinical examination and a regular cardiovascular follow-up. We advise that individuals with a typical MFS for whom no single-nucleotide pathogenic variant or exon deletion/duplication was identified should be tested by NGS capture panel with an adapted variant calling analysis.

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Whole-exome mutational landscape of neuroendocrine carcinomas of the gallbladder

Signal Transduction and Targeted Therapy ◽

10.1038/s41392-020-00412-3 ◽

2021 ◽

Vol 6 (1) ◽

Author(s):

Fatao Liu ◽

Yongsheng Li ◽

Dongjian Ying ◽

Shimei Qiu ◽

Yong He ◽

...

Keyword(s):

Gene Mutations ◽

Large Cell ◽

Molecular Signatures ◽

Single Nucleotide Variants ◽

Oncogenic Signaling ◽

Single Nucleotide ◽

Whole Exome ◽

Deadly Disease ◽

Oncogenic Signaling Pathways ◽

Neuroendocrine Carcinomas

AbstractNeuroendocrine carcinoma (NEC) of the gallbladder (GB-NEC) is a rare but extremely malignant subtype of gallbladder cancer (GBC). The genetic and molecular signatures of GB-NEC are poorly understood; thus, molecular targeting is currently unavailable. In the present study, we applied whole-exome sequencing (WES) technology to detect gene mutations and predicted somatic single-nucleotide variants (SNVs) in 15 cases of GB-NEC and 22 cases of general GBC. In 15 GB-NECs, the C > T mutation was predominant among the 6 types of SNVs. TP53 showed the highest mutation frequency (73%, 11/15). Compared with neuroendocrine carcinomas of other organs, significantly mutated genes (SMGs) in GB-NECs were more similar to those in pulmonary large-cell neuroendocrine carcinomas (LCNECs), with driver roles for TP53 and RB1. In the COSMIC database of cancer-related genes, 211 genes were mutated. Strikingly, RB1 (4/15, 27%) and NAB2 (3/15, 20%) mutations were found specifically in GB-NECs; in contrast, mutations in 29 genes, including ERBB2 and ERBB3, were identified exclusively in GBC. Mutations in RB1 and NAB2 were significantly related to downregulation of the RB1 and NAB2 proteins, respectively, according to immunohistochemical (IHC) data (p values = 0.0453 and 0.0303). Clinically actionable genes indicated 23 mutated genes, including ALK, BRCA1, and BRCA2. In addition, potential somatic SNVs predicted by ISOWN and SomVarIUS constituted 6 primary COSMIC mutation signatures (1, 3, 30, 6, 7, and 13) in GB-NEC. Genes carrying somatic SNVs were enriched mainly in oncogenic signaling pathways involving the Notch, WNT, Hippo, and RTK-RAS pathways. In summary, we have systematically identified the mutation landscape of GB-NEC, and these findings may provide mechanistic insights into the specific pathogenesis of this deadly disease.

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