scholarly journals 5-Fluorouracil treatment induces characteristic T>G mutations in human cancer

2019 ◽  
Author(s):  
Sharon Christensen ◽  
Bastiaan Van der Roest ◽  
Nicolle Besselink ◽  
Roel Janssen ◽  
Sander Boymans ◽  
...  
Keyword(s):  
Whole Genome Sequencing ◽  
Genome Sequencing ◽  
Human Cancer ◽  
Whole Genome Sequencing Data ◽  
Tumor Evolution ◽  
Whole Genome ◽  
Sequencing Analysis ◽  
Breast Cancer Patients ◽  
Sequencing Data ◽  
Nucleotide Synthesis

Abstract5-Fluorouracil (5-FU) is a chemotherapeutic drug component that is commonly used for the treatment of solid cancers. It is proposed that 5-FU possesses anticancer properties via the interference with nucleotide synthesis and incorporation into DNA. As both mechanisms may have a mutational impact on both surviving tumor and healthy cells, we treated intestinal organoids with 5-FU followed by whole genome sequencing analysis and uncovered a highly characteristic mutational pattern that is dominated by T>G substitutions in a CTT context. Analysis of tumor whole genome sequencing data confirmed that this signature can also be identified in vivo in colorectal and breast cancer patients that have undergone treatment with 5-FU. We also found that more 5-FU mutations are induced in TP53 null backgrounds which may be of clinical relevance. Taken together, our results demonstrate that 5-FU is mutagenic and may drive tumor evolution and increase the risk of secondary malignancies. Furthermore, the identified signature shows a strong resemblance to COSMIC signature 17, the hallmark signature of treatment-naive esophageal and gastric tumors, which indicates that distinct endogenous and exogenous triggers can converge onto highly similar mutational signatures.

scholarly journals Whole-genome sequencing analysis of clozapine-induced myocarditis

2021 ◽  
Author(s):  
Ankita Narang ◽  
Paul Lacaze ◽  
Kathlyn Ronaldson ◽  
John McNeil ◽  
Mahesh Jayaram ◽  
...  
Keyword(s):  
Whole Genome Sequencing ◽  
Genome Sequencing ◽  
Genome Wide Association Study ◽  
Copy Number Variants ◽  
Whole Genome Sequencing Data ◽  
Whole Genome ◽  
Sequencing Analysis ◽  
Sequencing Data ◽  
Dna Variation ◽  
Rare Genetic Variants

One of the concerns limiting the use of clozapine in schizophrenia treatment is the risk of rare but potentially fatal myocarditis. Our previous genome-wide association study and human leucocyte antigen analyses identified putative loci associated with clozapine-induced myocarditis. However, the contribution of DNA variation in cytochrome P450 genes, copy number variants and rare deleterious variants have not been investigated. We explored these unexplored classes of DNA variation using whole-genome sequencing data from 25 cases with clozapine-induced myocarditis and 25 demographically-matched clozapine-tolerant control subjects. We identified 15 genes based on rare variant gene-burden analysis (MLLT6, CADPS, TACC2, L3MBTL4, NPY, SLC25A21, PARVB, GPR179, ACAD9, NOL8, C5orf33, FAM127A, AFDN, SLC6A11, PXDN) nominally associated (p<0.05) with clozapine-induced myocarditis. Of these genes, 13 were expressed in human myocardial tissue. Although independent replication of these findings is required, our study provides preliminary insights into the potential role of rare genetic variants in susceptibility to clozapine-induced myocarditis.

scholarly journals Comprehensive analysis of chromothripsis in 2,658 human cancers using whole-genome sequencing

2018 ◽  
Author(s):  
Isidro Cortés-Ciriano ◽  
June-Koo Lee ◽  
Ruibin Xi ◽  
Dhawal Jain ◽  
Youngsook L. Jung ◽  
...  
Keyword(s):  
Whole Genome Sequencing ◽  
Genome Sequencing ◽  
Copy Number ◽  
Human Cancer ◽  
Whole Genome Sequencing Data ◽  
Whole Genome ◽  
Sequencing Data ◽  
End Joining ◽  
Cancer Types ◽  
Non Homologous End Joining

SummaryChromothripsis is a newly discovered mutational phenomenon involving massive, clustered genomic rearrangements that occurs in cancer and other diseases. Recent studies in cancer suggest that chromothripsis may be far more common than initially inferred from low resolution DNA copy number data. Here, we analyze the patterns of chromothripsis across 2,658 tumors spanning 39 cancer types using whole-genome sequencing data. We find that chromothripsis events are pervasive across cancers, with a frequency of >50% in several cancer types. Whereas canonical chromothripsis profiles display oscillations between two copy number states, a considerable fraction of the events involves multiple chromosomes as well as additional structural alterations. In addition to non-homologous end-joining, we detect signatures of replicative processes and templated insertions. Chromothripsis contributes to oncogene amplification as well as to inactivation of genes such as mismatch-repair related genes. These findings show that chromothripsis is a major process driving genome evolution in human cancer.

scholarly journals Validation of HER2 status in whole genome sequencing data of breast cancers with AI-driven, ploidy-corrected approach

2021 ◽  
Author(s):  
Marzena Wojtaszewska ◽  
Rafal Stepien ◽  
Alicja Wozna ◽  
Maciej Piernik ◽  
Maciej Dabrowski ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Whole Genome Sequencing ◽  
Genome Sequencing ◽  
Cancer Diagnostics ◽  
Her2 Status ◽  
Whole Genome Sequencing Data ◽  
Whole Genome ◽  
Breast Cancer Patients ◽  
Sequencing Data ◽  
Genomic Context

The HER2 protein overexpression is one of the most significant biomarkers for breast cancer diagnostics, prediction, and prognostics. The availability of HER2-inhibitors in routine clinical practice directly translates into a diagnostic need for precise and robust marker identification. At the brink of the genomic era, multigene next-generation sequencing methodologies slowly take over the field of single-biomarker molecular and cytogenetic tests. However, copy number alterations such as amplification of the HER2-coding ERBB2 gene, are certainly harder to validate as an NGS biomarker than simple SNV mutations. They are characterized by several compound genomic factors i.a. structural heterogeneity, dependence on chromosome count and genomic context of ploidy. In our study, we tested the approach of using whole genome sequencing instead of NGS panels to robustly and accurately determine HER2 status in clinical setup. Based on the large dataset of 877 breast cancer patients' genomes with curated clinical data and a machine learning approach for optimization of an unbiased diagnostic classifier, we provide a reliable algorithm of HER2 status assessment.

scholarly journals 5-Fluorouracil treatment induces characteristic T>G mutations in human cancer

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Sharon Christensen ◽  
Bastiaan Van der Roest ◽  
Nicolle Besselink ◽  
Roel Janssen ◽  
Sander Boymans ◽  
...  
Keyword(s):  
Human Cancer ◽  
Whole Genome Sequencing Data ◽  
Tumor Evolution ◽  
Breast Cancer Patients ◽  
Sequencing Data ◽  
Nucleotide Synthesis ◽  
Mutational Pattern ◽  
Treatment Naïve ◽  
Strong Resemblance

Abstract 5-Fluorouracil (5-FU) is a chemotherapeutic drug commonly used for the treatment of solid cancers. It is proposed that 5-FU interferes with nucleotide synthesis and incorporates into DNA, which may have a mutational impact on both surviving tumor and healthy cells. Here, we treat intestinal organoids with 5-FU and find a highly characteristic mutational pattern that is dominated by T>G substitutions in a CTT context. Tumor whole genome sequencing data confirms that this signature is also identified in vivo in colorectal and breast cancer patients who have received 5-FU treatment. Taken together, our results demonstrate that 5-FU is mutagenic and may drive tumor evolution and increase the risk of secondary malignancies. Furthermore, the identified signature shows a strong resemblance to COSMIC signature 17, the hallmark signature of treatment-naive esophageal and gastric tumors, which indicates that distinct endogenous and exogenous triggers can converge onto highly similar mutational signatures.

scholarly journals Defects in 8-oxo-guanine repair pathway cause high frequency of C > A substitutions in neuroblastoma

2021 ◽  
Vol 118 (36) ◽  
pp. e2007898118
Author(s):  
Marlinde L. van den Boogaard ◽  
Rurika Oka ◽  
Anne Hakkert ◽  
Linda Schild ◽  
Marli E. Ebus ◽  
...  
Keyword(s):  
Whole Genome Sequencing ◽  
Genome Sequencing ◽  
High Frequency ◽  
Neuroblastoma Cells ◽  
Whole Genome Sequencing Data ◽  
Induction Treatment ◽  
Tumor Evolution ◽  
Copy Number Loss ◽  
Whole Genome ◽  
Sequencing Data

Neuroblastomas are childhood tumors with frequent fatal relapses after induction treatment, which is related to tumor evolution with additional genomic events. Our whole-genome sequencing data analysis revealed a high frequency of somatic cytosine > adenine (C > A) substitutions in primary neuroblastoma tumors, which was associated with poor survival. We showed that increased levels of C > A substitutions correlate with copy number loss (CNL) of OGG1 or MUTYH. Both genes encode DNA glycosylases that recognize 8-oxo-guanine (8-oxoG) lesions as a first step of 8-oxoG repair. Tumor organoid models with CNL of OGG1 or MUTYH show increased 8-oxoG levels compared to wild-type cells. We used CRISPR-Cas9 genome editing to create knockout clones of MUTYH and OGG1 in neuroblastoma cells. Whole-genome sequencing of single-cell OGG1 and MUTYH knockout clones identified an increased accumulation of C > A substitutions. Mutational signature analysis of these OGG1 and MUTYH knockout clones revealed enrichment for C > A signatures 18 and 36, respectively. Clustering analysis showed that the knockout clones group together with tumors containing OGG1 or MUTYH CNL. In conclusion, we demonstrate that defects in 8-oxoG repair cause accumulation of C > A substitutions in neuroblastoma, which contributes to mutagenesis and tumor evolution.

scholarly journals Development and evaluation of an outbreak surveillance system integrating whole genome sequencing data for non-typhoidal Salmonella in London and South East of England, 2016-17

2021 ◽  
pp. 1-26
Author(s):  
Karthik Paranthaman ◽  
Piers Mook ◽  
Daniele Curtis ◽  
Edward-Wynne Evans ◽  
Emma Crawley-Boevey ◽  
...  
Keyword(s):  
Whole Genome Sequencing ◽  
Genome Sequencing ◽  
Surveillance System ◽  
Whole Genome Sequencing Data ◽  
Whole Genome ◽  
Sequencing Data

scholarly journals Whole genome sequencing reveals high differentiation, low levels of genetic diversity and short runs of homozygosity among Swedish wels catfish

Heredity ◽  
2021 ◽  
Author(s):  
Axel Jensen ◽  
Mette Lillie ◽  
Kristofer Bergström ◽  
Per Larsson ◽  
Jacob Höglund
Keyword(s):  
Genetic Diversity ◽  
Whole Genome Sequencing ◽  
Genome Sequencing ◽  
Whole Genome Sequencing Data ◽  
Peripheral Populations ◽  
Whole Genome ◽  
Runs Of Homozygosity ◽  
Sequencing Data ◽  
Isolated Populations ◽  
Native Populations

AbstractThe use of genetic markers in the context of conservation is largely being outcompeted by whole-genome data. Comparative studies between the two are sparse, and the knowledge about potential effects of this methodology shift is limited. Here, we used whole-genome sequencing data to assess the genetic status of peripheral populations of the wels catfish (Silurus glanis), and discuss the results in light of a recent microsatellite study of the same populations. The Swedish populations of the wels catfish have suffered from severe declines during the last centuries and persists in only a few isolated water systems. Fragmented populations generally are at greater risk of extinction, for example due to loss of genetic diversity, and may thus require conservation actions. We sequenced individuals from the three remaining native populations (Båven, Emån, and Möckeln) and one reintroduced population of admixed origin (Helge å), and found that genetic diversity was highest in Emån but low overall, with strong differentiation among the populations. No signature of recent inbreeding was found, but a considerable number of short runs of homozygosity were present in all populations, likely linked to historically small population sizes and bottleneck events. Genetic substructure within any of the native populations was at best weak. Individuals from the admixed population Helge å shared most genetic ancestry with the Båven population (72%). Our results are largely in agreement with the microsatellite study, and stresses the need to protect these isolated populations at the northern edge of the distribution of the species.

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