Similar Datasets
Project description:Sulfur mustard (SM) is a chemical warfare agent that can damage DNA via alkylation and oxidative stress. Because of its genotoxicity, SM is cancerogenic and the progenitor of many chemotherapeutics. Previously, we developed an SM-resistant cell line via chronic exposure of the popular keratinocyte cell line HaCaT to increasing doses of SM over a period of 40 months. In this study, we compared the genomic landscape of the SM-resistant cell line HaCaT/SM to its sensitive parental line HaCaT in order to gain insights into genetic changes associated with continuous alkylation and oxidative stress. We established chromosome numbers by cytogenetics, analyzed DNA copy number changes by means of array Comparative Genomic Hybridization (array CGH), employed the genome-wide chromosome conformation capture technique Hi-C to detect chromosomal translocations, and derived mutational signatures by whole-genome sequencing. We observed that chronic SM exposure eliminated the initially prevailing hypotetraploid cell population in favor of a hyperdiploid one, which contrasts with previous observations that link polyploidization to increased tolerance and adaptability toward genotoxic stress. Furthermore, we observed an accumulation of chromosomal translocations, frequently flanked by DNA copy number changes, which indicates a high rate of DNA double-strand breaks and their misrepair. HaCaT/SM-specific single-nucleotide variants showed enrichment of C > A and T > A transversions and a lower rate of deaminated cytosines in the CpG dinucleotide context. Given the frequent use of HaCaT in toxicology, this study provides a valuable data source with respect to the original genotype of HaCaT and the mutational signatures associated with chronic alkylation and oxidative stress.
| S-EPMC7865644 | biostudies-literature
Project description:In this study, we compared the genomic landscape of resistant cell line HaCaT/SM to its progenitor HaCaT in order to gain insights into genetic changes associated with continuous alkylation and oxidative stress. We established chromosome numbers by cytogenetics, analyzed DNA copy number changes by means of array CGH, employed the genome-wide chromosome conformation capture technique Hi-C to detect chromosomal translocations and defined mutational signatures based on whole genome sequencing data. We observed the SM-associated elimination of the initially prevailing hypotetraploid cell population in favor of a hyperdiploid one, which contrasts with previous observations that link polyploidization to increased tolerance and adaptability towards genotoxic stress. Furthermore, we observed an accumulation of chromosomal translocations, frequently flanked by DNA copy number changes, which indicates a high rate of DNA double strand break misrepair. HaCaT/SM-specific single nucleotide variants showed enrichment of C>A and T>A transversions and a lower rate of deaminated cytosines in the CpG dinucleotide context. Given the frequent use of HaCaT in toxicology this study provides a valuable data source with respect to the original genotype of HaCaT and the mutational signatures associated with chronic alkylation and oxidative stress.
2021-01-27 | GSE162401 | GEO
Project description:In this study, we compared the genomic landscape of resistant cell line HaCaT/SM to its progenitor HaCaT in order to gain insights into genetic changes associated with continuous alkylation and oxidative stress. We established chromosome numbers by cytogenetics, analyzed DNA copy number changes by means of array CGH, employed the genome-wide chromosome conformation capture technique Hi-C to detect chromosomal translocations and defined mutational signatures based on whole genome sequencing data. We observed the SM-associated elimination of the initially prevailing hypotetraploid cell population in favor of a hyperdiploid one, which contrasts with previous observations that link polyploidization to increased tolerance and adaptability towards genotoxic stress. Furthermore, we observed an accumulation of chromosomal translocations, frequently flanked by DNA copy number changes, which indicates a high rate of DNA double strand break misrepair. HaCaT/SM-specific single nucleotide variants showed enrichment of C>A and T>A transversions and a lower rate of deaminated cytosines in the CpG dinucleotide context. Given the frequent use of HaCaT in toxicology this study provides a valuable data source with respect to the original genotype of HaCaT and the mutational signatures associated with chronic alkylation and oxidative stress.
2021-01-27 | GSE162645 | GEO
Project description:In this study, we compared the genomic landscape of resistant cell line HaCaT/SM to its progenitor HaCaT in order to gain insights into genetic changes associated with continuous alkylation and oxidative stress. We established chromosome numbers by cytogenetics, analyzed DNA copy number changes by means of array CGH, employed the genome-wide chromosome conformation capture technique Hi-C to detect chromosomal translocations and defined mutational signatures based on whole genome sequencing data. We observed the SM-associated elimination of the initially prevailing hypotetraploid cell population in favor of a hyperdiploid one, which contrasts with previous observations that link polyploidization to increased tolerance and adaptability towards genotoxic stress. Furthermore, we observed an accumulation of chromosomal translocations, frequently flanked by DNA copy number changes, which indicates a high rate of DNA double strand break misrepair. HaCaT/SM-specific single nucleotide variants showed enrichment of C>A and T>A transversions and a lower rate of deaminated cytosines in the CpG dinucleotide context. Given the frequent use of HaCaT in toxicology this study provides a valuable data source with respect to the original genotype of HaCaT and the mutational signatures associated with chronic alkylation and oxidative stress.
2021-01-27 | GSE162388 | GEO
Project description:Genomic adaptation and mutational patterns in a HaCaT subline resistant to alkylating agents and ionizing radiation
| PRJNA682535 | ENA
Project description:Genomic adaptation and mutational patterns in a HaCaT subline resistant to alkylating agents and ionizing radiation [WGS]
| PRJNA681787 | ENA
Project description:Genomic adaptation and mutational patterns in a HaCaT subline resistant to alkylating agents and ionizing radiation [aCGH]
| PRJNA682537 | ENA
Project description:Genomic adaptation and mutational patterns in a HaCaT subline resistant to alkylating agents and ionizing radiation [Hi-C]
| PRJNA681800 | ENA
Project description:Ionizing radiation (IR) is a mutagen that promotes tumorigenesis in multiple exposure contexts. One severe consequence of IR is the development of second malignant neoplasms (SMNs), a radiotherapy-associated complication in survivors of cancers, particularly pediatric cancers. SMN genomes are poorly characterized, and the influence of genetic background on genotoxin-induced mutations has not been examined. Using our mouse models of SMNs, we performed whole exome sequencing of neoplasms induced by fractionated IR in wild-type and Nf1 mutant mice. Using non-negative matrix factorization, we identified mutational signatures that did not segregate by genetic background or histology. Copy-number analysis revealed recurrent chromosomal alterations and differences in copy number that were background dependent. Pathway analysis identified enrichment of non-synonymous variants in genes responsible for cell assembly and organization, cell morphology, and cell function and maintenance. In this model system, ionizing radiation and Nf1 heterozygosity each exerted distinct influences on the mutational landscape.
| S-EPMC6810600 | biostudies-literature
Project description:Ionizing radiation is a potent carcinogen, inducing cancer through DNA damage. The signatures of mutations arising in human tissues following in vivo exposure to ionizing radiation have not been documented. Here, we searched for signatures of ionizing radiation in 12 radiation-associated second malignancies of different tumour types. Two signatures of somatic mutation characterize ionizing radiation exposure irrespective of tumour type. Compared with 319 radiation-naive tumours, radiation-associated tumours carry a median extra 201 deletions genome-wide, sized 1-100 base pairs often with microhomology at the junction. Unlike deletions of radiation-naive tumours, these show no variation in density across the genome or correlation with sequence context, replication timing or chromatin structure. Furthermore, we observe a significant increase in balanced inversions in radiation-associated tumours. Both small deletions and inversions generate driver mutations. Thus, ionizing radiation generates distinctive mutational signatures that explain its carcinogenic potential.
| S-EPMC5027243 | biostudies-literature