DNA Replication Stress Generates Distinctive landscapes of DNA copy number alterations and chromosome scale losses
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ABSTRACT:
PROVIDER: PRJNA713395 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR13931500.fastq.gz | Fastqsanger.gz | |||
| SRR13931501.fastq.gz | Fastqsanger.gz | |||
| SRR13931490.fastq.gz | Fastqsanger.gz | |||
| SRR13931491.fastq.gz | Fastqsanger.gz | |||
| SRR13931492.fastq.gz | Fastqsanger.gz |
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Project description:BackgroundA major driver of cancer chromosomal instability is replication stress, the slowing or stalling of DNA replication. How replication stress and genomic instability are connected is not known. Aphidicolin-induced replication stress induces breakages at common fragile sites, but the exact causes of fragility are debated, and acute genomic consequences of replication stress are not fully explored.ResultsWe characterize DNA copy number alterations (CNAs) in single, diploid non-transformed cells, caused by one cell cycle in the presence of either aphidicolin or hydroxyurea. Multiple types of CNAs are generated, associated with different genomic regions and features, and observed copy number landscapes are distinct between aphidicolin and hydroxyurea-induced replication stress. Coupling cell type-specific analysis of CNAs to gene expression and single-cell replication timing analyses pinpointed the causative large genes of the most recurrent chromosome-scale CNAs in aphidicolin. These are clustered on chromosome 7 in RPE1 epithelial cells but chromosome 1 in BJ fibroblasts. Chromosome arm level CNAs also generate acentric lagging chromatin and micronuclei containing these chromosomes.ConclusionsChromosomal instability driven by replication stress occurs via focal CNAs and chromosome arm scale changes, with the latter confined to a very small subset of chromosome regions, potentially heavily skewing cancer genome evolution. Different inducers of replication stress lead to distinctive CNA landscapes providing the opportunity to derive copy number signatures of specific replication stress mechanisms. Single-cell CNA analysis thus reveals the impact of replication stress on the genome, providing insights into the molecular mechanisms which fuel chromosomal instability in cancer.
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Project description:Diploid human cell lines were treated with aphidicolin as a model to see how DNA replication stress affects the genome, by identifying which copy number alterations appear in the first cell cycle. RNAseq was used to see whether there is any link between loci with recurrent CNAs and gene transcription in the genes located there.
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Project description:Infant T-cell Acute Lymphoblastic Leukaemia (iT-ALL) is a very rare and poorly defined entity with a poor prognosis. We assembled a unique series of thirteen cases of infants with T-ALL which allowed us to identify genotypic abnormalities and to investigate prenatal origins. Matched samples (diagnosis/remission) were analysed by SNP-array to identify genomic losses and gains. In three cases, we identified a recurrent somatic chromosome 3 deletion. These losses, confirmed by FISH, result in the complete deletion of MLF1, not previously described in T-ALL. We observed two cases with an 11p13 deletion (LMO2-related), one of which also harboured a deletion of RB1. Another case presented a large 11q14.1-11q23.2 deletion that included ATM and only five patients (38%) showed deletions of CDKN2A/B. Four cases showed NOTCH1 mutations, in one case FBXW7 was the sole mutation and three cases showed alterations in PTEN. MLL rearrangements (MLL-r) were detected in three out of thirteen cases. For three patients, mutations and CNAs could be backtracked to birth using neonatal blood spot DNA, demonstrating an in utero origin. Overall, our data indicates iT-ALL has a diverse but distinctive profile of genotypic abnormalities when compared to T-ALL in older children and adults. Affymetrix SNP6.0 arrays were performed according to the manufacturer's directions on DNA extracted from diagnostic bone marrow or peripheral blood samples. Copy number analyses of Affymetrix SNP6.0 arrays were performed for 13 infant T-ALL samples.
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Project description:Infant T-cell acute lymphoblastic leukaemia (iT-ALL) is a very rare and poorly defined entity with a poor prognosis. We assembled a unique series of 13 infants with T-ALL, which allowed us to identify genotypic abnormalities and to investigate prenatal origins. Matched samples (diagnosis/remission) were analysed by single nucleotide polymorphism-array to identify genomic losses and gains. In three cases, we identified a recurrent somatic deletion on chromosome 3. These losses result in the complete deletion of MLF1 and have not previously been described in T-ALL. We observed two cases with an 11p13 deletion (LMO2-related), one of which also harboured a deletion of RB1. Another case presented a large 11q14·1-11q23·2 deletion that included ATM and only five patients (38%) showed deletions of CDKN2A/B. Four cases showed NOTCH1 mutations; in one case FBXW7 was the sole mutation and three cases showed alterations in PTEN. KMT2A rearrangements (KMT2A-r) were detected in three out of 13 cases. For three patients, mutations and copy number alterations (including deletion of PTEN) could be backtracked to birth using neonatal blood spot DNA, demonstrating an in utero origin. Overall, our data indicates that iT-ALL has a diverse but distinctive profile of genotypic abnormalities when compared to T-ALL in older children and adults.
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Project description:Purpose: To improve clinical outcome of gastric cancer patients, most emphasis is on improving therapeutic regimens, including more extensive surgery as well as (neo)adjuvant chemotherapy. The present study set out to identify, based on DNA copy number profiling, subgroups of patients with different clinical outcomes who thus would qualify for different therapy intensities. Experimental Design: DNA of 206 gastric cancer patients was isolated and analyzed by genome wide array comparative genomic hybridization. DNA copy number profiles were evaluated and correlated to lymph node status and survival. In addition, HSP90 protein expression was analyzed and correlated to survival in 290 gastric cancer patients. Results: Frequent (>20%) DNA copy number gains were observed on chromosomes 1p, 6p, 7p, 7q, 8q, 11q, 12q, 13q, 16p, 16q, 17q, 19p, 19q, 20p, 20q, 21q and 22q, and losses on chromosomes 4p, 4q, 6p, 6q, 9p, 13q and 21q. Lymph node negative gastric cancers showed significantly more losses on chromosomes 5q11.2-q35.1, 10q11.23-21.3 and 14q32.11-q32.33. In addition, losses on 5q11.2-q31.3 and 14q32.11-q32.33 were highly correlated to good clinical outcome, in both lymph node negative and positive gastric cancer patients. Loss of expression of HSP90, located on chromosome 14q32.2, correlated to good survival time. Conclusion: Genome wide DNA copy number profiling allows to identify a subgroup of gastric cancers, marked by losses on chromosomes 5q11.2-q31.3 and 14q32.11-q32.33 that have an excellent clinical outcome after surgery alone, and patients with these tumors are unlikely to benefit from additional intensified therapies. Possible biological mechanisms could involve loss of heat shock proteins, of which the coding genes are located at these chromosomal regions. 183 gastric adenocarcinomas
2012-05-09 | E-GEOD-26389 | biostudies-arrayexpress
Project description:Purpose: To improve clinical outcome of gastric cancer patients, most emphasis is on improving therapeutic regimens, including more extensive surgery as well as (neo)adjuvant chemotherapy. The present study set out to identify, based on DNA copy number profiling, subgroups of patients with different clinical outcomes who thus would qualify for different therapy intensities. Experimental Design: DNA of 206 gastric cancer patients was isolated and analyzed by genome wide array comparative genomic hybridization. DNA copy number profiles were evaluated and correlated to lymph node status and survival. In addition, HSP90 protein expression was analyzed and correlated to survival in 290 gastric cancer patients. Results: Frequent (>20%) DNA copy number gains were observed on chromosomes 1p, 6p, 7p, 7q, 8q, 11q, 12q, 13q, 16p, 16q, 17q, 19p, 19q, 20p, 20q, 21q and 22q, and losses on chromosomes 4p, 4q, 6p, 6q, 9p, 13q and 21q. Lymph node negative gastric cancers showed significantly more losses on chromosomes 5q11.2-q35.1, 10q11.23-21.3 and 14q32.11-q32.33. In addition, losses on 5q11.2-q31.3 and 14q32.11-q32.33 were highly correlated to good clinical outcome, in both lymph node negative and positive gastric cancer patients. Loss of expression of HSP90, located on chromosome 14q32.2, correlated to good survival time. Conclusion: Genome wide DNA copy number profiling allows to identify a subgroup of gastric cancers, marked by losses on chromosomes 5q11.2-q31.3 and 14q32.11-q32.33 that have an excellent clinical outcome after surgery alone, and patients with these tumors are unlikely to benefit from additional intensified therapies. Possible biological mechanisms could involve loss of heat shock proteins, of which the coding genes are located at these chromosomal regions.
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