Complex amplification in human cancer
Ontology highlight
ABSTRACT:
PROVIDER: PRJEB45367 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| LS.bnx.gz | Other | |||
| LS_EXP_REFINEFINAL1.smap | Other | |||
| NGP.bnx.gz | Other | |||
| NGP_EXP_REFINEFINAL1.smap | Other | |||
| TR14.bnx.gz | Other |
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Project description:The mechanisms behind the evolution of complex genomic amplifications in cancer have remained largely unclear. We here identified a type of amplification, termed as “seismic amplificationâ€Â, that is characterized by multiple rearrangements and discontinuous copy number levels. Seismic amplifications occurred in 9.9% (274/2,756) of cases across 38 cancer types and were associated with massively increased copy numbers and elevated oncogene expression. Reconstruction of the development of seismic amplification revealed a stepwise evolution, starting with a chromothripsis event, followed by formation of circular extrachromosomal DNA that subsequently underwent repetitive rounds of circular recombination. The resulting amplicons persisted as extrachromosomal DNA circles or had reintegrated into the genome in overt tumors. Together, our data indicate that the sequential occurrence of chromothripsis and circular recombination drives oncogene amplification and over-expression in a substantial fraction of human malignancies.
| EGAS00001005424 | EGA
Project description:Gene amplification leading to increased oncogene expression or anticancer drug resistance is a frequent event in cancer. Cytogenetic, genomic, and transcriptomic analyses were used to determine the initiating events of gene amplification in a tunable cell culture system developing resistance to chemotherapy. Chromosome shattering (chromothripsis) was found to be a major resistance driver through the production of extra-chromosomal double minutes either directly or subsequent to formation of a homogenous staining region (HSR). Formation and maintenance of double minutes were enhanced by PARP and DNA-PK activities. Double minutes were found to be highly dynamic, undergoing structural evolution to produce increased drug tolerance or re-integration into ectopic chromosomes under conditions of DNA damage. Genome rearrangement profiles produced through acquired drug resistance are similar to human cancer examples with oncogene amplification. Thus, chromothripsis is a driver of genome evolution that enables rapid acquisition of tolerance to altered growth conditions.
2020-09-14 | GSE119979 | GEO
Project description:Gene amplification leading to increased oncogene expression or anticancer drug resistance is a frequent event in cancer. Cytogenetic, genomic, and transcriptomic analyses were used to determine the initiating events of gene amplification in a tunable cell culture system developing resistance to chemotherapy. Chromosome shattering (chromothripsis) was found to be a major resistance driver through the production of extra-chromosomal double minutes either directly or subsequent to formation of a homogenous staining region (HSR). Formation and maintenance of double minutes were enhanced by PARP and DNA-PK activities. Double minutes were found to be highly dynamic, undergoing structural evolution to produce increased drug tolerance or re-integration into ectopic chromosomes under conditions of DNA damage. Genome rearrangement profiles produced through acquired drug resistance are similar to human cancer examples with oncogene amplification. Thus, chromothripsis is a driver of genome evolution that enables rapid acquisition of tolerance to altered growth conditions.
2020-09-23 | GSE119825 | GEO
Project description:Chromothripsis drives DNA amplification in cancer cells developing drug resistance
| PRJNA490891 | ENA
Project description:Chromothripsis drives DNA amplification in cancer cells developing drug resistance
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Project description:In mammalian cells, gene copy number is tightly controlled to maintain gene expression and genome stability. However, a near-universal molecular feature across cancer types is oncogene amplification, which promotes cancer progression by dramatically increasing the copy number and expression of tumor-promoting genes. For example, in tyrosine kinase inhibitor (TKI)-resistant lung adenocarcinoma (LUAD), oncogene amplification occurs in over 40% of patients’ tumors. Despite the prevalence of oncogene amplification in TKI-resistant tumors, the mechanisms facilitating oncogene amplification are not fully understood. Here, we find that LUAD tumors exhibit a unique chromatin signature demarcated by strong CTCF and cohesin deposition in drug-naïve tumors, which correlates with the boundaries of oncogene amplicons in TKI-resistant LUAD cells. Throughout the acquisition of TKI resistance, we identified a global chromatin priming effect, marked by a dynamic increase of H3K27Ac, cohesin loading, and inter-TAD interactions, which occurs before the onset of oncogene amplification. Furthermore, we have identified that the protein METTL7A, which was previously reported to localize to the ER and inner nuclear membrane, has a novel chromatin regulatory function in binding to amplified oncogenes and regulating cohesin recruitment and inter-TAD interactions. Surprisingly, we discovered that METTL7A remodels the chromatin landscape prior to any noticeable oncogene copy number gains. Furthermore, while METTL7A depletion has little effect on drug-naïve cells, METTL7A depletion prevents the formation of TKI resistant-clones, highlighting the specific role of METTL7A as cells are acquiring resistance. In summary, we discovered an unexpected mechanism required for the acquisition of TKI resistance regulated by a largely uncharacterized factor, METTL7A. This discovery sheds new light into maintenance of oncogene copy number and paves the way to the development of new therapeutics for preventing TKI resistance in LUAD.
2025-02-26 | GSE287666 | GEO
Project description:In mammalian cells, gene copy number is tightly controlled to maintain gene expression and genome stability. However, a near-universal molecular feature across cancer types is oncogene amplification, which promotes cancer progression by dramatically increasing the copy number and expression of tumor-promoting genes. For example, in tyrosine kinase inhibitor (TKI)-resistant lung adenocarcinoma (LUAD), oncogene amplification occurs in over 40% of patients’ tumors. Despite the prevalence of oncogene amplification in TKI-resistant tumors, the mechanisms facilitating oncogene amplification are not fully understood. Here, we find that LUAD tumors exhibit a unique chromatin signature demarcated by strong CTCF and cohesin deposition in drug-naïve tumors, which correlates with the boundaries of oncogene amplicons in TKI-resistant LUAD cells. Throughout the acquisition of TKI resistance, we identified a global chromatin priming effect, marked by a dynamic increase of H3K27Ac, cohesin loading, and inter-TAD interactions, which occurs before the onset of oncogene amplification. Furthermore, we have identified that the protein METTL7A, which was previously reported to localize to the ER and inner nuclear membrane, has a novel chromatin regulatory function in binding to amplified oncogenes and regulating cohesin recruitment and inter-TAD interactions. Surprisingly, we discovered that METTL7A remodels the chromatin landscape prior to any noticeable oncogene copy number gains. Furthermore, while METTL7A depletion has little effect on drug-naïve cells, METTL7A depletion prevents the formation of TKI resistant-clones, highlighting the specific role of METTL7A as cells are acquiring resistance. In summary, we discovered an unexpected mechanism required for the acquisition of TKI resistance regulated by a largely uncharacterized factor, METTL7A. This discovery sheds new light into maintenance of oncogene copy number and paves the way to the development of new therapeutics for preventing TKI resistance in LUAD.
2025-02-26 | GSE254520 | GEO
Project description:In mammalian cells, gene copy number is tightly controlled to maintain gene expression and genome stability. However, a near-universal molecular feature across cancer types is oncogene amplification, which promotes cancer progression by dramatically increasing the copy number and expression of tumor-promoting genes. For example, in tyrosine kinase inhibitor (TKI)-resistant lung adenocarcinoma (LUAD), oncogene amplification occurs in over 40% of patients’ tumors. Despite the prevalence of oncogene amplification in TKI-resistant tumors, the mechanisms facilitating oncogene amplification are not fully understood. Here, we find that LUAD tumors exhibit a unique chromatin signature demarcated by strong CTCF and cohesin deposition in drug-naïve tumors, which correlates with the boundaries of oncogene amplicons in TKI-resistant LUAD cells. Throughout the acquisition of TKI resistance, we identified a global chromatin priming effect, marked by a dynamic increase of H3K27Ac, cohesin loading, and inter-TAD interactions, which occurs before the onset of oncogene amplification. Furthermore, we have identified that the protein METTL7A, which was previously reported to localize to the ER and inner nuclear membrane, has a novel chromatin regulatory function in binding to amplified oncogenes and regulating cohesin recruitment and inter-TAD interactions. Surprisingly, we discovered that METTL7A remodels the chromatin landscape prior to any noticeable oncogene copy number gains. Furthermore, while METTL7A depletion has little effect on drug-naïve cells, METTL7A depletion prevents the formation of TKI resistant-clones, highlighting the specific role of METTL7A as cells are acquiring resistance. In summary, we discovered an unexpected mechanism required for the acquisition of TKI resistance regulated by a largely uncharacterized factor, METTL7A. This discovery sheds new light into maintenance of oncogene copy number and paves the way to the development of new therapeutics for preventing TKI resistance in LUAD.
2025-02-26 | GSE254519 | GEO
Project description:In mammalian cells, gene copy number is tightly controlled to maintain gene expression and genome stability. However, a near-universal molecular feature across cancer types is oncogene amplification, which promotes cancer progression by dramatically increasing the copy number and expression of tumor-promoting genes. For example, in tyrosine kinase inhibitor (TKI)-resistant lung adenocarcinoma (LUAD), oncogene amplification occurs in over 40% of patients’ tumors. Despite the prevalence of oncogene amplification in TKI-resistant tumors, the mechanisms facilitating oncogene amplification are not fully understood. Here, we find that LUAD tumors exhibit a unique chromatin signature demarcated by strong CTCF and cohesin deposition in drug-naïve tumors, which correlates with the boundaries of oncogene amplicons in TKI-resistant LUAD cells. Throughout the acquisition of TKI resistance, we identified a global chromatin priming effect, marked by a dynamic increase of H3K27Ac, cohesin loading, and inter-TAD interactions, which occurs before the onset of oncogene amplification. Furthermore, we have identified that the protein METTL7A, which was previously reported to localize to the ER and inner nuclear membrane, has a novel chromatin regulatory function in binding to amplified oncogenes and regulating cohesin recruitment and inter-TAD interactions. Surprisingly, we discovered that METTL7A remodels the chromatin landscape prior to any noticeable oncogene copy number gains. Furthermore, while METTL7A depletion has little effect on drug-naïve cells, METTL7A depletion prevents the formation of TKI resistant-clones, highlighting the specific role of METTL7A as cells are acquiring resistance. In summary, we discovered an unexpected mechanism required for the acquisition of TKI resistance regulated by a largely uncharacterized factor, METTL7A. This discovery sheds new light into maintenance of oncogene copy number and paves the way to the development of new therapeutics for preventing TKI resistance in LUAD.
2025-02-26 | GSE254485 | GEO
Project description:We isolated and analyzed, at single-nucleotide resolution, cancer-associated neochromosomes from well- and/or dedifferentiated liposarcomas. Neochromosomes, which can exceed 600 Mb in size, initially arise as circular structures following chromothripsis involving chromosome 12. The core of the neochromosome is amplified, rearranged, and corroded through hundreds of breakage-fusion-bridge cycles. Under selective pressure, amplified oncogenes are overexpressed, while coamplified passenger genes may be silenced epigenetically. New material may be captured during punctuated chromothriptic events. Centromeric corro- sion leads to crisis, which is resolved through neocentromere formation or native centromere capture. Finally, amplification terminates, and the neochromosome core is stabilized in linear form by telomere capture. This study investigates the dynamic mutational processes underlying the life history of a special form of cancer mutation.
2015-01-13 | E-MTAB-3235 | biostudies-arrayexpress