Complex amplification in human cancer
Ontology highlight
ABSTRACT:
PROVIDER: PRJEB45367 | ENA |
REPOSITORIES: ENA
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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.
2020-09-23 | GSE119825 | 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.
2020-09-14 | GSE119979 | 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
| PRJNA490379 | ENA
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
Project description:Hepatitis B virus (HBV) contains a partially double-stranded relaxed circular DNA (rcDNA) genome that is converted into a covalently closed circular DNA (cccDNA) in the nucleus of infected hepatocyte by cellular DNA repair machinery. cccDNA associates with nucleosomes to form a minichromosome that transcribes RNA to support the expression of viral proteins and reverse transcriptional replication of viral DNA. In addition to the de novo synthesis from incoming virion rcDNA, cccDNA can also been synthesized from rcDNA in the progeny nucleocapsids in the cytoplasm of infected hepatocytes via the intracellular amplification pathway. In our efforts to identify cellular DNA repair proteins required for cccDNA synthesis by a chemogenetic screen, we found that B02, a small molecular inhibitor of DNA homologous recombination repair protein RAD51, significantly enhanced the synthesis of cccDNA via intracellular amplification pathway in human hepatoma cells. Ironically, neither siRNA knockdown of RAD51 expression nor treatment with another structurally distinct RAD51 inhibitor or activator altered cccDNA amplification. However, further mechanistic studies revealed that B02 treatment significantly elevated the levels of multiple heat shock protein mRNA and siRNA knockdown of HSPA1A expression or treatment with HSPA1 inhibitors significantly attenuated B02 enhancement of cccDNA amplification. Moreover, B02 enhanced cccDNA amplification was efficiently inhibited by compounds that selectively inhibit DNA polymerase α or topoisomerase II, the enzymes required for cccDNA intracellular amplification. Our results thus indicate that B02 treatment induces a heat shock protein-mediated cellular response that positively regulates the conversion of rcDNA into cccDNA via the authentic intracellular amplification pathway
2022-12-08 | GSE209863 | GEO
Project description:We demonstrate that, in human bladder cancer, amplification of the E2F3 gene, located at 6p22, is associated with overexpression of its encoded mRNA transcripts and high levels of expression of E2F3 protein. Immunohistochemical analyses of E2F3 protein levels have established that around one-third (33/101) of primary transitional cell carcinomas of the bladder overexpress nuclear E2F3 protein, with the proportion of tumours containing overexpressed nuclear E2F3 increasing with tumour stage and grade. When considered together with the established role of E2F3 in cell cycle progression, these results suggest that the E2F3 gene represents a candidate bladder cancer oncogene that is activated by DNA amplification and overexpression. Keywords: Tumour vs normal comparison, array CGH
2006-10-27 | GSE6123 | GEO
Project description:Amplifications, regions of focal high level copy number change, lead to overexpression of oncogenes or drug resistance genes in tumors. Their presence is often associated with poor prognosis; however the use of amplification as a mechanism for overexpression of a particular gene in tumors varies. To investigate the influence of genome position on propensity to amplify, we integrated a mutant form of DHFR into different positions in the human genome, challenged cells with methotrexate and then studied the genomic alterations arising in drug resistant cells. We observed site specific differences in methotrexate sensitivity, organization of amplicons and amplification frequency. One site was uniquely associated with a significantly enhanced propensity to amplify and recurrent amplicon boundaries, possibly implicating a rare folate sensitive fragile site in initiating amplification. Hierarchical clustering of gene expression patterns and subsequent gene enrichment analysis revealed two clusters differing significantly in expression of MYC target genes independent of integration site. These studies suggest that genome context together with the particular challenges to genome stability experienced during the progression to cancer contribute to the propensity to amplify a specific oncogene or drug resistance gene, whereas the overall functional response to drug (or other) challenge may be independent of the genomic location of an oncogene. Keywords: Gene amplification, array CGH, chromosomal fragile sites
2007-10-08 | GSE6262 | GEO
Project description:<p>DNA Inverted Repeats as an At-risk Motif for Palindromic Gene Amplificatio defines oncogene amplification that is configured as a series of inverted duplications (palindromic gene amplification). There are several, recurrently amplified oncogenes throughout the human genome. However, it remains unclear whether this recurrent amplification is solely a manifestation of increased fitness resulting from random amplification mechanisms, or if genomic locus-specific amplification mechanism plays a role. </p> <p>In this study, we show that the ERBB2 oncogene at 17q12 is susceptible to palindromic gene amplification in HER2-positive breast tumors. We investigated eight tumors in this study, of which five tumors were HER2-positive, and three tumors were HER2-negative. HER2-status was determined by clinical FISH tests. We applied three genomic approaches to investigate the amplification mechanism: (1) copy number analysis by array-CGH on the Affymetrix SNP6.0 platform (8 files), (2) sequencing of DNA libraries enriched with tumor-derived palindromic DNA (Genome-wide Analysis of Palindrome Formation, GAPF-seq) (8 files) and (3) unbiased whole genome sequencing (WGS) (1 file). These molecular data is made available in the dbGaP. </p> <p>Genomic studies using tumor DNA was approved under the Internal Institutional Review Board at the Cleveland Clinic (IRB07-136: EXEMPT: Chromosome Breakage and DNA Palindrome Formation). Specimens were obtained and methods were carried out under the auspices of IRB 7881 (Evaluation of Genetic and Molecular Markers in Patients with Breast Cancer). All patients consented to allow their cancer specimens to be used by researchers in an anonymized fashion. The consent form indicates that publication will take place without identifiers to protect the identity of any specific individual.</p> <p>We observed significant and enrichment of palindromic DNA within amplified ERBB2 genomic segments in four out of five HER2-positive tumors. None of three HER2-negative tumors showed such enrichment. Palindromic DNA was particularly enriched at amplification peaks and boundaries between amplified and normal copy-number regions. Thus, palindromic gene amplification shaped the amplified ERBB2 locus. The moderate enrichment of palindromic DNA throughout the amplified segments leads us to propose that the ERBB2 locus is amplified through a mechanism that repeatedly generates palindromic DNA, such as Breakage-Fusion-Bridge cycles. Our results reveal a potential interaction between local genomic environments and gene amplification mechanisms. </p> <p>This study is published under the title "Palindromic amplification of the ERBB2 oncogene in primary HER2-positive breast tumors" <a href="https://www.ncbi.nlm.nih.gov/pubmed/?term=28211519" target="_blank">(PMID:28211519)</a>. </p>
| phs001261 | dbGaP