Chromothripsis in neuroblastoma
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Project description:RNA-seq for four neuroblastoma samples (Paired-end protocol). Neuroblastoma is a pediatric cancer of the peripheral nervous system in which structural chromosome aberrations are emblematic of aggressive tumors. In this study, we investigated somatic rearrangements in two neuroblastoma cell lines and two primary tumors using paired-end sequencing of mate-pair libraries (SRA accession number ERP001414) and RNA-seq. In one cell line and in the two primary tumors, this approach confirmed the localization of the majority of rearrangements within one or two chromosomes, consistent with the phenomenon of chromothripsis. RNA-seq experiments confirmed expression of several predicted chimeric genes and genes with disrupted exon structure including ALK, NBAS, FHIT, PTPRD and ODZ4. RNA-seq analysis allowed the identification of abnormal transcripts expressed from genomic rearrangements that may be involved in neuroblastoma oncogenesis.
2013-03-03 | E-MTAB-1367 | biostudies-arrayexpress
Project description:Genomic rearrangements typically occur progressively during tumor development. Recent findings, however, suggest an alternative mechanism, involving chromosome shattering and reshuffling ('chromothripsis'), for which no genetic basis has yet been described. Whole-genome sequencing of a Sonic-Hedgehog medulloblastoma (SHH-MB) brain tumor from a patient with a germline TP53 mutation (Li-Fraumeni syndrome) revealed massive, complex rearrangements resulting from chromothripsis. Integrating TP53 status with genomic rearrangement data in additional medulloblastomas revealed a striking association between TP53 mutation and chromothripsis in SHH-MBs. Unexpectedly, five seemingly sporadic SHH-MB patients with chromothripsis harbored TP53 germline mutations – findings relevant for clinical management. Analysis of additional tumor entities substantiated a link between TP53 mutation and chromothripsis, beyond general genomic instability. Among these, we observed a strong association between somatic TP53 mutations and chromothripsis in acute myeloid leukemia. These findings implicate p53 in the initiation of, or cellular reaction to, chromothripsis – a novel role for the 'guardian of the genome'.
2012-01-20 | GSE34258 | GEO
Project description:Expression data of medulloblastoma patient derived xenograft spheroids upon BGB 290 and romidepsin treatment alone and in combination: Romidepsin and BGB 290 shows synergistic growth inhibition in medulloblastoma patient derived xenograft spheroid models in vitro and in vivo. Chromothripsis is a form of genomic instability characterized by the occurrence of tens to hundreds of clustered DNA double-strand breaks in a one-off catastrophic event. Rearrangements associated with chromothripsis are detectable in numerous tumor entities and linked with poor prognosis in some of these, such as Sonic Hedgehog medulloblastoma, neuroblastoma and osteosarcoma. Hence, there is a need for therapeutic strategies eliminating tumor cells with chromothripsis. Defects in DNA double-strand break repair, and in particular homologous recombination repair, have been linked with chromothripsis. Targeting DNA repair deficiencies by synthetic lethality approaches, we performed a synergy screen using drug libraries (n = 375 compounds, 15 models) combined with either a PARP inhibitor or cisplatin. This revealed a synergistic interaction between the HDAC inhibitor romidepsin and PARP inhibition. Functional assays, transcriptome analyses, and in vivo validation in patient-derived xenograft mouse models confirmed the efficacy of the combinatorial treatment.
2022-02-08 | GSE188894 | GEO
Project description:Breast cancer in Spain remains the first leading cause of cancer-related death in women from all age, and in younger women breast tumors often exhibit more aggressive phenotypes, worse prognosis and more frequently germline mutation in BRCA1/2 genes. Chromothripsis, a massive genome rearrangement, has been recently described but its etiology and effect on cancer cells remain unknown. Chromothripsis in breast cancer has been poorly studied and prevalence rates vary between 11-61%. We have studied chromothripsis-like patterns (CTLPs) in 58 DNA extracted from formalin-fixed paraffin-embedded (FFPE) breast cancer tissues from patients below 40 years old. Chromothripsis was confirmed with website tool CTLPScanner in 10/58 (17%) and most frequently involved chromosomal segment was 17q12-q21 (5/10 cases, 50%). We have also find that chromothripsis was related to low recurrence rates and familial history of breast cancer. In summary, we have analyzed chromothripsis in early-onset breast cancer for the first time and could have a prognostic value for this patients
2021-03-31 | GSE128586 | GEO
Project description:Breast cancer in Spain remains the first leading cause of cancer-related death in women from all age, and in younger women breast tumors often exhibit more aggressive phenotypes, worse prognosis and more frequently germline mutation in BRCA1/2 genes. Chromothripsis, a massive genome rearrangement, has been recently described but its etiology and effect on cancer cells remain unknown. Chromothripsis in breast cancer has been poorly studied and prevalence rates vary between 11-61%. We have studied chromothripsis-like patterns (CTLPs) in 58 DNA extracted from formalin-fixed paraffin-embedded (FFPE) breast cancer tissues from patients below 40 years old. Chromothripsis was confirmed with website tool CTLPScanner in 10/58 (17%) and most frequently involved chromosomal segment was 17q12-q21 (5/10 cases, 50%). We have also find that chromothripsis was related to low recurrence rates and familial history of breast cancer. In summary, we have analyzed chromothripsis in early-onset breast cancer for the first time and could have a prognostic value for this patients
2021-03-31 | GSE128584 | GEO
Project description:Breast cancer in Spain remains the first leading cause of cancer-related death in women from all age, and in younger women breast tumors often exhibit more aggressive phenotypes, worse prognosis and more frequently germline mutation in BRCA1/2 genes. Chromothripsis, a massive genome rearrangement, has been recently described but its etiology and effect on cancer cells remain unknown. Chromothripsis in breast cancer has been poorly studied and prevalence rates vary between 11-61%. We have studied chromothripsis-like patterns (CTLPs) in 58 DNA extracted from formalin-fixed paraffin-embedded (FFPE) breast cancer tissues from patients below 40 years old. Chromothripsis was confirmed with website tool CTLPScanner in 10/58 (17%) and most frequently involved chromosomal segment was 17q12-q21 (5/10 cases, 50%). We have also find that chromothripsis was related to low recurrence rates and familial history of breast cancer. In summary, we have analyzed chromothripsis in early-onset breast cancer for the first time and could have a prognostic value for this patients
2021-03-31 | GSE128583 | GEO
Project description:Whole genome sequencing detected structural rearrangements of TERT in 17/75 high stage neuroblastoma with 5 cases resulting from chromothripsis. Rearrangements were associated with increased TERT expression and targeted immediate up- and down-stream regions of TERT, placing in 7 cases a super-enhancer close to the breakpoints. TERT rearrangements (23%), ATRX deletions (11%) and MYCN amplifications (37%) identify three almost non-overlapping groups of high stage neuroblastoma, each associated with very poor prognosis
2015-10-21 | GSE73537 | GEO
Project description:This dataset contains data from two acute myeloid leukaemia (AML) specimens processed with the Illumina CytoSNP-12 SNP array platform. SNP array data showed evidence of chromothripsis in these two specimens. Each deletion in the mosaic specimen was present in the same proportion of cells, which supports the view that the many breaks occur as a single event. Complementary FISH studies highlighted the inclusion of centromeres from different chromosomes during the formation of the new chromosomes.
2013-08-04 | GSE43522 | GEO
Project description:Genomic rearrangements typically occur progressively during tumor development. Recent findings, however, suggest an alternative mechanism, involving chromosome shattering and reshuffling ('chromothripsis'), for which no genetic basis has yet been described. Whole-genome sequencing of a Sonic-Hedgehog medulloblastoma (SHH-MB) brain tumor from a patient with a germline TP53 mutation (Li-Fraumeni syndrome) revealed massive, complex rearrangements resulting from chromothripsis. Integrating TP53 status with genomic rearrangement data in additional medulloblastomas revealed a striking association between TP53 mutation and chromothripsis in SHH-MBs. Unexpectedly, five seemingly sporadic SHH-MB patients with chromothripsis harbored TP53 germline mutations – findings relevant for clinical management. Analysis of additional tumor entities substantiated a link between TP53 mutation and chromothripsis, beyond general genomic instability. Among these, we observed a strong association between somatic TP53 mutations and chromothripsis in acute myeloid leukemia. These findings implicate p53 in the initiation of, or cellular reaction to, chromothripsis – a novel role for the 'guardian of the genome'. The DNA copy-number profiles of 11 primary medulloblastoma samples were analyzed on the Affymetrix Mapping250K Nsp array, together with data from 70 primary samples taken from GSE21140. Data from diploid reference samples were taken from GSE9222. Additionally, DNA copy-number profiles for 19 additional medulloblastoma samples were generated on the Affymetrix SNP6 platform with matched blood samples.
2012-01-20 | E-GEOD-34258 | biostudies-arrayexpress
Project description:Chromothripsis represents an extreme class of complex chromosome rearrangements (CCRs) with major effects on chromosomal architecture. Although recent studies have associated chromothripsis with congenital abnormalities, the incidence and pathogenic effects of this phenomenon require further investigation. Here, we analyzed the genomes of three families in which chromothripsis rearrangements were transmitted from a female carrier to her child. The chromothripsis in the carriers resulted in completely balanced rearrangements involving 8-23 breakpoint junctions across 3-5 chromosomes. Two carriers did not show any phenotypic malformations, although 3-13 protein coding genes were affected by breakpoints. Unbalanced but stable transmission of a subset of the derivative chromosomes caused apparently de novo complex copy number changes in two children. This resulted in gene dosage changes, which are likely responsible for their severe congenital phenotypes. In contrast, one patient with severe congenital disease, carried all three chromothripsis chromosomes from his healthy mother, but one of the chromosomes acquired de novo rearrangements leading to copy number changes. These results show that the human genome can tolerate extreme reshuffling of chromosomal architecture, including breakage of multiple protein coding genes, without noticeable phenotypic effects. The presence of chromothripsis in healthy carriers strongly affects reproduction and is expected to substantially increase the risk of spontaneous abortions and severe congenital disease.
2015-01-31 | GSE65452 | GEO