Genome Sequencing of Pediatric Medulloblastoma Links Catastrophic DNA Rearrangements with TP53 Mutations

Rausch, Tobias; Jones, David; Zapatka, Marc; Stütz, Adrian M.; Zichner, Thomas; Weischenfeldt, Joachim; Jäger, Natalie; Remke, Marc; Shih, David; Northcott, Paul A.; Pfaff, Elke; Tica, Jelena; Wang, Qi; Massimi, Luca; Witt, Hendrik; Bender, Sebastian; Pleier, Sabrina; Cin, Huriye; Hawkins, Cynthia; Beck, Christian; Deimling, Andreas von; Hans, Volkmar; Brors, Benedikt; Eils, Roland; Scheurlen, Wolfram; Blake, Jonathon; Beneš, Vladimír; Kulozik, Andreas E.; Witt, Olaf; Martin, Dianna C.; Zhang, Cindy; Porat, Rinnat M.; Merino, Diana M.; Wasserman, Jonathan D.; Jabado, Nada; Fontebasso, Adam M.; Bullinger, Lars; Rücker, Frank G.; Döhner, Konstanze; Döhner, Hartmut; Koster, Jan; Molenaar, Jan J.; Versteeg, Rogier; Kool, Marcel; Tabori, Uri; Malkin, David; Korshunov, Andrey; Taylor, Michael D.; Lichter, Peter; Pfister, Stefan M.; Korbel, Jan O.

doi:10.1016/j.cell.2011.12.013

Cited by 755 publications

(836 citation statements)

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“…18,37 To infer chromothripsis with array-based copy number profiling data, various criteria have been applied, the central common part of which is to identify oscillating copy number states on a single chromosome. [38][39][40][41] On the basis of copy number profiling, chromothripsis was present in an estimated 1-3% of human cancers. 18,42 By contrast, 19% (3/16) of cases (and 38% of the 'S' group) in the current series presented copy number profiles suggesting chromothripsis, a phenomenon unprecedented in adenosarcoma.…”

Section: Discussionmentioning

confidence: 99%

“…It has been implied that chromothripsis causes amplifications in the form of double minutes. 18,38 The chromosome painting analysis suggested that amplification of chromosome 12 in cases S1 and S6 might have resulted from chromothripsis through double minute formation, whereas amplifications in chromosomes without chromothripsis might have been caused by other mechanisms. 44 Indeed, the mixed chromosome 12 painting and MDM2 FISH in Figure 5d might give a hint of homogeneously staining region as the mechanism of amplification.…”

Section: Discussionmentioning

confidence: 99%

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Genomewide copy number analysis of Müllerian adenosarcoma identified chromosomal instability in the aggressive subgroup

Lee

Changou

et al. 2016

Modern Pathology

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Müllerian adenosarcomas are malignant gynecologic neoplasms. Advanced staging and sarcomatous overgrowth predict poor prognosis. Because the genomic landscape remains poorly understood, we conducted this study to characterize the genomewide copy number variations in adenosarcomas. Sixteen tumors, including eight with and eight without sarcomatous overgrowth, were subjected to a molecular inversion probe array analysis. Copy number variations, particularly losses, were significantly higher in cases with sarcomatous overgrowth. Frequent gains of chromosomal 12q were noted, often involving cancer-associated genes CDK4 (six cases), MDM2, CPM, YEATS4, DDIT3, GLI1 (five each), HMGA2 and STAT6 (four), without association with sarcomatous overgrowth status. The most frequent losses involved chromosomes 13q (five cases), 9p, 16q and 17q (four cases each) and were almost limited to cases with sarcomatous overgrowth. MDM2 and CDK4 amplification, as well as losses of RB1 (observed in two cases) and CDKN2A/B (one case), was verified by FISH. By immunohistochemistry, all MDM2/CDK4-coamplified cases were confirmed to overexpress both encoded proteins, whereas all four cases with (plus an additional four without) gain of HMGA2 overexpressed the HMGA2 protein. Both cases with RB1 loss were negative for the immunostaining of the encoded protein. Chromothripsis-like copy number profiles involving chromosome 12 or 14 were observed in three fatal cases, all of which harbored sarcomatous overgrowth. With whole chromosome painting and deconvolution fluorescent microscopy, dividing tumor cells in all three cases were shown to have scattered extrachromosomal materials derived from chromosomes involved by chromothripsis, suggesting that this phenomenon may serve as visual evidence for chromothripsis in paraffin

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Genomewide copy number analysis of Müllerian adenosarcoma identified chromosomal instability in the aggressive subgroup

Lee

Changou

et al. 2016

Modern Pathology

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“…For this test, we analyzed whole-genome sequence data from another mantle cell lymphoma sample (M003) and a sample from a pediatric form of a medulloblastoma (MB1), both known to present complex landscapes of chromosomal rearrangements 12,13 . Because these representative examples corresponded to a hematological and a solid tumor, each sequenced in a different sequencing facility, this analysis also measured SMUFIN's consistency across different types of data.…”

Section: Complex Structural Variation In Aggressive Tumorsmentioning

confidence: 99%

Comprehensive characterization of complex structural variations in cancer by directly comparing genome sequence reads

et al. 2014

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The development of high-throughput sequencing technologies has advanced our understanding of cancer. However, characterizing somatic structural variants in tumor genomes is still challenging because current strategies depend on the initial alignment of reads to a reference genome. Here, we describe SMUFIN (somatic mutation finder), a single program that directly compares sequence reads from normal and tumor genomes to accurately identify and characterize a range of somatic sequence variation, from single-nucleotide variants (SNV) to large structural variants at base pair resolution. Performance tests on modeled tumor genomes showed average sensitivity of 92% and 74% for SNVs and structural variants, with specificities of 95% and 91%, respectively. Analyses of aggressive forms of solid and hematological tumors revealed that SMUFIN identifies breakpoints associated with chromothripsis and chromoplexy with high specificity. SMUFIN provides an integrated solution for the accurate, fast and comprehensive characterization of somatic sequence variation in cancer.The recent development of high-throughput sequencing technologies has made possible the sequencing of genomes at an unprecedented speed, allowing the identification of the genetic basis of numerous diseases. These advances have been particularly important in the study of cancer, providing information on thousands of tumor genomes and a large catalog of genomic alteration associated with oncogenesis 1 .The characterization of somatic variation in tumor samples is, therefore, rapidly becoming a standard practice in biomedicine 2 . In a large fraction of biomedical studies that rely on high-throughput sequencing, the production of genome sequence data exceeds available computer resources and the capabilities of analytic protocols. This is particularly pertinent in the field of cancer genomics, where the increasing sequencing of tumor genomes calls for faster and more accurate analyses.The identification of somatic variants associated with cancer typically requires sequencing tumor and normal genome samples from the same patient, followed by multiple sequence comparisons. Normal and pathological reads are aligned to a reference genome, and the alignment is used to identify sequence changes to isolate the somatic fraction of variants (i.e., those detected only in the tumor). In principle, this simple strategy can be used to detect single-nucleotide variants (SNVs) and structural variants. Existing methods for the detection of somatic SNVs show high sensitivity and specificity 3,4 , but identifying structural variants is still challenging and remains largely unsolved. The need for a reference sequence is particularly limiting. Reads carrying variations, such as those covering somatic changes in the tumor, are more difficult to align to the reference genome 5 , and corresponding variants might become undetectable. Moreover, reference-based methods also must discriminate germline changes from somatic variants. In addition to these limitations at detection level, this a...

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“…12 Example of an image menu on the same page as the article. Source: [62] Finally, the information in the images only partially benefits the whole article, as alt text and labels are not exploited in the retrieval systems of the journals.…”

Section: Sciencementioning

confidence: 99%

Do Physicians Make Their Articles Readable for Their Blind or Low-Vision Patients? An Analysis of Current Image Processing Practices in Biomedical Journals from the Point of View of Accessibility

et al. 2014

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Visual content in biomedical academic papers is a growing source of critical information, but it is not always fully readable for people with visual impairments. We aimed to assess current image processing practices, accessibility policies, and submission policies in a sample of 12 highly cited biomedical journals. We manually checked the application of text-based alternative image descriptions for every image in 12 articles (one for each journal). We determined whether the journals claimed to follow an accessibility policy and we reviewed their submission policy and their guidelines related to the visual content. We identified important features concerning the processing of images and the characteristics of the visual and the retrieval options of visual content offered by the publishers. The evaluation shows that the actual practices of textual image description in highly cited biomedical journals do not follow general guidelines on accessibility. The images within the articles analyzed lack alternative descriptions or have uninformative descriptions, even in the case of journals claiming to follow an accessibility policy. Consequently, the visual information of scientific articles is not accessible to people with severe visual disabilities.Instructions on image submission are heterogeneous and a declaration of accessibility guidelines was only found in two thirds of the sample of journals, with one third not explicitly following any accessibility policy, although they are required to by law.

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Genome Sequencing of Pediatric Medulloblastoma Links Catastrophic DNA Rearrangements with TP53 Mutations

Cited by 755 publications

References 64 publications

Genomewide copy number analysis of Müllerian adenosarcoma identified chromosomal instability in the aggressive subgroup

Genomewide copy number analysis of Müllerian adenosarcoma identified chromosomal instability in the aggressive subgroup

Comprehensive characterization of complex structural variations in cancer by directly comparing genome sequence reads

Do Physicians Make Their Articles Readable for Their Blind or Low-Vision Patients? An Analysis of Current Image Processing Practices in Biomedical Journals from the Point of View of Accessibility

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