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High-grade Glioma
Published in David A. Walker, Giorgio Perilongo, Roger E. Taylor, Ian F. Pollack, Brain and Spinal Tumors of Childhood, 2020
Donald C. Macarthur, Christof M. Kramm, Matthias A. Karajannis
In addition to mutations, chromosomal structural abnormalities are common in pediatric HGG. The landscape of copy number alterations (CNA) in pediatric HGG is highly variable, and includes a wide range, including balanced genomes, simple rearrangements, and complex abnormalities caused by chromothripsis.10 Oncogenic gene fusions can be found in subsets of pediatric HGG, such as NTRK fusions prevalent in infant HGG,8,10 and MET fusions found in older children.18
Preimplantation Genetic Testing for Structural Rearrangements
Published in Darren K. Griffin, Gary L. Harton, Preimplantation Genetic Testing, 2020
SRs are formed via double-stranded breaks and subsequent joining of those breakpoints by DNA repair machinery [8]. This creates derivative chromosomes where the order and the linkage relationships of genes differ. They can be formed in any of the chromosomes; however, there are hot-spots or frequent breakpoints in the genome. Mechanisms such as non-allelic homologous recombination (NAHR) [9,10], DNA double strand break repair via non-homologous end-joining (NHEJ) [8,11], microhomology-mediated break-induced replication (MMBIR), fork stalling and template switching (FoSTeS) [12], “chromothripsis” [1,13], palindrome-mediated mechanisms [14], nucleolar localization of chromosomes, and exposure to chemicals and radiation [15] are thought to be responsible in the generation of rearrangements. Within the scope of PGT-SR, the types and the reproductive outcomes of rearrangement carriers are usually restricted to balanced reciprocal and Robertsonian translocations (RecT and RobT), inversions, complex chromosome rearrangements, and insertions (Figure 4.1).
Medulloblastoma
Published in Dongyou Liu, Tumors and Cancers, 2017
The medulloblastoma SHH-activated and TP53 mutant subset harbors aberrations in the SHH pathway genes (including PTCH1, PTCH2, SMO, SUFU, GLI2, and MYCN). Other genetic alternations include chromosome 14q and 17p losses, chromosome 9q and 10q deletions, chromosome 3q gain, chromothripsis, p53 amplification, and TP53 mutation [2].
Combining metaphase cytogenetics with single nucleotide polymorphism arrays can improve the diagnostic yield and identify prognosis more precisely in myelodysplastic syndromes
Published in Annals of Medicine, 2022
Yao Qin, Hang Zhang, Lin Feng, Haichen Wei, Yuling Wu, Chaoran Jiang, Zhihong Xu, Huanling Zhu, Ting Liu
In addition, chromothripsis is a unique type of genomic instability and plays a vital role in the development of cancer [29]. In haematopoietic neoplasms, chromothripsis was linked to poor prognosis and specific genetic alterations: complex karyotype, 5q deletions, and loss of TP53 [30]. Gao et al. identified chromothripsis in nine AML and two MDS cases, and noted that all chromothripsis-positive AML cases were with MDS-related changes. Chromothripsis in AML-MDS most frequently involves chromosomes eight and 11 with consequent amplification of either MYC or KMT2A [31]. Abáigar et al. found that three high-risk MDS patients displayed chromothripsis involving exclusively chromosome 13 and affecting some cancer genes: FLT3, BRCA2 and RB1, and all of them carried TP53 mutations [32]. In our study, chromothripsis were detected by SNP-A in 14 patients (12.7%) with mostly on chromosomes 20, 3, 6, 9, and 21. All chromothripsis occurred in the MDS patients with complex karyotypes, including in subtypes of MDS-EB2, MDS-EB1, and MDS-MLD, which implicates a poor prognosis in MDS.
Deep sequencing as an approach to understanding the complexity and improving the treatment of multiple myeloma
Published in Expert Review of Precision Medicine and Drug Development, 2020
Louis S. Williams, Jessica Caro, Beatrice Razzo, Eileen M. Boyle, Gareth J. Morgan
As large-scale sequencing of genomes in multiple myeloma has illuminated the variable evolutionary trajectories and mutational processes in the disease, attention has turned toward the role of reciprocal and complex structural variants located in the non-coding regions of the genome. These are common events which result in significant deregulation of gene expression and significantly impact prognosis. Of particular interest is the phenomena of chromothripsis, which entails the shattering and subsequent reconstruction of chromosomes secondary to the formation of micronuclei or chromatin bridging. Importantly, chromothripsis shatters a region of a chromosome in a single catastrophic event with the potential to deregulate multiple genes. A second complex structural event is chromoplexy, which generates chained rearrangement to form new chromosomal structures [64–66]. Investigators first described these events using WGS applied to multiple tumor types but initially focused on prostate cancer to chromoplexy [67].
Large extracellular vesicles carry most of the tumour DNA circulating in prostate cancer patient plasma
Published in Journal of Extracellular Vesicles, 2018
Tatyana Vagner, Cristiana Spinelli, Valentina R. Minciacchi, Leonora Balaj, Mandana Zandian, Andrew Conley, Andries Zijlstra, Michael R. Freeman, Francesca Demichelis, Subhajyoti De, Edwin M. Posadas, Hisashi Tanaka, Dolores Di Vizio
Using an approach that allows to estimate the size of the intact DNA fragments in EVs, we showed that L-EVs contain unusually high molecular weight DNA. This is the first DNA evaluation directly in intact EVs. Similar size DNA has been reported to derive from DNA damage and likely chromosomal fragmentation that occurs in micronuclei, which can induce chromothripsis [42]. Chromothripsis consists of massive clustered chromosomal rearrangements usually involving one chromosome. This process can induce the formation of double minute chromosomes, which are extrachromosomal circular DNA structures harbouring amplified oncogenes [43–46]. Given the size of L-EVs and their tumour-specific origin, it seems plausible that the extrachromosomal DNA from the cytosol of cancer cells is loaded in L-EVs forming at the plasma membrane. This hypothesis, although speculative, is supported by our data showing that L-EV DNA is chromatinized. However, the molecular mechanisms of DNA loading into EVs are largely unknown and need to be further explored. The nature of L-EV DNA could be interrogated by sequencing the high molecular weight DNA strands, which are uniquely present in L-EVs, to investigate if they are enriched in particular sequences (e.g. amplified oncogenes). In addition, this might also provide some cues to L-EV biogenesis.