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The Role of Chromosomal Instability in Cancer and Therapeutic Responses
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Cancers 2018, 10(1), 13; https://doi.org/10.3390/cancers10010013

Translocation Breakpoints Preferentially Occur in Euchromatin and Acrocentric Chromosomes

1
University of Queensland Diamantina Institute, The University of Queensland, Translational Research Institute, 37 Kent Street, Brisbane, QLD 4102, Australia
2
Institute of Health and Biomedical Innovation, Queensland University of Technology, Translational Research Institute, 37 Kent Street, Brisbane, QLD 4102, Australia
3
Mater Research Institute-The University of Queensland, Translational Research Institute, 37 Kent Street, Brisbane, QLD 4102, Australia
*
Author to whom correspondence should be addressed.
Received: 27 October 2017 / Revised: 11 December 2017 / Accepted: 5 January 2018 / Published: 8 January 2018
(This article belongs to the Special Issue Chromosomal Instability and Cancers)
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Abstract

Chromosomal translocations drive the development of many hematological and some solid cancers. Several factors have been identified to explain the non-random occurrence of translocation breakpoints in the genome. These include chromatin density, gene density and CCCTC-binding factor (CTCF)/cohesin binding site density. However, such factors are at least partially interdependent. Using 13,844 and 1563 karyotypes from human blood and solid cancers, respectively, our multiple regression analysis only identified chromatin density as the primary statistically significant predictor. Specifically, translocation breakpoints preferentially occur in open chromatin. Also, blood and solid tumors show markedly distinct translocation signatures. Strikingly, translocation breakpoints occur significantly more frequently in acrocentric chromosomes than in non-acrocentric chromosomes. Thus, translocations are probably often generated around nucleoli in the inner nucleoplasm, away from the nuclear envelope. Importantly, our findings remain true both in multivariate analyses and after removal of highly recurrent translocations. Finally, we applied pairwise probabilistic co-occurrence modeling. In addition to well-known highly prevalent translocations, such as those resulting in BCR-ABL1 (BCR-ABL) and RUNX1-RUNX1T1 (AML1-ETO) fusion genes, we identified significantly underrepresented translocations with putative fusion genes, which are probably subject to strong negative selection during tumor evolution. Taken together, our findings provide novel insights into the generation and selection of translocations during cancer development. View Full-Text
Keywords: translocations; DNA double strand breaks; DNA repair; leukemia; lymphoma; V(D)J recombination; CTCF; cohesin; nucleolus; acrocentric chromosomes translocations; DNA double strand breaks; DNA repair; leukemia; lymphoma; V(D)J recombination; CTCF; cohesin; nucleolus; acrocentric chromosomes
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Lin, C.-Y.; Shukla, A.; Grady, J.P.; Fink, J.L.; Dray, E.; Duijf, P.H. Translocation Breakpoints Preferentially Occur in Euchromatin and Acrocentric Chromosomes. Cancers 2018, 10, 13.

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