Translocation breakpoints preferentially occur in euchromatin and acrocentric chromosomes

Cheng Yu Lin, Ankit Shukla, John P. Grady, J. Lynn Fink, Eloise Dray, Pascal H.G. Duijf

Research output: Contribution to journalArticlepeer-review

8 Scopus citations

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.

Original languageEnglish (US)
Article number13
JournalCancers
Volume10
Issue number1
DOIs
StatePublished - Jan 2018

Keywords

  • Acrocentric chromosomes
  • CTCF
  • Cohesin
  • DNA double strand breaks
  • DNA repair
  • Leukemia
  • Lymphoma
  • Nucleolus
  • Translocations
  • V(D)J recombination

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Fingerprint Dive into the research topics of 'Translocation breakpoints preferentially occur in euchromatin and acrocentric chromosomes'. Together they form a unique fingerprint.

Cite this