Translocation Breakpoints Preferentially Occur in Euchromatin and Acrocentric Chromosomes.
Cheng-Yu LinAnkit ShuklaJohn P GradyJ Lynn FinkEloise DrayPascal H G DuijfPublished in: Cancers (2018)
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.
Keyphrases
- genome wide
- transcription factor
- tyrosine kinase
- chronic myeloid leukemia
- dna methylation
- copy number
- genome wide identification
- gene expression
- dna damage
- acute lymphoblastic leukemia
- risk assessment
- papillary thyroid
- acute myeloid leukemia
- dna binding
- minimally invasive
- oxidative stress
- squamous cell carcinoma
- childhood cancer
- squamous cell
- bioinformatics analysis
- finite element