Translocation Breakpoints Preferentially Occur in Euchromatin and Acrocentric Chromosomes

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.

Chromosome arm aneuploidies shape tumour evolution and drug response

“…Solid cancers show a considerably higher CAA burden than haematological cancers. This may reflect the fact that haematological cancer development is largely driven by translocations, or that TP53 mutations are less prevalent in these cancers 16,17,32,33 . Another discriminating feature between haematological and solid cancers is their opposing bias towards gain and loss of chromosome arms, respectively.…”

“…Pairwise probabilistic cooccurrence modelling. Probabilistic modelling of pairs of CAAs co-occurring in the same tumour sample was based on a previously described model 27,33 . This model is summarised in Eq.…”

Role of GFI1 in Epigenetic Regulation of MDS and AML Pathogenesis: Mechanisms and Therapeutic Implications

“…Recent in vitro studies using leukemic cell lines suggest that histone modification associated with less dense DNA packing can positively promote chromosomal rearrangements (84, 85). Additional studies revealed that in the case of human leukemia, chromosomal rearrangements take place preferentially at transcriptionally active sites (86, 87). H3K9 acetylation leads to a less densely packed configuration of the DNA in chromatin and, as a consequence, to increased accessibility of RNA polymerases to initiate and elongate transcription resulting in an activation of gene expression.…”

Non-Random Distribution of Reciprocal Translocation Breakpoints in the Pig Genome

“…Longer chromosome arms tended to have more translocation breakpoints, and chromosome arms typically rearranged in proportion to their length. As with whole chromosomes, longer chromosome arms have been previously suggested to be predisposed to having more translocation breakpoints [10]. Examining the translocation frequencies of the p and q arms of each chromosome, however, revealed a different trend.…”

“…Research that involves the human genome has suggested that translocation breakpoints occurred nonrandomly for each individual chromosome pair, with specific chromosomes and cytogenetic landmarks being particularly susceptible to breakage. Various chromosomal features recognizable in a karyotype such as the total length of chromosomes and chromosome arms, chromosome morphology, as well as, chromatin density (heterochromatic and euchromatic), and the presence of common fragile sites have all been suggested to influence the frequency at which chromosome regions rearrange [7,8,9,10].…”