Genome-Wide Analysis of Interchromosomal Interaction Probabilities Reveals Chained Translocations and Overrepresentation of Translocation Breakpoints in Genes in a Cutaneous T-Cell Lymphoma Cell Line

Abstract

In classical models of tumorigenesis, the accumulation of tumor promoting chromosomal aberrations is described as a gradual process. Next-generation sequencing-based methods have recently revealed complex patterns of chromosomal aberrations, which are beyond explanation by these classical models of karyotypic evolution of tumor genomes. Thus, the term chromothripsis has been introduced to describe a phenomenon, where temporarily and spatially confined genomic instability results in dramatic chromosomal rearrangements limited to segments of one or a few chromosomes. Simultaneously arising and misrepaired DNA double-strand breaks are also the cause of another phenomenon called chromoplexy, which is characterized by the presence of chained translocations and interlinking deletion bridges involving several chromosomes. In this study, we demonstrate the genome-wide identification of chromosomal translocations based on the analysis of translocation-associated changes in spatial proximities of chromosome territories on the example of the cutaneous T-cell lymphoma cell line Se-Ax. We have used alterations of intra- and interchromosomal interaction probabilities as detected by genome-wide chromosome conformation capture (Hi-C) to infer the presence of translocations and to fine-map their breakpoints. The outcome of this analysis was subsequently compared to datasets on DNA copy number alterations and gene expression. The presence of chained translocations within the Se-Ax genome, partly connected by intervening deletion bridges, indicates a role of chromoplexy in the etiology of this cutaneous T-cell lymphoma. Notably, translocation breakpoints were significantly overrepresented in genes, which highlight gene-associated biological processes like transcription or other gene characteristics as a possible cause of the observed complex rearrangements. Given the relevance of chromosomal aberrations for basic and translational research, genome-wide high-resolution analysis of structural chromosomal aberrations will gain increasing importance.

Inferring chromosome radial organization from Hi-C data

“…For example, genes corresponding to olfactory receptors from different chromosomes form specific inter-chromosomal contacts in mouse olfactory sensory neurons which strengthen upon differentiation from a progenitor cell [ 37 ]. In an another set of studies, by analyzing Hi-C inter-chromosomal contacts obtained from different malignant diseases, researchers have identified several novel chromosomal rearrangements [ 38 , 39 ]. Though Hi-C does not directly capture the radial position of the CTs, approaches that infer 3D chromosome positioning information from Hi-C contact data provide a valuable supplement to microscopic data, greatly increasing the number of cell types for which CT positions can be analyzed.…”

Genomic Adaption and Mutational Patterns in a HaCaT Subline Resistant to Alkylating Agents and Ionizing Radiation

“…The software package Juicer was employed for alignment and data analysis using the default setting [ 90 ]. Translocation breakpoints were defined by visual inspection of the Hi-C interaction matrices as described previously [ 42 ] employing the webtool Juicebox [ 43 ] and Circos [ 46 ].…”

“…Translocations drastically change the spatial proximity of chromosomes within the nucleus. This fact can be used to infer chromosomal translocation partners and chromosomal breakpoints on the basis of analysis of chromosome interaction probabilities by means of Hi-C [38][39][40][41][42] (Figure 3; Supplementary Table S2). Previous studies revealed that the mechanisms mediating resistance in HaCaT/SM also protect from other chemical stressors [37].…”

Case for genome sequencing in infants and children with rare, undiagnosed or genetic diseases

“…For cases involving a recessive disorder, variants in cis can be distinguished from variants in trans obviating the need to test other family members to establish the phase of the variants. This technique can also detect chromosomal rearrangements 56…”