Spatial proximity of translocation-prone gene loci in human lymphomas

Abstract

Cancer cells frequently have disease-specific chromosome rearrangements. It is poorly understood why translocations between chromosomes recur at specific breakpoints in the genome. Here we provide evidence that higher-order spatial genome organization is a contributing factor in the formation of recurrent translocations. We show that MYC, BCL and immunoglobulin loci, which are recurrently translocated in various B-cell lymphomas, are preferentially positioned in close spatial proximity relative to each other in normal B cells. Loci in spatial proximity are non-randomly positioned towards the nuclear interior in normal B cells. This locus proximity is the consequence of higher-order genome structure rather than a property of individual genes. Our results suggest that the formation of specific translocations in human lymphomas, and perhaps other tissues, is determined in part by higher-order spatial organization of the genome.

The significance of telomeric aggregates in the interphase nuclei of tumor cells

“…Thomas and Diehl [2003] state that the proximity between translocating chromosomes is a prerequisite for their rearrangement. Roix et al [2003] support this interpretation.…”

MYC activation associated with the integration of HPV DNA at the MYC locus in genital tumors

“…Fragile sites have also been reported to facilitate HPV DNA integration (Thorland et al, 2003), but other factors may influence the nature of the genetic rearrangements that implicate insertion of foreign DNA and illegitimate recombination. In Burkitt lymphoma, the frequency of the different types of translocation observed was highly correlated with the probability that the two partners were in physical proximity in the cell nucleus (Roix et al, 2003). DNA repair mechanisms have also been found involved in the process of viral integration.…”

The radial arrangement of the human chromosome 7 in the lymphocyte cell nucleus is associated with chromosomal band gene density

“…We determined the radial nuclear location of each locus using a 2-dimensional (2-D) analysis, following previously described criteria (Croft et al 1999;Bridger et al 2000;Roix et al 2003;D'Antoni et al 2004;Masny et al 2004;Ono et al 2007). More precisely, a high number of hybridized nuclei were captured with MacProbe v4.2 software and the hybridization signals were localized in each cell nucleus using a dedicated computer software developed in our lab at the University of Catania (freely available on request).…”