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Chromosomal Rearrangements in Cancer: Detection and potential causal mechanisms.

ABSTRACT: Many cancers exhibit chromosomal rearrangements. These rearrangements can be simple with a single balanced fusion preserving the proper complement of genetic information or they can be complex with one or more fusions that distort this balance. A range of technological advances has improved our ability to detect and understand these rearrangements leading to speculation of causal mechanisms including defective DNA double strand break (DSB) repair and faulty DNA replication. A better understanding of these potential cancer-causing mechanisms will lead to novel therapeutic regimes to fight cancer. This review describes the technological advances used to detect simple and complex chromosomal rearrangements, cancers that exhibit these rearrangements, potential mechanisms that rearrange chromosomes and intervention strategies designed to specifically attack fusion gene products and causal DNA repair/synthesis pathways.

SUBMITTER: Hasty P

PROVIDER: S-EPMC4507279 | biostudies-other | 2014 Jul

REPOSITORIES: biostudies-other

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Project description:At the organismal level, genome rearrangements are usually deleterious and are often associated with disease. Yet, on an evolutionary scale, they can be beneficial as they provide for rapid genetic diversification. DNA lesions, particularly double-strand breaks (DSBs), are sources of genome instability that can be rectified by various repair processes. Homologous recombination (HR) is highly effective at protecting the genome from DSBs and provides for accurate repair between sister chromatids and homologous chromosomes. Here we show that although random DSBs induced by ionizing radiation in yeast chromosomes are repaired efficiently by HR in G-2 diploid cells, rearrangements are frequent. The chromosome aberrations (ABs) primarily resulted from recombination between Ty retrotransposable elements, the most abundant class of dispersed repetitive DNAs in the genome, while some rearrangements involved other classes of repetitive DNA. Few, if any, of the ABs could be attributed to nonhomologous end-joining (NHEJ). We conclude that only those few DSBs that fall at or near the 3-5% of the genome composed of repetitive DNA elements are effective at generating rearrangements, while other lesions that appear in unique (single copy) sequences are correctly repaired. Thus, by successfully competing with repair that normally occurs between large homologous chromosomal DNAs, the combination of repetitive elements and DSBs provides genome plasticity and a rich source of evolutionary opportunities. Keywords: CGH-array Diploid G-2 yeast cells were exposed to 80 krad of ionizing radiation and plated on rich media to obtain survivor colonies. Genomic DNA from each of 37 survivors (Cy5/red; JW1 to JW13, and A1 to A24) was competitively hybridized to DNA from the parent diploid strain (Cy3/green). Gains of genomic segments in the survivors were detected as continuous regions of positive Log2 Red:Green ratios, while losses were detected as negative Log2 Red:Green ratios.

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Chromosomal Rearrangements in Cancer: Detection and potential causal mechanisms.

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