Mechanistic origins of diverse genome rearrangements in cancer

Abstract

Cancer genomes frequently harbor structural chromosomal rearrangements that disrupt the linear DNA sequence order and copy number. To date, diverse classes of structural variants have been identified across multiple cancer types. These aberrations span a wide spectrum of complexity, ranging from simple translocations to intricate patterns of rearrangements involving multiple chromosomes. Although most somatic rearrangements are acquired gradually throughout tumorigenesis, recent interrogation of cancer genomes have uncovered novel categories of complex rearrangements that arises rapidly through a one-off catastrophic event, including chromothripsis and chromoplexy. Here we review the cellular and molecular mechanisms contributing to the formation of diverse structural rearrangement classes during cancer development. Genotoxic stress from a myriad of extrinsic and intrinsic sources can trigger DNA double-strand breaks that are subjected to DNA repair with potentially mutagenic outcomes. We also highlight how aberrant nuclear structures generated through mitotic cell division errors, such as rupture-prone micronuclei and chromosome bridges, can instigate massive DNA damage and the formation of complex rearrangements in cancer genomes.

Keywords: Cancer genomes; Chromosome rearrangements; Chromothripsis; DNA damage; DNA repair; Genomic instability; Micronuclei; Mitosis.

Figure 1.. Karyotypic differences between normal and cancer genomes.

Representative multi-color DNA fluorescence in situ hybridization analysis of metaphase spreads derived from A) non-transformed diploid human epithelial cells or B) aneuploid human cervical cancer cells (HeLa). Arrows indicate chromosomes with detectable cytogenetic abnormalities.

Figure 2.. Diverse spectrum of chromosome rearrangements types in cancer.

Examples of structural rearrangement types shown in relative order of increasing complexity with or without DNA copy number changes. Note that variation in each rearrangement type is frequent in cancer and will shift its relative location on the spectrum.

Figure 3.. Mutagenic repair outcomes of DNA double-strand breaks.

Major DNA double-strand break repair pathways operative in mammalian cells are shown with an emphasis on their repair outcomes to generate chromosomal rearrangements. Blue and pink lines depict distinct DNA double-strand breaks arising from different genomic loci that are simultaneously present. Light shaded lines represent stretches of microhomologous or homologous sequence.

Figure 4.. Complex rearrangements formed through cell division errors and aberrant nuclear structures.

A) Whole-chromosome segregation errors during mitosis can generate micronuclei, which acquire extensive DNA damage to trigger catastrophic shattering. Chromosome fragments that are reintegrated into daughter cell nuclei activate the DNA damage response and serve as substrates for error-prone DNA repair. B) Chromosome fusions producing a dicentric chromosome can form a bridge during mitosis when pulled toward opposing spindle poles. These bridges connect both daughter cells and become resolved during interphase, which can trigger micronucleus formation, subsequent cycles of breakage-fusion-bridge, and/or additional complex DNA rearrangements.