Chromothripsis under the microscope: a cytogenetic perspective of two cases of AML with catastrophic chromosome rearrangement

Chromothripsis is a recently described phenomenon identified in cancer cells that produces catastrophic chromosome reorganization of one or a small number of chromosomes. It has been proposed that the multiple breakage events occur at a single point in time. Here we introduce the term anachromosome to describe an abnormal chromosome produced by chromothripsis. We report two cases of acute myeloid leukemia matching the description of chromothripsis that illustrate different aspects of this phenomenon from a cytogenetic perspective. Fluorescence in situ hybridization (FISH) analyses, including multicolor FISH and FISH for repeat elements that are not present on microarrays and that are resistant to sequencing, helped interpret the rearrangements but did not reveal their level of complexity. The anachromosomes conformed to the normal constraints of chromosome structure by including segments that provide two telomeres and a centromere. In patient samples, there are mixtures of cells with and without deletions. The deletion B allele frequencies for heterozygous loci in a mixture of cells with and without the deletions create a distinctive array pattern that is consistent with all the deletions in the anachromosomes having occurred concurrently. This evidence supporting the single-event hypothesis for chromothripsis has not previously been highlighted, to our knowledge. In the context of exploring mechanisms for chromosome shattering, we discuss a possible connection between chromosome pulverization and fragile sites. Understanding chromothripsis in the context of chromosome biology will help us identify its causes and consequences.