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Chromothripsis in Acute Myeloid Leukemia

المؤلف:  Hoffman, R., Benz, E. J., Silberstein, L. E., Heslop, H., Weitz, J., & Salama, M. E.

المصدر:  Hematology : Basic Principles and Practice

الجزء والصفحة:  8th E , P862

2026-09-06

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Chromothripsis describes a process whereby hundreds of genomic rearrangements have been acquired as a result of a single catastrophic event. A chromosomal region or a chromosome or telomere belonging to other chromosomes is shattered into hundreds of pieces; some but not all are stitched together by the DNA repair machinery in a mosaic patchwork of genomic fragments. Cells not only survive this crisis but emerge with a genomic landscape that confers a selective advantage, thereby promoting further malignant evolution. In addition to the clustering of structural variants, multiple base-pair mutations can also be acquired in a single mitotic explosion, called kataegis. This process drives cytosine-specific mutagenesis in regions flanking sites of genomic rearrangement, and can result in the rapid occurrence of up to 20 base-pair substitutions. The best methodology to identify chromothripsis is high-resolution array SNP karyotyping using at least three of five criteria: (1) Regularity of oscillating copy-number states. In chromothripsis, the copy number value should typically oscillate between two or occasionally three states; (2) the presence of “interspersed regions with loss and retention of heterozygosity,” which means that the segments in the highest copy number state should retain het erozygosity; (3) clustering of breakpoints, 5 to 10 breakpoints should be observed within 50 kb genomic interval; (4) more than 10 break points within a minimum segment size of 10 kb; and (5) 0.3 kb as signal distance between adjacent segments. Using these criteria, chromothripsis has been identified in 6.5% of 395 newly diagnosed AML and these patients are older, higher risk, lower WBC, TP53 loss and/ or mutations, while FLT3 and NPM1 mutations were mutually exclusive with chromothripsis. Chromothripsis-positive patients with AML (and MDS) have a poor OS, particularly those with deletion 5q31.1 to 5q33.1, containing key genes involved in DNA damage and histone modifications, as well as P53 deletion and/or mutation.