Chromothripsis in acute myeloid leukemia: biological features and impact on survival

Abstract

Chromothripsis is a one-step genome-shattering catastrophe resulting from disruption of one or few chromosomes in multiple fragments and consequent random rejoining and repair. This study defines incidence of chromothripsis in 395 newly diagnosed adult acute myeloid leukemia (AML) patients from three institutions, its impact on survival and its genomic background. SNP 6.0 or CytoscanHD Array (Affymetrix^®) were performed on all samples. We detected chromothripsis with a custom algorithm in 26/395 patients. Patients harboring chromothripsis had higher age (p = 0.002), ELN high risk (HR) (p < 0.001), lower white blood cell (WBC) count (p = 0.040), TP53 loss, and/or mutations (p < 0.001) while FLT3 (p = 0.025), and NPM1 (p = 0.032) mutations were mutually exclusive with chromothripsis. Chromothripsis-positive patients showed a worse overall survival (OS) (p < 0.001) compared with HR patients (p = 0.011) and a poor prognosis in a COX-HR optimal regression model. Chromothripsis presented the hallmarks of chromosome instability [i.e., TP53 alteration, 5q deletion, higher mean of copy number alteration (CNA), complex karyotype, alterations in DNA repair, and cell cycle] and focal deletions on chromosomes 4, 7, 12, 16, and 17. CBA. FISH showed that chromothripsis is associated with marker, derivative, and ring chromosomes. In conclusion, chromothripsis frequently occurs in AML (6.6%) and influences patient prognosis and disease biology.

Fig. 1

Association between chromothripsis and OS in AML. OS in patients with (green line) and without chromothripsis (blue line): a overall cohort; b survival censored at HSCT; c patients with ELN [37] HR features; d patients with ELN [37] HR features censoring survival at HSCT; e patients treated with intensive chemotherapy with ELN 2017h features; f patients treated with intensive chemotherapy with ELN [37] HR features censoring survival at HSCT

Fig. 2

COX-HR model. COX-HR model in patients’ set considering (a) forest plot of risk factors in COX-HR optimal model (b) in COX-HR model, difference in OS (OS) representing population with (green line) and without (blue line) chromothripsis

Fig. 3

Representation of two chromosomes affected by chromothripsis in different patients, plotted with Rawcopy v. 1.0. a Chromosome 17q with 36 switches and 2–3 changes in CN (involving also homozygous gains). b Chromosome 12p with 28 switches and 2–3 changes in CN (involving also homozygous losses)

Fig. 4

CIRCOS plot representing the overall CNA and genes altered in the two groups (chromothripsis-positive patients vs. chromothripsis-negative patients). a External circular level: genomic landscape in CNA per group of patients (external line represents chromothripsis-positive patients, internal line represents chromothripsis-negative patients). Green lines represent amplifications, red lines represent deletions. b Internal list of selected genes (basing on Fisher's exact test and Atlas of Genetics and Cytogenetics in Oncology and Haematology) deleted in heterozygosis and/or homozygosis with relative frequency in CNA displayed with histograms: chromothripsis-positive patients (external level) and chromothripsis-negative patients (internal level)

Fig. 5

Karyotype analysis in AML patients harboring chromothripsis. FISH analysis with a MYC breakapart probe showing five fusion signals of MYC localized on normal chromosome 8 and on three different marker chromosomes in patient with chromothripsis of chromosome 8. b KMT2A (MLL) breakapart probe showing four copies of KMT2A (four fusion signals) localized on the marker chromosome resulted from chromothripsis of chromosome 11. c With whole chromosome paint probe for chromosome 12 marked in blue revealing part of chromosome 12 on the marker chromosome and on the derivative chromosome 3 from translocation t (3;12). d Showing deletion of TP53 gene (red signal) in the case with chromothripsis of chromosome 17 annotated as ring chromosome by CBA