Genomic landscape of -mutated myeloid malignancies.

UNLABELLED

-mutated myeloid malignancies are most frequently associated with complex cytogenetics. The presence of complex and extensive structural variants complicates detailed genomic analysis by conventional clinical techniques. We performed whole genome sequencing of 42 AML/MDS cases with paired normal tissue to characterize the genomic landscape of -mutated myeloid malignancies. The vast majority of cases had multi-hit involvement at the genetic locus (94%), as well as aneuploidy and chromothripsis. Chromosomal patterns of aneuploidy differed significantly from -mutated cancers arising in other tissues. Recurrent structural variants affected regions that include on chr12p, on chr21, and on chr17q. Most notably for , transcript expression was low in cases of -mutated myeloid malignancies both with and without structural rearrangements involving chromosome 12p. Telomeric content is increased in -mutated AML/MDS compared other AML subtypes, and telomeric content was detected adjacent to interstitial regions of chromosomes. The genomic landscape of -mutated myeloid malignancies reveals recurrent structural variants affecting key hematopoietic transcription factors and telomeric repeats that are generally not detected by panel sequencing or conventional cytogenetic analyses.

KEY POINTS

WGS comprehensively determines mutation status, resulting in the reclassification of 12% of cases from mono-allelic to multi-hit Chromothripsis is more frequent than previously appreciated, with a preference for specific chromosomes is deleted in 45% of cases, with evidence for epigenetic suppression in non-deleted cases is mutated in 48% of cases, with multi-hit mutations in 17% of these cases -mutated AML/MDS is associated with altered telomere content compared with other AMLs.