Genomic landscape ofTP53-mutated myeloid malignancies

Abstract

AbstractTP53-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 ofTP53-mutated myeloid malignancies. The vast majority of cases had multi-hit involvement at theTP53genetic locus (94%), as well as aneuploidy and chromothripsis. Chromosomal patterns of aneuploidy differed significantly fromTP53-mutated cancers arising in other tissues. Recurrent structural variants affected regions that includeETV6on chr12p,RUNX1on chr21, andNF1on chr17q. Most notably forETV6, transcript expression was low in cases ofTP53-mutated myeloid malignancies both with and without structural rearrangements involving chromosome 12p. Telomeric content is increased inTP53-mutated AML/MDS compared other AML subtypes, and telomeric content was detected adjacent to interstitial regions of chromosomes. The genomic landscape ofTP53-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 PointsWGS comprehensively determinesTP53mutation status, resulting in the reclassification of 12% of cases from mono-allelic to multi-hitChromothripsis is more frequent than previously appreciated, with a preference for specific chromosomesETV6is deleted in 45% of cases, with evidence for epigenetic suppression in non-deleted casesNF1is mutated in 48% of cases, with multi-hit mutations in 17% of these casesTP53-mutated AML/MDS is associated with altered telomere content compared with other AMLs