Genomic landscape of TP53-mutated myeloid malignancies

TP53 -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 TP53 -mutated myeloid malignancies. The vast majority of cases had multi-hit involvement at the TP53 genetic locus (94%), as well as aneuploidy and chromothripsis. Chromosomal patterns of aneuploidy differed significantly from TP53 -mutated cancers arising in other tissues. Recurrent structural variants affected regions that include ETV6 on chr12p, RUNX1 on chr21, and NF1 on chr17q. Most notably for ETV6 , transcript expression was low in cases of TP53 -mutated myeloid malignancies both with and without structural rearrangements involving chromosome 12p. Telomeric content is increased in TP53 -mutated AML/MDS compared other AML subtypes, and telomeric content was detected adjacent to interstitial regions of chromosomes. The genomic landscape of TP53 -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 ### Competing Interest Statement J.F.D. has an equity ownership position in Magenta Therapeutics and WUGEN and receives research funding from Amphivena Therapeutics, NeoImmune Tech, Macrogenics, Incyte, BiolineRx, and WUGEN. D.H.S. has received research funding from Illumina and consultant fees and stock options from WUGEN. E.J.D. is a consultant for Cofactor Genomics, Genescopy LLC, and Vertex, and has received honoraria from Blueprint Bio, AbbVie, and Illumina. Funding from these sources was not used for this study. The remaining authors declare no competing financial interests. ### Funding Statement Research support includes the Genomics of Acute Myeloid Leukemia Program Project grant NCI P01 CA101937 (D.C.L and T.J.L.), Specialized Program of Research Excellence in Leukemia NCI P50 CA171963 (D.C.L.), NCI K12 CA167540 (K.A.O. and R.B.D.), NCI R50 CA211782 (C.A.M), and American Society of Hematology Scholar Award (K.A.O.). Core services were provided by the Alvin J. Siteman Cancer Center Tissue Procurement Core and Biostatistics Shared Resource Core through an NCI Cancer Center grant (P30CA091842) and by the Cytogenomics and Molecular Pathology Laboratory, Genome Technology Access Center, and the McDonnell Genome Institute at the Washington University School of Medicine. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: IRB of Washington University in School of Medicine gave ethical approval for this work. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes The datasets generated during and analyzed during the current study are deposited in the dbGap repository, in study phs000159. The supplementary tables for this study are deposited in Zenodo repository doi: 10.5281/zenodo.7523559.