Genomic landscape of TP53 -mutated myeloid malignancies
Genomic landscape of TP53 -mutated myeloid malignancies
Abstract 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 PointsWGS comprehensively determines TP53 mutation 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 chromosomesETV6 is deleted in 45% of cases, with evidence for epigenetic suppression in non-deleted casesNF1 is 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
Duncavage Eric J.、Oetjen Karolyn A.、Miller Christopher A.、Helton Nichole M.、Fulton Robert S.、Tarnawsky Stefan P.、Walter Matthew J.、DiPersio John F.、Heath Sharon E.、Payton Jacqueline E.、Day Ryan B.、Ramakrishnan Sai M.、Fronick Catrina C.、Schroeder Molly C.、Srivatsan Sridhar Nonavinkere、Spencer David H.、Ley Timothy J.、Link Daniel C.、Abel Haley J.、Westervelt Peter
Department of Pathology & Immunology, Washington University School of MedicineDivision of Oncology, Department of Medicine, Washington University School of MedicineDivision of Oncology, Department of Medicine, Washington University School of MedicineDivision of Oncology, Department of Medicine, Washington University School of MedicineMcDonnell Genome Institute, Washington University School of MedicineDivision of Oncology, Department of Medicine, Washington University School of MedicineDivision of Oncology, Department of Medicine, Washington University School of MedicineDivision of Oncology, Department of Medicine, Washington University School of MedicineDivision of Oncology, Department of Medicine, Washington University School of MedicineDepartment of Pathology & Immunology, Washington University School of MedicineDivision of Oncology, Department of Medicine, Washington University School of MedicineDivision of Oncology, Department of Medicine, Washington University School of MedicineMcDonnell Genome Institute, Washington University School of MedicineDepartment of Pathology & Immunology, Washington University School of MedicineDivision of Oncology, Department of Medicine, Washington University School of MedicineDivision of Oncology, Department of Medicine, Washington University School of Medicine||McDonnell Genome Institute, Washington University School of Medicine||Department of Pathology & Immunology, Washington University School of MedicineDivision of Oncology, Department of Medicine, Washington University School of MedicineDivision of Oncology, Department of Medicine, Washington University School of MedicineDivision of Oncology, Department of Medicine, Washington University School of MedicineDivision of Oncology, Department of Medicine, Washington University School of Medicine
医学研究方法基础医学肿瘤学
Duncavage Eric J.,Oetjen Karolyn A.,Miller Christopher A.,Helton Nichole M.,Fulton Robert S.,Tarnawsky Stefan P.,Walter Matthew J.,DiPersio John F.,Heath Sharon E.,Payton Jacqueline E.,Day Ryan B.,Ramakrishnan Sai M.,Fronick Catrina C.,Schroeder Molly C.,Srivatsan Sridhar Nonavinkere,Spencer David H.,Ley Timothy J.,Link Daniel C.,Abel Haley J.,Westervelt Peter.Genomic landscape of TP53 -mutated myeloid malignancies[EB/OL].(2025-03-28)[2025-05-25].https://www.medrxiv.org/content/10.1101/2023.01.10.23284322.点此复制
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