Comprehensive genomic analysis reveals molecular heterogeneity in pediatric ALK-positive anaplastic large cell lymphoma.

Autor: Shaw TI; Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN, USA.; Department of Biostatistics and Bioinformatics, Moffitt Cancer Center, Tampa, FL, USA., Pounds S; Department of Biostatistics, St. Jude Children's Research Hospital, Memphis, TN, USA., Cao X; Department of Biostatistics, St. Jude Children's Research Hospital, Memphis, TN, USA.; Department of Health Promotion and Disease Prevention, University of Tennessee Health Science Center, Memphis, TN, USA., Ma J; Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN, USA., Palacios G; Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN, USA., Mason J; Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN, USA., Perkins S; Department of Pathology, University of Utah Health Sciences, Salt Lake City, UT, USA., Wu G; Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN, USA., Fan Y; Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN, USA., Wang J; Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN, USA., Zhou X; Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN, USA., Obermayer A; Department of Biostatistics and Bioinformatics, Moffitt Cancer Center, Tampa, FL, USA., Kinney MC; Department of Pathology and Laboratory Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA., Kraveka J; Division of Pediatric Hematology-Oncology, Medical University of South Carolina, Charleston, SC, USA., Gross T; Department of Pediatric Hematology-Oncology, Nationwide Children's Hospital, Columbus, OH, USA., Sandlund J; Department of Oncology, St. Jude Children's Research Hospital, Memphis, TN, USA., Zhang J; Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN, USA., Mullighan C; Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN, USA., Lim MS; Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA., Leventaki V; Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN, USA. vleventaki@mdanderson.org.; Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. vleventaki@mdanderson.org.
Jazyk: angličtina
Zdroj: Leukemia [Leukemia] 2024 Nov 26. Date of Electronic Publication: 2024 Nov 26.
DOI: 10.1038/s41375-024-02468-4
Abstrakt: Anaplastic large cell lymphoma (ALCL) is a mature T-cell lymphoma that accounts for 10-15% of childhood lymphomas. Despite the observation that more than 90% of pediatric cases harbor the anaplastic lymphoma kinase (ALK) rearrangement resulting in aberrant ALK kinase expression, there is significant clinical, morphologic, and biological heterogeneity. To gain insights into the genomic aberrations and molecular heterogeneity within ALK-positive ALCL (ALK+ ALCL), we analyzed 46 pediatric ALK+ ALCLs by whole-exome sequencing, RNA sequencing, and DNA methylation profiling. Whole-exome sequencing found on average 25 SNV/Indel events per sample with recurring genetic events in regulators of DNA damage (TP53, MDM4), transcription (JUNB), and epigenetic regulators (TET1, KMT2B, KMT2A, KMT2C, KMT2E). Gene expression and methylation profiling consistently subclassified ALK+ ALCLs into two groups characterized by differential ALK expression levels. The ALK-low group showed enrichment of pathways associated with immune response, cytokine signaling, and a hypermethylated predominant pattern compared to the ALK-high group, which had more frequent copy number changes and was enriched with pathways associated with cell growth, proliferation, and metabolism. Altogether, these findings suggest that there is molecular heterogeneity within pediatric ALK+ ALCL, predicting distinct biological mechanisms that may provide novel insights into disease pathogenesis and represent prognostic markers.
Competing Interests: Competing interests: TIS reports a patent for EBD CAR pending. CGM reports personal fees from Illumina during the conduct of the study, as well as grants from Pfizer and AbbVie, and other support from Amgen outside the submitted work. No disclosures were reported by the other authors. Ethics approval and consent to participate: This study was conducted in accordance with the International Ethical Guidelines for Biomedical Research Involving Human Subjects. Informed written consent was obtained from all patients and/or their legal guardians before enrollment in the study. The St. Jude Children’s Research Hospital Institutional Review Board approved the use of excess diagnostic material and data for this study (XPD14-018). All methods were performed in accordance with the relevant guidelines and regulations.
(© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)
Databáze: MEDLINE
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