Genetic hallmarks and clinical implications of chromothripsis in childhood T-cell acute lymphoblastic leukemia

• Published in: Leukemia 2024-11, Vol.38 (11), p.2344-2354
• Main Authors: Pastorczak, Agata, Urbanska, Zuzanna, Styka, Borys, Miarka-Walczyk, Karolina, Sedek, Lukasz, Wypyszczak, Kamila, Wakulinska, Anna, Nowicka, Zuzanna, Szczepański, Tomasz, Stańczak, Marcin, Fendler, Wojciech, Kowalczyk, Jerzy, Młynarski, Wojciech, Lejman, Monika
• Format: Article
• Language: English
• Subjects: 45/22; 45/23; 631/208/68; 631/208/69; Acute lymphoblastic leukemia; Cancer; Cancer Research; Catastrophic events; Childhood; Children; Chromosome rearrangements; Copy number; Critical Care Medicine; Genes; Genomic instability; Hematology; Intensive; Internal Medicine; Leukemia; Li-Fraumeni syndrome; Lymphocytes T; Medical prognosis; Medicine; Medicine & Public Health; Nijmegen breakage syndrome; Oncology; p53 Protein; Patients; Pediatrics; Structural stability; Survival; Tumor suppressor genes; Tumors
• ISSN: 0887-6924; 1476-5551; 1476-5551
• DOI: 10.1038/s41375-024-02370-z

Chromothripsis (cth) is a form of genomic instability leading to massive de novo structural chromosome rearrangements in a one-time catastrophic event. It can cause cancer-promoting alterations, such as loss of sequences for tumor-suppressor genes, formation of oncogenic fusions, and oncogene amplifications. We investigated the genetic background and clinical significance of cth in childhood T-cell acute lymphoblastic leukemia (T-ALL) patients. For this purpose, whole-genome copy number alterations were analyzed in 173 children with newly diagnosed T-ALL using high-density microarrays. Cth was identified in 10 T-ALL samples (5.78%). In six of them, cth occurred in a constitutional background of Nijmegen breakage syndrome ( n  = 5) or Li-Fraumeni syndrome ( n  = 1). Cth generated alterations, including deletions of CDKN2A/B ( n  = 4) and EZH2 ( n  = 4), amplifications of CDK6 ( n  = 2), and NUP214 :: ABL1 and TFG :: GPR128 fusions. Cth-positive leukemias exhibited deletions involving the tumor-suppressor genes RB1 ( n  = 3), TP53 ( n  = 1) and MED12 ( n  = 2). Cth-positive T-ALL patients had a lower probability of 5-year overall survival (OS) [0.56 vs. 0.81; hazard ratio (HR) = 4.14 (1.42–12.02) p  = 0.017] as did 5-year event-free survival [0.45 vs. 0.74; HR = 3.91 (1.52–10.08); p  = 0.012]. Chromothripsis is an infrequent genomic phenomenon in pediatric T-ALL but is significantly associated with cancer-predisposing syndromes and may associate with inferior prognosis.