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

Author:

Pastorczak Agata1ORCID,Urbanska Zuzanna1ORCID,Styka Borys2,Miarka-Walczyk Karolina1,SĘDEK Łukasz3,Wypyszczak Kamila1,Wakulinska Anna4,Nowicka Zuzanna1,Szczepański Tomasz5ORCID,Stańczak Marcin1ORCID,Fendler Wojciech1,Kowalczyk JerzyORCID,Mlynarski WojciechORCID,Lejman Monika2

Affiliation:

1. Medical University of Lodz

2. Medical University of Lublin

3. Medical University of Silesia, Zabrze, POLAND

4. The Children's Memorial Health Institute

5. Medical University of Silesia

Abstract

Abstract

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 inferior prognosis.

Publisher

Springer Science and Business Media LLC

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