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

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 may associate with inferior prognosis.