Landscape of driver mutations and their clinical impacts in pediatric B-cell precursor acute lymphoblastic leukemia

Hiroo Ueno, Kenichi Yoshida, Yusuke Shiozawa, Yasuhito Nannya, Yuka Iijima-Yamashita, Nobutaka Kiyokawa, Yuichi Shiraishi, Kenichi Chiba, Hiroko Tanaka, Tomoya Isobe, Masafumi Seki, Shunsuke Kimura, Hideki Makishima, Masahiro M. Nakagawa, Nobuyuki Kakiuchi, Keisuke Kataoka, Tetsuichi Yoshizato, Dai Nishijima, Takao Deguchi, Kentaro OhkiAtsushi Sato, Hiroyuki Takahashi, Yoshiko Hashii, Sadao Tokimasa, Junichi Hara, Yoshiyuki Kosaka, Koji Kato, Takeshi Inukai, Junko Takita, Toshihiko Imamura, Satoru Miyano, Atsushi Manabe, Keizo Horibe, Seishi Ogawa, Masashi Sanada

Research output: Contribution to journalArticlepeer-review

5 Citations (Scopus)

Abstract

Recent genetic studies using high-throughput sequencing have disclosed genetic alterations in B-cell precursor acute lymphoblastic leukemia (B-ALL). However, their effects on clinical outcomes have not been fully investigated. To address this, we comprehensively examined genetic alterations and their prognostic impact in a large series of pediatric B-ALL cases. We performed targeted capture sequencing in a total of 1003 pediatric patients with B-ALL from 2 Japanese cohorts. Transcriptome sequencing (n 5 116) and/or array-based gene expression analysis (n 5 120) were also performed in 203 (84%) of 243 patients who were not categorized into any disease subgroup by panel sequencing or routine reverse transcription polymerase chain reaction analysis for major fusions in B-ALL. Our panel sequencing identified novel recurrent mutations in 2 genes (CCND3 and CIC), and both had positive correlations with ETV6-RUNX1 and hypodiploid ALL, respectively. In addition, positive correlations were also newly reported between TCF3-PBX1 ALL with PHF6 mutations. In multivariate Cox proportional hazards regression models for overall survival, TP53 mutation/deletion, hypodiploid, and MEF2D fusions were selected in both cohorts. For TP53 mutations, the negative effect on overall survival was confirmed in an independent external cohort (n 5 466). TP53 mutation was frequently found in IGH-DUX4 (5 of 57 [9%]) ALL, with 4 cases having 17p LOH and negatively affecting overall survival therein, whereas TP53 mutation was not associated with poor outcomes among NCI (National Cancer Institute) standard risk (SR) patients. A conventional treatment approach might be enough, and further treatment intensification might not be necessary, for patients with TP53 mutations if they are categorized into NCI SR.

Original languageEnglish
Pages (from-to)5165-5173
Number of pages9
JournalBlood Advances
Volume4
Issue number20
DOIs
Publication statusPublished - 2020 Oct 23
Externally publishedYes

ASJC Scopus subject areas

  • Hematology

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