TY - JOUR
T1 - Therapy-induced mutations drive the genomic landscape of relapsed acute lymphoblastic leukemia
AU - Li, Benshang
AU - Brady, Samuel W.
AU - Ma, Xiaotu
AU - Shen, Shuhong
AU - Zhang, Yingchi
AU - Li, Yongjin
AU - Szlachta, Karol
AU - Dong, Li
AU - Liu, Yu
AU - Yang, Fan
AU - Wang, Ningling
AU - Flasch, Diane A.
AU - Myers, Matthew A.
AU - Mulder, Heather L.
AU - Ding, Lixia
AU - Liu, Yanling
AU - Tian, Liqing
AU - Hagiwara, Kohei
AU - Xu, Ke
AU - Zhou, Xin
AU - Sioson, Edgar
AU - Wang, Tianyi
AU - Yang, Liu
AU - Zhao, Jie
AU - Zhang, Hui
AU - Shao, Ying
AU - Sun, Hongye
AU - Sun, Lele
AU - Cai, Jiaoyang
AU - Sun, Hui Ying
AU - Lin, Ting Nien
AU - Du, Lijuan
AU - Li, Hui
AU - Rusch, Michael
AU - Edmonson, Michael N.
AU - Easton, John
AU - Zhu, Xiaofan
AU - Zhang, Jingliao
AU - Cheng, Cheng
AU - Raphael, Benjamin J.
AU - Tang, Jingyan
AU - Downing, James R.
AU - Alexandrov, Ludmil B.
AU - Zhou, Bin Bing S.
AU - Pui, Ching Hon
AU - Yang, Jun J.
AU - Zhang, Jinghui
N1 - Publisher Copyright:
© 2020 by The American Society of Hematology.
PY - 2020
Y1 - 2020
N2 - To study the mechanisms of relapse in acute lymphoblastic leukemia (ALL), we performed whole-genome sequencing of 103 diagnosis-relapse-germline trios and ultra-deep sequencing of 208 serial samples in 16 patients. Relapse-specific somatic alterations were enriched in 12 genes (NR3C1, NR3C2, TP53, NT5C2, FPGS, CREBBP, MSH2, MSH6, PMS2, WHSC1, PRPS1, and PRPS2) involved in drug response. Their prevalence was 17% in very early relapse (<9 months from diagnosis), 65% in early relapse (9-36 months), and 32% in late relapse (>36 months) groups. Convergent evolution, in which multiple subclones harbor mutations in the same drug resistance gene, was observed in 6 relapses and confirmed by single-cell sequencing in 1 case. Mathematical modeling and mutational signature analysis indicated that early relapse resistance acquisition was frequently a 2-step process in which a persistent clone survived initial therapy and later acquired bona fide resistance mutations during therapy. In contrast, very early relapses arose from preexisting resistant clone(s). Two novel relapse-specific mutational signatures, one of which was caused by thiopurine treatment based on in vitro drug exposure experiments, were identified in early and late relapses but were absent from 2540 pan-cancer diagnosis samples and 129 non-ALL relapses. The novel signatures were detected in 27% of relapsed ALLs and were responsible for 46% of acquired resistance mutations in NT5C2, PRPS1, NR3C1, and TP53. These results suggest that chemotherapy-induced drug resistance mutations facilitate a subset of pediatric ALL relapses.
AB - To study the mechanisms of relapse in acute lymphoblastic leukemia (ALL), we performed whole-genome sequencing of 103 diagnosis-relapse-germline trios and ultra-deep sequencing of 208 serial samples in 16 patients. Relapse-specific somatic alterations were enriched in 12 genes (NR3C1, NR3C2, TP53, NT5C2, FPGS, CREBBP, MSH2, MSH6, PMS2, WHSC1, PRPS1, and PRPS2) involved in drug response. Their prevalence was 17% in very early relapse (<9 months from diagnosis), 65% in early relapse (9-36 months), and 32% in late relapse (>36 months) groups. Convergent evolution, in which multiple subclones harbor mutations in the same drug resistance gene, was observed in 6 relapses and confirmed by single-cell sequencing in 1 case. Mathematical modeling and mutational signature analysis indicated that early relapse resistance acquisition was frequently a 2-step process in which a persistent clone survived initial therapy and later acquired bona fide resistance mutations during therapy. In contrast, very early relapses arose from preexisting resistant clone(s). Two novel relapse-specific mutational signatures, one of which was caused by thiopurine treatment based on in vitro drug exposure experiments, were identified in early and late relapses but were absent from 2540 pan-cancer diagnosis samples and 129 non-ALL relapses. The novel signatures were detected in 27% of relapsed ALLs and were responsible for 46% of acquired resistance mutations in NT5C2, PRPS1, NR3C1, and TP53. These results suggest that chemotherapy-induced drug resistance mutations facilitate a subset of pediatric ALL relapses.
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U2 - 10.1182/blood.2019002220
DO - 10.1182/blood.2019002220
M3 - Article
C2 - 31697823
AN - SCOPUS:85077477476
SN - 0006-4971
VL - 135
SP - 41
EP - 55
JO - Blood
JF - Blood
IS - 1
ER -