Mutational Landscape of Pediatric Acute Lymphoblastic Leukemia

被引：73

作者：

Ding, Ling-Wen ^{[1
]}

Sun, Qiao-Yang ^{[1
]}

Tan, Kar-Tong ^{[1
]}

Chien, Wenwen ^{[1
]}

Thippeswamy, Anand Mayakonda ^{[1
]}

Yeoh, Allen Eng Juh ^{[1
]}

Kawamata, Norihiko ^{[2
,3
]}

Nagata, Yasunobu ^{[4
]}

Xiao, Jin-Fen ^{[1
]}

Loh, Xin-Yi ^{[1
]}

Lin, De-Chen ^{[1
,3
]}

Garg, Manoj ^{[1
,5
]}

Jiang, Yan-Yi ^{[1
]}

Xu, Liang ^{[1
]}

Lim, Su-Lin ^{[1
]}

Liu, Li-Zhen ^{[1
]}

Madan, Vikas ^{[1
]}

Sanada, Masashi ^{[4
,6
]}

Fernandez, Lucia Torres ^{[1
]}

Preethi, Hema ^{[1
]}

Lill, Michael ^{[3
]}

Kantarjian, Hagop M. ^{[7
]}

Kornblau, Steven M. ^{[7
]}

Miyano, Satoru ^{[8
,9
]}

Liang, Der-Cherng ^{[10
]}

Ogawa, Seishi ^{[4
]}

Shih, Lee-Yung ^{[11
]}

Yang, Henry ^{[1
]}

Koeffler, H. Phillip ^{[1
,2
]}

机构：

[1] Natl Univ Singapore, Canc Sci Inst Singapore, Singapore, Singapore

[2] City Hope Natl Med Ctr, Beckman Res Inst, Dept Mol & Cellular Biol, Duarte, CA USA

[3] Univ Calif Los Angeles, Cedars Sinai Med Ctr, Sch Med, Div Hematol Oncol, Los Angeles, CA 90048 USA

[4] Kyoto Univ, Grad Sch Med, Dept Pathol & Tumor Biol, Kyoto, Japan

[5] Canc Inst WIA, Dept Med Oncol & Clin Res, Madras, Tamil Nadu, India

[6] Nagoya Med Ctr, Dept Adv Diag, Clin Res Ctr, Nagoya, Aichi, Japan

[7] Univ Texas Houston, MD Anderson Canc Ctr, Dept Leukemia, 1515 Holcombe Blvd, Houston, TX 77030 USA

[8] Univ Tokyo, Inst Med Sci, Human Genome Ctr, Lab DNA Informat Anal, Tokyo, Japan

[9] Univ Tokyo, Inst Med Sci, Ctr Human Genome, Lab Sequence Anal, Tokyo, Japan

[10] Mackay Mem Hosp, Dept Pediat, Taipei, Taiwan

[11] Chang Gung Univ, Chang Gung Mem Hosp, Div Hematol Oncol, Taipei, Taiwan

来源：

CANCER RESEARCH | 2017年 / 77卷 / 02期

基金：

新加坡国家研究基金会;

关键词：

ACUTE MYELOID-LEUKEMIA; EPIGENETIC REGULATORS; CLONAL EVOLUTION; CELL-CYCLE; SOMATIC MUTATIONS; MONOZYGOTIC TWINS; GENOMIC LANDSCAPE; CHILDHOOD; RELAPSE; EXPRESSION;

D O I：

10.1158/0008-5472.CAN-16-1303

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Current standard of care for patients with pediatric acute lymphoblastic leukemia (ALL) ismainly effective, with high remission rates after treatment. However, the genetic perturbations that give rise to this disease remain largely undefined, limiting the ability to address resistant tumors or develop less toxic targeted therapies. Here, we report the use of next-generation sequencing to interrogate the genetic and pathogenic mechanisms of 240 pediatric ALL cases with their matched remission samples. Commonly mutated genes fell into several categories, including RAS/receptor tyrosine kinases, epigenetic regulators, transcription factors involved in lineage commitment, and the p53/cell-cycle pathway. Unique recurrent mutational hotspots were observed in epigenetic regulators CREBBP (R1446C/H), WHSC1 (E1099K), and the tyrosine kinase FLT3 (K663R, N676K). The mutant WHSC1 was established as a gain-of-function oncogene, while the epigenetic regulator ARID1A and transcription factor CTCF were functionally identified as potential tumor suppressors. Analysis of 28 diagnosis/relapse trio patients plus 10 relapse cases revealed four evolutionary paths and uncovered the ordering of acquisition of mutations in these patients. This study provides a detailed mutational portrait of pediatric ALL and gives insights into the molecular pathogenesis of this disease. (C) 2016 AACR.

引用

页码：390 / 400

页数：11

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