Spectrum of somatic mutations detected by targeted next-generation sequencing and their prognostic significance in adult patients with acute lymphoblastic leukemia
verfasst von:
Juan Feng, Yan Li, Yujiao Jia, Qiuyun Fang, Xiaoyuan Gong, Xiaobao Dong, Kun Ru, Qinghua Li, Xingli Zhao, Kaiqi Liu, Min Wang, Zheng Tian, Yannan Jia, Ying Wang, Dong Lin, Hui Wei, Kejing Tang, Yingchang Mi, Jianxiang Wang
Target-specific next-generation sequencing technology was used to analyze 112 genes in adult patients with acute lymphoblastic leukemia (ALL). This sequencing mainly focused on the specific mutational hotspots. Among the 121 patients, 93 patients were B-ALL (76.9%), and 28 patients (23.1%) were T-ALL. Of the 121 patients, 110 (90.9%) harbored at least one mutation. The five most frequently mutated genes in T-ALL are NOTCH1, JAK3, FBXW7, FAT1, and NRAS. In B-ALL, FAT1, SF1, CRLF2, TET2, and PTPN1 have higher incidence of mutations. Gene mutations are different between Ph+ALL and Ph−ALL patients. B-ALL patients with PTPN11 mutation and T-ALL patients with NOTCH1 and/or FBXW7 mutations showed better survival. But B-ALL with JAK1/JAK2 mutations showed worse survival. The results suggest that gene mutations exist in adult ALL patients universally, they are related with prognosis.
The online version of this article (doi:10.1186/s13045-017-0431-1) contains supplementary material, which is available to authorized users.
Abkürzungen
ALL
Acute lymphoblastic leukemia
CR
Complete remission
NGS
Next-generation sequencing
OS
Overall survival
PCR
Polymerase chain reaction
RFS
Relapse-free survival
SNP
Single nucleotide polymorphisms
WBC
White blood cell
To the editor
Acute lymphoblastic leukemia (ALL) represents one of the most common malignant diseases of childhood, accounts for about 15 ~ 25% of acute leukemia in adults [1]. Adult ALL is generally characterized by diverse biological features, evident clinical heterogeneity, and worse prognosis than pediatric ALL [2]. With the development of genetics in ALL, several new subtypes of ALL and a series of prognostic-related molecular markers are put forward [3‐5].
In the recent years, with the application of next-generation sequencing (NGS) technology, genomics has been extensively developed in both pediatric and adult ALL patients [6]. Samples and clinical information were collected from 121 adult ALL patients (Additional file 1:Table S1) with informed consent (ethical approval serial number is KT2015001-EC-1). These patients were from the Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences. Target regions of 112 genes (Additional file 2: Table S2) were selected on the basis of known or suspected involvement in the pathogenesis of malignant hematologic disorder and were enriched and analyzed using a custom targeted NGS gene panel (Additional file 3). Then, the relationships between the mutations with higher incidence and the prognosis of ALL patients were analyzed (Additional file 4).
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Of the 121 patients, a total of 110 patients (90.9%) harbored at least one gene mutation with a median of 2 (0–7) mutations per sample. Thirty-nine patients (32.2%) had more than 3 gene mutations (Additional file 5: Figure S1). Sixty genes were considered as possible pathogenic mutations when compared against multiple databases (Fig. 1a. The top 38 mutated genes were listed). The five most frequently mutated genes were FAT1, NOTCH1, SF1, CRLF2, and NRAS (mutated in >8% of the cases).
Fig. 1
Frequency of gene mutations and related signal pathways in ALL subtypes. a Frequency of the top 38 gene mutations in different ALL subtypes, which are shown in indicated colors. b Frequency of gene mutations involved in different functional pathways
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In 28 T-ALL cases, the most common mutated gene was NOTCH1, with a mutation rate of 39.3% (n = 11), then JAK3, FBXW7, FAT1, NRAS, CREBBP, DNM2 (mutated in >10% of the cases) (Additional file 6: Figure S2A). In B-ALL, FAT1 was the most accepted mutated gene (10.75%), then SF1, CRLF2, TET2, PTPN11, NRAS, CREBBP, JAK2, DIS3, MPL, and KML2D (mutated in >5% of the cases) (Additional file 6: Figure S2B). In Ph+ B-ALL, FAT1, CRLF2, SF1, EP300, and CREBBP genes mutated at higher incidences (Additional file 6: Figure S2C). However, PTPN11, SF1, TET2, NRAS, JAK2, DIS3, and FAT1 gene mutations occurred popularly in Ph−B-ALL (Additional file 6: Figure S2D).
The main signaling pathways involved in this targeted NGS gene panel were transcription factor/regulator, Ras/protein phosphatase/MARK signaling pathway, JAK-STAT pathway, splicing and mRNA processing regulation, epigenetic modulators, and so on [7‐9]. Frequencies of different signaling pathways involved are listed in Fig. 1b. Genes involved in these signaling pathways are listed in Additional file 7:Table S3.
In full cohort, the median overall survival (OS) was 34.88 (1.25–74.55) months, median relapse-free survival (RFS) was 30.85 (0–73.55) months and 3-year OS and RFS rates were 49%. In the full cohort, patients with PTPN11 mutation had a better prognosis compared with patients without PTPN11 mutation (p = 0.040, p = 0.047), and the patients with JAK2 mutation (7/117) had a worse prognosis compared with patients without JAK2 mutation (p = 0.031, p = 0.018) (Additional file 8: Figure S3). B-ALL patients with PTPN11 mutation (7/93) had a better OS and RFS compared with those without PTPN11 mutation (p = 0.041, p = 0.047) (Additional file 9: Figure S4).
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In T-ALL, patients with NOTCH1 and/or FBXW7 mutations had a better OS and RFS than patients without these mutations (p = 0.035, p = 0.048) (Additional file 10: Figure S5).
Multivariate analysis of OS and RFS showed that the prognostic factors included JAK2 mutations (OS; p= 0.045, RFS; p = 0.021) in the total adult ALL patients cohort. JAK1 mutations (OS; p = 0.004, RFS; p = 0.005) and JAK2 mutations (OS; p = 0.049, RFS; p = 0.044) for Ph−B-ALL. The data was summarized in Table 1.
Table 1
Univariate and multivariate analysis for OS and RFS
OS
RFS
HR2
P value
HR2
P value
Univarite analysis (mut/all)
PTPN11 mut; positive vs negative in full cohort (8/117)
0.043
0.040
0.044
0.047
In B-ALL (7/92)
0.042
0.041
0.042
0.047
In Ph−B-ALL (7/54)
0.035
0.030
0.037
0.047
JAK2 Mut; positive vs negative in full cohort (7/117)
3.02
0.031
3.309
0.018
In B-ALL (5/92)
3.033
0.061
3.145
0.051
In Ph−B-ALL (5/54)
3.728
0.035
3.780
0.031
JAK1 mut; positive vs negative in Ph−B-ALL (4/54)
6.808
0.001
6.562
0.001
NOTCH1 and/or FBXW7 mut; positive vs negative
In T-ALL (12/25)
0.204
0.035
0.223
0.048
Multivariate analysis
PTPN11 mut; positive vs negative in full cohort
0.043
0.052
0.044
0.056
In B-ALL
0.042
0.063
0.042
0.056
In Ph−B-ALL
0.035
0.178
0.037
0.212
JAK2 mut; positive vs negative in full cohort
3.02
0.045
3.309
0.021
In Ph−B-ALL
3.728
0.049
3.780
0.044
JAK1 mut; positive vs negative in Ph−B-ALL
6.808
0.004
6.562
0.005
NOTCH1 and/or FBXW7 mut; positive vs negative
In T-ALL
0.204
0.055
0.223
0.069
In summary, our study suggests that gene mutations exists in adult ALL patients universally, involving a variety of signaling pathways. The frequency and species are varied in different types of ALL. B-ALL patients were accompanied with PTPN11 mutation for good prognosis, while abnormal JAK family often indicates poor prognosis. In T-ALL, mutation of NOTCH1 and/or FBXW7 indicates good prognosis.
Acknowledgements
The authors thank Drs. Tian Yuan and Qi Zhang of MD Anderson Cancer Center for their valuable suggestions.
Funding
This study was supported by the National Science & Technology Pillar Program (Grant no. 2014BAI09B12), Tianjin Major Research Program of Application Foundation and Advanced Technology (15JCZDJC36400), and Science and technology project of Tianjin (15ZXLCSY00010).
Availability of data and materials
Not applicable. All data used for conclusions are presented in the manuscript and figures.
Authors’ contributions
YM and JW were responsible for the conception and design of the study. JF, YL, YJ, and XD participated in the development of methodology of the study. JF, YL, YJ, QF, XG, QL, XZ, KL, ZT, and KT contributed to the acquisition of data (acquired and managed patients’ samples, provided facilities, etc.). JF, YL, KR, YJ, QF, XD, YJ, YW, and DL cooperated with the analysis and interpretation of data (e.g., statistical analysis, biostatistics, computational analysis). JF, YL, YM, JW, MW, and HW wrote, reviewed, and/or revised the manuscript. KR, QL, YJ, and XD contributed to administrative, technical, or material support (i.e., reporting or organizing data, constructing databases). YM supervised the study. All authors read and approved the final manuscript.
Competing interests
The authors declare that they have no competing interests.
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Consent for publication
Not applicable.
Ethics approval and consent to participate
The study design was approved by Ethics Committee of Blood Diseases Hospital, Chinese Academy of Medical Sciences. The reference number is KT2015001-EC-1.
Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
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Spectrum of somatic mutations detected by targeted next-generation sequencing and their prognostic significance in adult patients with acute lymphoblastic leukemia
verfasst von
Juan Feng Yan Li Yujiao Jia Qiuyun Fang Xiaoyuan Gong Xiaobao Dong Kun Ru Qinghua Li Xingli Zhao Kaiqi Liu Min Wang Zheng Tian Yannan Jia Ying Wang Dong Lin Hui Wei Kejing Tang Yingchang Mi Jianxiang Wang
