Spectrum of somatic mutations detected by targeted next-generation sequencing and their prognostic significance in adult patients with acute lymphoblastic leukemia

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. Electronic supplementary material The online version of this article (doi:10.1186/s13045-017-0431-1) contains supplementary material, which is available to authorized users.

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][4][5].
In the recent years, with the application of nextgeneration 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).
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][8][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 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. 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.