Prognostic Significance Of Comprehensive Gene Mutations And Clinical Characteristics In Adult Acute Lymphoblastic Leukemia Based On Next-Generation Sequencing

Background: Adult T-cell acute lymphoblastic leukemia(T-ALL)is a heterogeneous malignant tumor with poor prognosis.However,accurate prognostic stratification factors are still unclear.This study aims to comprehensively analyze the prognostic significance of gene mutations based on next-generation sequencing(NGS)and clinical characteristics,and to establish new novel risk stratification models for T-ALL.Methods: Data from 90 adult T-cell acute lymphoblastic leukemia/lymphoma(T-ALL/LBL)patients were collected.The association of gene mutations detected by NGS and clinical characteristics with the outcomes of T-ALL/LBL patients were retrospectively analyzed to build three novel risk stratification models through cox proportional hazards model.Results: 47 mutated genes were identified.73.3%(66/90)of patients had at least one mutation,and 36.7%(33/90)had ≥3 mutations.There were even 2 cases with 6 mutations.The genes with higher mutation frequency were NOTCH1 30.0%(27/90),FBXW7 16.7%(15/90),DNMT3 A 14.4%(13/90),PHF6 12.2%(11/90),RUNX1 11.1%(10/90)and JAK3 10.0%(9/90).Mutated genes are grouped by signaling pathways.The most frequently altered signaling pathways were NOTCH pathway(34.4%,31/90),transcriptional regulation pathway(24.4%,22/90),DNA methylation pathway(18.9%,17/90),JAK/STAT pathway(18.9%,17/90),lymphoid differentiation and development pathway(15.6%,14/90)and histone methylation pathway(14.4%,13/90).We further analyzed the pairwise relationship of all mutated genes and signal pathways.By integrated mutational-analysis,we found significant co-occurrence of NOTCH1 mutations and FBXW7 mutations,NOTCH1 mutations and IL7 R mutations,FBXW7 mutations and IL7 R mutations,DNMT3 A mutations and IDH2 mutations,PHF6 mutations and NRAS mutations(P < 0.05 for all comparisons).Results also disclosed some frequently co-occurring signal pathways,including histone methylation signaling pathway and lymphoid differentiation and development signaling pathway,RAS signaling pathway and lymphoid differentiation and development signaling pathway,RAS signaling pathway and transcriptional regulation signaling pathway,lymphoid differentiation and development signaling pathway and transcriptional regulation signaling pathway,JAK/STAT signaling pathway and NOTCH signaling pathway(P < 0.05 for all comparisons).No mutated genes or altered signal pathways were found mutually exclusive in our study.Univariate analysis discovered some gene mutations and clinical characteristics related to patients’ outcomes by event-free survival(EFS),relapse-free survival(RFS)and overall survival(OS).Further multivariate analysis revealed that age(45 years old),PLT(50G/L),LDH(600U/L),response in D19-BMR detection,TP53 and cell cycle signaling pathway alterations and HSCT were integrated into a risk stratification model of EFS.Age(45 years old),WBC(30G/L),response in D19-BMR detection,TP53 and cell cycle signaling pathway alterations and HSCT were integrated into a risk stratification model of OS.According to our risk stratification models,the 1-year EFS and OS rates in low-risk group were significantly higher than that in high-risk group.Conclusions: Our risk stratification models exhibited good prognostic roles in adult T-ALL/LBL patients and might guide individualized treatment and ultimately improve their outcomes.Background: Adult B-cell acute lymphoblastic leukemia(B-ALL)is a system originated in hematopoietic malignancies,and featured by heterogeneous with poor prognosis.Whereas,accurate prognostic stratification factors are still indecisive and unified.This study aims to comprehensively analyze the prognostic significance of gene mutations based on next-generation sequencing(NGS)and clinical characteristics,and to establish new novel risk stratification models for B-ALL.Methods: Data from 180 B-ALL patients were collected,we retrospectively analyzed the association of gene mutations detected by NGS and clinical characteristics with the outcomes of B-ALL patients,thus building two novel risk stratification models through cox proportional hazards model.Results: 66 mutated genes were identified.57.2%(103/180)of patients had at least one mutation,and 11.7%(21/180)had ≥3 mutations.There were even 2 cases with 6 mutations.The genes with higher mutation frequency were TP53 10.6%(19/180),FLT3 6.1%(11/180),NRAS 5.0%(9/180),SETD2 5.0%(9/180),TTN 4.4%(8/180),RUNX1 3.9%(7/180),KRAS 3.9%(7/180),IKZF1 3.9%(7/180)and ABL1 3.9%(7/180).The most frequently altered signaling pathways were RAS pathway(18.3%,33/180),histone methylation pathway(15.0%,27/180),TP53 and cell cycle pathway(11.7%,21/180)and lymphoid differentiation and development pathway(8.3%,15/180).We further analyzed the pairwise relationship of all mutated genes and signal pathways.Whereas,no mutated genes or altered signal pathways were found frequently co-occurred or mutually exclusive in our study.Univariate analysis discovered some gene mutations and clinical characteristics related to patients’ outcomes by event-free survival(EFS),relapse-free survival(RFS)and overall survival(OS).Further multivariate analysis revealed that extramedullary infiltration,WBC(15G/L),response in D19-BMR detection,histone methylation signaling pathway alterations and HSCT were integrated into a risk stratification model of EFS.Age at diagnosis(20 years old),response in D19-BMR detection,histone methylation signaling pathway alterations and HSCT were integrated into a risk stratification model of OS.According to the two novel risk stratification models,the 1-year EFS and OS rates in low-risk group were significantly higher than that in high-risk group.Conclusions: Our risk stratification models exhibited advanced prognostic roles in adult B-ALL and might guide individualized treatment and ultimately promoting their outcomes.