Mutations of Epigenetic Modifier Genes as a Poor Prognostic Factor in Acute Promyelocytic Leukemia Under Treatment With All-Trans Retinoic Acid and Arsenic Trioxide.
BACKGROUND
Acute promyelocytic leukemia (APL) is a model for synergistic target cancer therapy using all-trans retinoic acid (ATRA) and arsenic trioxide (ATO), which yields a very high 5-year overall survival (OS) rate of 85 to 90%. Nevertheless, about 15% of APL patients still get early death or relapse. We performed this study to address the possible impact of additional gene mutations on the outcome of APL.


METHODS
We included a consecutive series of 266 cases as training group, and then validated the results in a testing group of 269 patients to investigate the potential prognostic gene mutations, including FLT3-ITD or -TKD, N-RAS, C-KIT, NPM1, CEPBA, WT1, ASXL1, DNMT3A, MLL (fusions and PTD), IDH1, IDH2 and TET2.


RESULTS
More high-risk patients (50.4%) carried additional mutations, as compared with intermediate- and low-risk ones. The mutations of epigenetic modifier genes were associated with poor prognosis in terms of disease-free survival in both training (HR = 6.761, 95% CI 2.179-20.984; P = 0.001) and validation (HR = 4.026, 95% CI 1.089-14.878; P = 0.037) groups. Sanz risk stratification was associated with CR induction and OS.


CONCLUSIONS
In an era of ATRA/ATO treatment, both molecular markers and clinical parameter based stratification systems should be used as prognostic factors for APL.
State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Rui Jin Hospital Affiliated to Shanghai Jiao Tong University (SJTU) School of Medicine and Collaborative Innovation Center of Systems Biomedicine, SJTU, Shanghai, China.
Yang
Y
Shen
State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Rui Jin Hospital Affiliated to Shanghai Jiao Tong University (SJTU) School of Medicine and Collaborative Innovation Center of Systems Biomedicine, SJTU, Shanghai, China.
Ya-Kai
YK
Fu
State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Rui Jin Hospital Affiliated to Shanghai Jiao Tong University (SJTU) School of Medicine and Collaborative Innovation Center of Systems Biomedicine, SJTU, Shanghai, China.
Yong-Mei
YM
Zhu
Zhejiang Institute of Hematology, First Affiliated Hospital, Zhejiang University School of Medicine Peking, China.
Yin-Jun
YJ
Lou
State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Rui Jin Hospital Affiliated to Shanghai Jiao Tong University (SJTU) School of Medicine and Collaborative Innovation Center of Systems Biomedicine, SJTU, Shanghai, China.
Zhao-Hui
ZH
Gu
State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Rui Jin Hospital Affiliated to Shanghai Jiao Tong University (SJTU) School of Medicine and Collaborative Innovation Center of Systems Biomedicine, SJTU, Shanghai, China.
Jing-Yi
JY
Shi
State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Rui Jin Hospital Affiliated to Shanghai Jiao Tong University (SJTU) School of Medicine and Collaborative Innovation Center of Systems Biomedicine, SJTU, Shanghai, China.
Bing
B
Chen
State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Rui Jin Hospital Affiliated to Shanghai Jiao Tong University (SJTU) School of Medicine and Collaborative Innovation Center of Systems Biomedicine, SJTU, Shanghai, China.
Chao
C
Chen
Peking University People's Hospital, China.
Hong-Hu
HH
Zhu
State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Rui Jin Hospital Affiliated to Shanghai Jiao Tong University (SJTU) School of Medicine and Collaborative Innovation Center of Systems Biomedicine, SJTU, Shanghai, China.
Jiong
J
Hu
State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Rui Jin Hospital Affiliated to Shanghai Jiao Tong University (SJTU) School of Medicine and Collaborative Innovation Center of Systems Biomedicine, SJTU, Shanghai, China.
Wei-Li
WL
Zhao
State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Rui Jin Hospital Affiliated to Shanghai Jiao Tong University (SJTU) School of Medicine and Collaborative Innovation Center of Systems Biomedicine, SJTU, Shanghai, China.
Jian-Qing
JQ
Mi
State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Rui Jin Hospital Affiliated to Shanghai Jiao Tong University (SJTU) School of Medicine and Collaborative Innovation Center of Systems Biomedicine, SJTU, Shanghai, China.
Li
L
Chen
State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Rui Jin Hospital Affiliated to Shanghai Jiao Tong University (SJTU) School of Medicine and Collaborative Innovation Center of Systems Biomedicine, SJTU, Shanghai, China.
Hong-Ming
HM
Zhu
State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Rui Jin Hospital Affiliated to Shanghai Jiao Tong University (SJTU) School of Medicine and Collaborative Innovation Center of Systems Biomedicine, SJTU, Shanghai, China.
Zhi-Xiang
ZX
Shen
Zhejiang Institute of Hematology, First Affiliated Hospital, Zhejiang University School of Medicine Peking, China.
Jie
J
Jin
State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Rui Jin Hospital Affiliated to Shanghai Jiao Tong University (SJTU) School of Medicine and Collaborative Innovation Center of Systems Biomedicine, SJTU, Shanghai, China.
Zhen-Yi
ZY
Wang
State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Rui Jin Hospital Affiliated to Shanghai Jiao Tong University (SJTU) School of Medicine and Collaborative Innovation Center of Systems Biomedicine, SJTU, Shanghai, China.
Jun-Min
JM
Li
State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Rui Jin Hospital Affiliated to Shanghai Jiao Tong University (SJTU) School of Medicine and Collaborative Innovation Center of Systems Biomedicine, SJTU, Shanghai, China.
Zhu
Z
Chen
State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Rui Jin Hospital Affiliated to Shanghai Jiao Tong University (SJTU) School of Medicine and Collaborative Innovation Center of Systems Biomedicine, SJTU, Shanghai, China.
Sai-Juan
SJ
Chen
D000293:Adolescent; D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000235:genetics; D004252:DNA Mutational Analysis; D018572:Disease-Free Survival; D044127:Epigenesis, Genetic / Q000235:genetics; D005260:Female; D060045:Genes, Modifier / Q000235:genetics; D006801:Humans; D015473:Leukemia, Promyelocytic, Acute / Q000188:drug therapy* / Q000235:genetics* / Q000401:mortality; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics; D000090243:Nucleophosmin; D010087:Oxides / Q000627:therapeutic use*; D011379:Prognosis; D016896:Treatment Outcome; D014212:Tretinoin / Q000627:therapeutic use*; D055815:Young Adult
D001152:Arsenicals; D014408:Biomarkers, Tumor; C000716967:NPM1 protein, human; D010087:Oxides; D000090243:Nucleophosmin; D014212:Tretinoin; D000077237:Arsenic Trioxide
Acute promyelocytic leukemia; Epigenetic; Mutation; Prognosis