Complex molecular genetic abnormalities involving three or more genetic mutations are important prognostic factors for acute myeloid leukemia.
We conducted a comprehensive analysis of 28 recurrently mutated genes in acute myeloid leukemia (AML) in 271 patients with de novo AML. Co-mutations were frequently detected in the intermediate cytogenetic risk group, at an average of 2.76 co-mutations per patient. When assessing the prognostic impact of these co-mutations in the intermediate cytogenetic risk group, overall survival (OS) was found to be significantly shorter (P=0.0006) and cumulative incidence of relapse (CIR) significantly higher (P=0.0052) in patients with complex molecular genetic abnormalities (CMGAs) involving three or more mutations. This trend was marked even among patients aged ⩽65 years who were also FLT3-ITD (FMS-like tyrosine kinase 3 internal tandem duplications)-negative (OS: P=0.0010; CIR: P=0.1800). Moreover, the multivariate analysis revealed that CMGA positivity was an independent prognostic factor associated with OS (P=0.0007). In stratification based on FLT3-ITD and CEBPA status and 'simplified analysis of co-mutations' using seven genes that featured frequently in CMGAs, CMGA positivity retained its prognostic value in transplantation-aged patients of the intermediate cytogenetic risk group (OS: P=0.0002. CIR: P<0.0001). In conclusion, CMGAs in AML were found to be strong independent adverse prognostic factors and simplified co-mutation analysis to have clinical usefulness and applicability.
Department of Hematology, Nippon Medical School, Tokyo, Japan.
S
S
Wakita
Department of Hematology, Nippon Medical School, Tokyo, Japan.
H
H
Yamaguchi
Department of Hematology, Nagano Red Cross Hospital, Nagano, Japan.
T
T
Ueki
Department of Hematology, NTT Medical Center Tokyo, Tokyo, Japan.
K
K
Usuki
Department of Hematopoietic Stem Cell Transplantation, National Cancer Center Hospital, Tokyo, Japan.
S
S
Kurosawa
Department of Hematology, Japanese Red Cross Kyoto Daini Hospital, Kyoto, Japan.
Y
Y
Kobayashi
Department of Hematology, Japanese Red Cross Kyoto Daini Hospital, Kyoto, Japan.
E
E
Kawata
Department of Hematology, Yokohama Minami Kyousai Hospital, Yokohama, Japan.
K
K
Tajika
Department of Hematology, Yokohama Minami Kyousai Hospital, Yokohama, Japan.
S
S
Gomi
Department of Gastroenterology, Asahi General Hospital, Chiba, Japan.
M
M
Koizumi
Department of Hematology, Nippon Medical School, Tokyo, Japan.
Y
Y
Fujiwara
Department of Hematology, Nippon Medical School, Tokyo, Japan.
S
S
Yui
Department of Hematology, Nippon Medical School, Tokyo, Japan.
K
K
Fukunaga
Department of Hematology, Nippon Medical School, Tokyo, Japan.
T
T
Ryotokuji
Department of Hematology, Nippon Medical School, Tokyo, Japan.
T
T
Hirakawa
Department of Hematology, Nippon Medical School, Tokyo, Japan.
K
K
Arai
Department of Hematology, Nippon Medical School, Tokyo, Japan.
T
T
Kitano
Department of Hematology, Nippon Medical School, Tokyo, Japan.
F
F
Kosaka
Department of Hematology, Nippon Medical School, Tokyo, Japan.
H
http://orcid.org/0000-0002-9652-4559
H
Tamai
Department of Hematology, Nippon Medical School, Tokyo, Japan.
K
K
Nakayama
Department of Hematopoietic Stem Cell Transplantation, National Cancer Center Hospital, Tokyo, Japan.
T
T
Fukuda
Department of Hematology, Nippon Medical School, Tokyo, Japan.
K
K
Inokuchi
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D022762:CCAAT-Enhancer-Binding Proteins / Q000235:genetics / Q000378:metabolism; D002869:Chromosome Aberrations; D002885:Chromosomes, Human, Pair 16; D002891:Chromosomes, Human, Pair 21; D002898:Chromosomes, Human, Pair 8; D020732:Cytogenetic Analysis; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000235:genetics / Q000378:metabolism; D000090205:DNA Methyltransferase 3A; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D049308:Dioxygenases; D005260:Female; D015870:Gene Expression; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000175:diagnosis* / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000235:genetics* / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D000090243:Nucleophosmin; D011379:Prognosis; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D012008:Recurrence; D012189:Retrospective Studies; D016019:Survival Analysis; D051941:fms-Like Tyrosine Kinase 3 / Q000235:genetics / Q000378:metabolism
D022762:CCAAT-Enhancer-Binding Proteins; C515848:CEBPA protein, human; D004268:DNA-Binding Proteins; C000717967:DNMT3A protein, human; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D000090243:Nucleophosmin; D049308:Dioxygenases; C541081:TET2 protein, human; D004248:DNA (Cytosine-5-)-Methyltransferases; D000090205:DNA Methyltransferase 3A; C497970:FLT3 protein, human; D051941:fms-Like Tyrosine Kinase 3