The association of a distinctive allele of NAD(P)H:quinone oxidoreductase with pediatric acute lymphoblastic leukemias with MLL fusion genes in Japan.
OBJECTIVE
The enzyme NAD(P)H:quinone oxidoreductase (NQO1) detoxifies chemicals with quinone rings including benzene metabolites and flavonoids. Previous studies in Caucasian populations have provided evidence that a loss of function allele at nt 609 (C609T, Pro187Ser) is associated with increased risk of infant acute lymphoblastic leukemia (ALL) with MLL-AF4 fusion genes.


METHODS
We genotyped 103 infants (<18 months) with ALL or acute myeloid leukemia (AML) in Japan and 185 controls for the frequency of allelic variation at nt 609 and 465 in NQO1 using standardized polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) methodology.


RESULTS
The C609T polymorphism is very common in Japan but we found no link with altered risk for infant ALL. However, a variant of another allele at nt 465 (C465T, Arg139Trp), also associated with diminished enzyme activity, was strongly associated (OR 6.36; CI 1.84-21.90; p=0.002) with infant ALL, especially in t(4;11)(q21;q23), MLL-AF4. No association was found between this allele and risk of infant AML with MLL gene fusions or infant ALL without MLL gene fusions. The same C465T allele has been linked recently, in an Oriental population, to sensitivity to benzene hematotoxicity.


CONCLUSIONS
These data endorse the notion that infant ALL with MLL fusion genes have a unique etiology possibly involving transplacental exposure to chemicals.
Eguchi-Ishimae
Minenori
M
Section of Haemato-Oncology, Institute of Cancer Research, London, UK.
Eguchi
Mariko
M
Ishii
Eiichi
E
Knight
Deborah
D
Sadakane
Yujirou
Y
Isoyama
Keiichi
K
Yabe
Hiromasa
H
Mizutani
Shuki
S
Greaves
Mel
M
D000483:Alleles; D044466:Asian People / Q000235:genetics*; D005787:Gene Frequency / Q000235:genetics; D014644:Genetic Variation / Q000235:genetics; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D007564:Japan; D051788:Myeloid-Lymphoid Leukemia Protein / Q000235:genetics*; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000235:genetics*; D015514:Oncogene Proteins, Fusion / Q000235:genetics*; D011110:Polymorphism, Genetic; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics*
C113855:MLL-AF4 fusion protein, human; D015514:Oncogene Proteins, Fusion; D051788:Myeloid-Lymphoid Leukemia Protein; D016660:NAD(P)H Dehydrogenase (Quinone); C447479:NQO1 protein, human