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NEOPLASIA
From the Division of Environmental Health Sciences,
School of Public Health, University of California, Berkeley, CA;
Leukaemia Research Fund Centre for Clinical Epidemiology, Leeds, United
Kingdom; and Department of Haematology, University of Leeds, Leeds,
United Kingdom.
NAD(P)H:quinone oxidoreductase 1 (NQO1) is an
enzyme that detoxifies quinones and reduces oxidative stress. A
cysteine-to-threonine (C Clues to the etiology of leukemia may be gained
through the study of genetic susceptibility in candidate genes.
NAD(P)H:quinone oxidoreductase 1 (NQO1; EC 1.6.99.2), originally called
DT-diaphorase,1 is an enzyme that is able to detoxify a
number of natural and synthetic compounds, including quinones and their
derivatives.2,3 It is induced by synthetic antioxidants
and cruciferous vegetables4,5 and protects cells against
oxidative stress.
A single nucleotide polymorphism (cysteine-to-threonine, [C Evidence that the NQO1 variant allele may be
significantly overrepresented in therapy-related myeloid leukemias and
in those with specific chromosome aberrations has been recently
presented.12 In addition, it has been reported that
infant leukemias with MLL gene rearrangements have a
significantly increased frequency of the NQO1 C609T
allele.13 The NQO1 C609T polymorphism has also been shown to be associated with a greater risk of leukopenia (low
white blood cell counts) in benzene-exposed individuals.14 Lack of, or low, NQO1 activity may therefore predispose individuals exposed to chemotherapy drugs and benzene to a greater risk of leukemia. These studies led us to ask whether low NQO1 activity may
play a role in the etiology of adult acute leukemia in the general
population. In the present study, we have applied a polymerase chain
reaction-restriction fragment length polymorphism (PCR-RFLP) assay to
survey the distribution of mutant NQO1 alleles in white patients with de novo acute leukemia and more than 800 control subjects.
Case-control study population and sample collection
Information collected from medical notes and cytogenetic
laboratories permitted further diagnostic classification. Acute
leukemia was defined as de novo if the patient had no history of
chemotherapy or radiotherapy and had no prior diagnoses of
myelodysplastic syndrome, chronic myeloid leukemia, or chronic
myeloproliferative disorder. Cytogenetic abnormalities among acute
myeloid leukemia (AML) cases were hierarchically classified into one of
the following groups: normal; reciprocal translocations/inversions
associated with good prognosis, that is t(15;17), t(8;21) or inv(16);
partial or complete deletion of chromosomes 5 or 7, that is
Cytogenetically characterized case series
Analysis of NQO1 genotype Laboratory personnel were blinded to case-control status (DNA was isolated in Leeds and sent encoded to Berkeley for analysis). NQO1 alleles were analyzed as previously described.12 Briefly, DNA from study subjects was PCR-amplified with sense primer NQO1 F: 5'-AAG CCC AGA CCA ACT TCT-3', and antisense primer DT-2: 5'-TCT CCT CAT CCT GTA CCT CT-3', amplifying a 304-base pair (bp) region including the NQO1 polymorphism. The PCR reaction mixture consisted of 0.1 to 0.5 µg DNA, 25 pmol of each primer, 50 mM KCl, 10 mM Tris-HCl (pH 8.3), 2.5 pmol of each dNTP, 5% dimethyl sulfoxide (DMSO), and 0.25 units Taq polymerase in a total volume of 50 µL. This was subjected to 40 cycles (94°C for 50 seconds, 52°C for 50 seconds, and 72°C for 30 seconds) followed by an extension at 72°C for 10 minutes. The PCR products were electrophoresed in 2% agarose.If the DNA did not amplify by regular PCR, a nested PCR was applied. The DNA was first PCR-amplified with the sense primer NQO1 454A: 5'-GAG ACG CTA GCT CTG AAC TGA T-3', and antisense primer NQO1 454B: 5'-GGA AAT CCA GGC TAA GGA AT-3'. The master mix contained 0.1 µg DNA (± 10 ng), 25 pmol of each primer, 50 mM KCl, 10 mM Tris-HCl (pH 8.3), 2.5 pmol of each dNTP, and 0.25 U Taq polymerase in a total volume of 50 µL and was subjected to 35 cycles (94°C for 30 seconds, 58°C for 30 seconds). A second nested PCR using 1 µL of the first PCR product was performed with the same reagents but with primers NQO1F and DT-2 (see above). This reaction was also subjected to 35 cycles (94°C for 30 seconds, 58°C for 30 seconds). The second PCR product was electrophoresed in 2% agarose. HinfI 10 × digestion buffer (1.5 µL) was added to 25 µL of the PCR product to adjust pH and salt concentration, followed by 10 units of HinfI enzyme (Boehringer Mannheim, Indianapolis, IN). The mixture was incubated at 37 °C for at least 2 hours. The digestion product was electrophoresed in 4% agarose and visualized by staining with ethidium bromide. The 304-bp PCR product contained one nonpolymorphic HinfI site as well as the polymorphic site. A 33-bp fragment was excised from the nonpolymorphic HinfI site independent of genotype. The polymorphism also introduces a second HinfI restriction site, which after digestion with HinfI resulted in 3 different combinations of bands: only one band of 271 bp corresponding to the genotype of homozygotes for the wild-type allele; 3 bands, 271 bp, 151 bp, and 120 bp in length, corresponding to the genotype of heterozygotes; and 2 bands, 151 bp and 120 bp in length, corresponding to the genotype of homozygotes for the mutant allele. Both positive and negative control samples were included in the analysis at all times. Data analysis For the case-control study, odds ratios and 95% confidence intervals were estimated by means of conditional logistic regression.18 The analysis was restricted to white case subjects and their individually matched white controls. Socioeconomic status was adjusted for using an area-based deprivation indicator that was created by linking to the 1991 United Kingdom census and coding the Townsend score of the address at diagnosis.19 The likelihood ratio test was used to test for interaction between NQO1 and other factors such as gender; age (as both a continuous variable and in the categories younger than 40 years, 40 to 54 years, and 55 years and older); and smoking status at 2 years before diagnosis (never/ever smoked). Subgroup analyses were conducted for AML and acute lymphoblastic leukemia (ALL), by French-American-British (FAB) group or immunophenotype, and by cytogenetics. For the case series, associations within specific cytogenetic subgroups were examined by means of Pearson's 2 test. All analyses were conducted by means
of the statistical package Stata (Stata, College Station, TX).
In the control population, the NQO1 C609T genotype was distributed as follows: 67% wild-type (CC), 29% heterozygotes (CT), and 4% homozygous mutants (TT). The mutant allele frequency was 0.188, which is consistent with previous reports in whites and the Hardy-Weinberg formula, as well as the first report of null NQO1 activity in 4% of the British population.20 Acute leukemia cases had the following distribution: 58% CC; 38% CT; 4% TT. Effect of the NQO1 C609T polymorphism on risk of de novo acute leukemia Being heterozygous or homozygous for the mutant NQO1 C609T allele was associated with a 49% increased risk of acute leukemia in 490 case patients, compared with 836 matched controls who were successfully genotyped (OR = 1.49; 95% CI, 1.17-1.89) (Table 1). This increased risk was higher for ALL than for AML, although the difference is not statistically significant. Subcategorization of the AMLs according to the FAB subtypes and of the ALLs by immunophenotype revealed no significant differences among groups (Table 1).
Effect of the NQO1 C609T polymorphism on risk of de novo acute myeloid leukemias with differing cytogenetics Table 2 shows, for the case-control study, odds ratios for de novo AMLs with specific cytogenetics, relative to their matched controls. There was a significant association of low or null NQO1 activity with AML of a normal karyotype (OR = 1.71; 95% CI, 1.09-2.69) and for those AMLs harboring specific translocations and inversions (OR = 2.39; 95% CI, 1.34-4.27). The highest and most significant association was found for AML with inv(16) (OR = 8.13; 95% CI, 1.43-46.42). Risks were increased, although not significantly, for AMLs with t(15;17), t(8;21), or loss or partial deletion of chromosomes 5 and 7. Conversely, acute myeloid leukemias with other cytogenetic abnormalities were not associated with the mutant NQO1 C609T allele.
Table 3 presents the distribution of NQO1
within the MRC case series excluding the 58 patients previously
analyzed in the case-control study. Within the case series,
the distribution of NQO1 among cytogenetic groups showed evidence of
heterogeneity (
Effect of age, sex, and smoking on risk associated with NQO1 C609T polymorphism Stratification by sex, age, or smoking status had no effect on the analysis, so the effect of NQO1 on the risk of acute leukemia is similar for males and females, for any age group, and for smokers and nonsmokers.
In a large case-control study of more than 1300 white adults, we report here that an inactivating C609T polymorphism in the NQO1 gene is associated with a significant excess of de novo acute leukemia, with increased risks for both ALL and AML. This builds upon earlier findings that the NQO1 C609T polymorphism is associated with an enhanced risk of therapy-related leukemia12 and infant leukemia with MLL gene rearrangements.13 The NQO1 C609T polymorphism has also been shown to be associated with a greater risk of benzene-induced hematotoxicity and leukemia.21 We subcategorized as many of the AML cases in our study as possible according to their clinically established cytogenetics. The strongest effect of the NQO1 C609T polymorphism was observed for AML cases harboring translocations or inversions, with inv(16) cases exhibiting the highest odds ratio of 8.13. We were concerned that this might be a chance finding, because it was based on a relatively small number of cases following subclassification by cytogenetics. However, performing an unmatched analysis on the case-control study data, using all control subjects and stratifying on the matching variables, still resulted in increased odds ratios within the same cytogenetic subgroups as were observed with a matched analysis. In particular, low activity of NQO1 remained associated with inv(16) (OR = 4.16; 95% CI, 1.54-11.24). Furthermore, analysis of the additional MRC cases of AML confirmed our findings for the cytogenetic subgroups in the case-control study, especially the high frequency of inv(16) cases with low or null activity at NQO1. Our finding is also consistent with the Larson et al study,12 which reported that the frequency of heterozygotes with low NQO1 activity in a small group of 10 cases with inv(16) or t(15;17) was 70%, twice the expected rate of 34%. Thus, it seems likely that low NQO1 activity confers a significantly increased risk of contracting AML with inv(16). The question then becomes why cases with inv(16) should have the highest risk. The obvious explanation for the strong association between AML cases with inv(16) and low or null NQO1 activity is that certain substrates that are normally detoxified by NQO1 are highly effective at causing inv(16). However, it is of interest that the NQO1 gene is located on chromosome 16q22.1, one of the breakpoints for the inv(16) rearrangement. It is possible that one copy of the NQO1 gene is disrupted by the rearrangement, with the result that heterozygotes would have null NQO1 activity in leukemic cells with the inv(16). This loss of activity could be strongly associated with the production of secondary genetic changes caused by exposure to NQO1 substrates after an inv(16) has arisen, leading to a leukemic clone. Although the risk for inv(16) is the highest for all the cytogenetic changes we analyzed, it should be noted that other classified cytogenetic subgroups of AML also had odds ratios of 1.46 or greater and that none of these differ significantly from one another as confidence intervals overlap (Table 2). Some of these increased odds ratios were not significantly elevated, however. For example, the increased risk for AML harboring alterations in chromosomes 5 and 7 had an odds ratio of 1.57 but was not significantly elevated, although our upper confidence limit certainly does not refute an excess of such cases. This is somewhat at odds with the earlier findings of Larson et al,12 in which the greatest risk associated with low NQO1 activity was for leukemias with alterations in chromosomes 5 or 7. There are many differences, however, between the leukemia cases studied here and those in the Larson et al study.12 More than half of the cases in the Larson et al study12 in Chicago were therapy-related AMLs, whereas we chose to examine only de novo leukemia cases. Some recent publications have indicated that therapy-related AMLs may be pathologically distinct from the de novo group. A much higher incidence of microsatellite instability and abnormalities of the mismatch repair pathway22,23 has been reported in t-AML, and although subsequent studies have not corroborated these findings,24 it remains a distinct possibility that risk factors important in these types of leukemia will be different. The source of DNA was also different in the 2 studies. The Larson et al study12 used lymphoblastoid cell lines, which may result in bias through analysis of a selected subgroup of patients who have transformable lymphocytes. The current study looked at patient material directly, which more accurately reflects the group as a whole. A slight concern is the potential for contamination of the material with leukemic blast DNA that could have a different genotype than the normal host DNA. However, it is highly unlikely that the NQO1 C609T polymorphism arises from a novel mutation in the leukemic cells or is selected for in tumor progression. At most, 1 or 2 cases may have been misclassified as a result of a different genotype in the leukemic blast cells. This would not significantly affect the data or alter the conclusions made. By inference, our data suggest that environmental agents that are
normally detoxified by NQO1 are risk factors for producing ALL and AML
with chromosomal translocations and inversions. Chromosome translocations and inversions most probably arise as a result of DNA
double-strand breaks followed by erroneous repair.25,26 Thus, agents that cause double-strand breaks, inhibit DNA repair, and
are normally detoxified by NQO1 are candidate environmental agents
responsible for leukemia. Interestingly, the phenolic metabolites of
the established leukemogen benzene accumulate in the bone
marrow.27 These metabolites One puzzling aspect of our finding of an association between null or low NQO1 activity and adult acute leukemia is that NQO1 protein expression in peripheral blood cells and bone marrow progenitors is normally very low, but is highly induc-ible.2,35 Aside from its inducibility, the presence of NQO1 in other cells such as the bone marrow stroma and/or liver hepatocytes, where it is highly expressed, may be important in protecting against leukemogenesis. In summary, we report that null or low NQO1 activity caused by inheritance of one or more mutant C609T alleles is associated with increased risk of de novo acute leukemia in adults. Further work is likely to elucidate a number of other low-penetrance genes that are associated with acute leukemia, and this will provide further clues to its potential etiology in the general population.
The authors thank A. Moorman for the cytogenetic classification and the staff of the Leukaemia Research Fund Centre for collection of interview data.
Submitted June 12, 2000; accepted October 31, 2000.
Supported by the National Foundation for Cancer Research and the Leukaemia Research Fund of Great Britain.
The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked "advertisement" in accordance with 18 U.S.C. section 1734.
Reprints: Martyn T. Smith, Professor of Toxicology, Division of Environmental Health Sciences, School of Public Health, 216 Earl Warren Hall, University of California, Berkeley, CA; e-mail: martynts{at}uclink4.berkeley.edu.
1. Ernster L, Danielson L, Ljunggren M. DT-diaphorase, I: purification from the soluble fraction of rat liver cytoplasm and properties. Biochim Biophys Acta. 1962;58:171[Medline] [Order article via Infotrieve]. 2. Ross D. Quinone reductases. In: Sipes IG,McQueen CA,Gandolfi AJ, eds. -in-chief; Guengerich FP, ed. Comprehensive Toxicology. Vol 3. New York, NY: Pergamon Press; 1997:179. 3. Ernster L. DT-diaphorase: its structure, function, regulation, and role in antioxidant defence and cancer chemotherapy. In: Yagi K, ed. Pathophysiology of Lipid Peroxides and Related Free Radicals. Basel, Switzerland: S. Karger; 1998:149.
4.
Benson AM, Hunkeler MJ, Talalay P.
Increase of NAD(P)H:quinone reductase by dietary antioxidants: possible role in protection against carcinogenesis and toxicity.
Proc Natl Acad Sci U S A.
1980;77:5216 5. Joseph P, Xie T, Xu Y, Jaiswal AK. NAD(P)H:quinone oxidoreductase1 (DT-diaphorase): expression, regulation, and role in cancer. Oncol Res. 1994;6:525[Medline] [Order article via Infotrieve].
6.
Traver RD, Horikoshi T, Danenberg KD, et al.
NAD(P)H:quinone oxidoreductase gene expression in human colon carcinoma cells: characterization of a mutation which modulates DT-diaphorase activity and mitomycin sensitivity.
Cancer Res.
1992;52:797 7. Siegel D, McGuinness SM, Winski SL, Ross D. Genotype-phenotype relationships in studies of a polymorphism in NAD(P)H:quinone oxidoreductase 1. Pharmacogenetics. 1999;9:113[Medline] [Order article via Infotrieve]. 8. Kelsey KT, Ross D, Traver RD, et al. Ethnic variation in the prevalence of a common NAD(P)H quinone oxidoreductase polymorphism and its implications for anti-cancer chemotherapy. Br J Cancer. 1997;76:852[Medline] [Order article via Infotrieve]. 9. Rosvold EA, McGlynn KA, Lustbader ED, Buetow KH. Identification of an NAD(P)H:quinone oxidoreductase polymorphism and its association with lung cancer and smoking. Pharmacogenetics. 1995;5:199[Medline] [Order article via Infotrieve]. 10. Schulz WA, Krummeck A, Rösinger I, et al. Increased frequency of a null-allele for NAD(P)H: quinone oxidoreductase in patients with urological malignancies. Pharmacogenetics. 1997;7:235[CrossRef][Medline] [Order article via Infotrieve]. 11. Wiencke JK, Spitz MR, McMillan A, Kelsey KT. Lung cancer in Mexican-Americans and African-Americans is associated with the wild-type genotype of the NAD(P)H: quinone oxidoreductase polymorphism. Cancer Epidemiol Biomarkers Prev. 1997;6:87[Abstract].
12.
Larson RA, Wang Y, Banerjee M, et al.
Prevalence of the inactivating 609C
13.
Wiemels JL, Pagnamenta A, Taylor GM, Eden OB, Alexander FE, Greaves MF.
A lack of a functional NAD(P)H:quinone oxidoreductase allele is selectively associated with pediatric leukemias that have MLL fusions: United Kingdom Childhood Cancer Study Investigators.
Cancer Res.
1999;59:4095 14. Rothman N, Li GL, Dosemeci M, et al. Hematotoxicity among Chinese workers heavily exposed to benzene [Comment appears in Am J Ind Med. 1996;29:225]. Am J Ind Med. 1996;29:236[CrossRef][Medline] [Order article via Infotrieve]. 15. Kane EV, Roman E, Cartwright R, Parker J, Morgan G. Tobacco and the risk of acute leukaemia in adults. Br J Cancer. 1999;81:1228[CrossRef][Medline] [Order article via Infotrieve].
16.
Grimwade D, Walker H, Oliver F, et al.
The importance of diagnostic cytogenetics on outcome in AML: analysis of 1,612 patients entered into the MRC AML 10 trial. The Medical Research Council Adult and Children's Leukaemia Working Parties.
Blood.
1998;92:2322-2333
17.
Hann IM, Stevens RF, Goldstone AH, et al.
Randomized comparison of DAT versus ADE as induction chemotherapy in children and younger adults with acute myeloid leukemia: results of the Medical Research Council's 10th AML trial (MRC AML10). Adult and Childhood Leukaemia Working Parties of the Medical Research Council.
Blood.
1997;89:2311-2318 18. Breslow NE, Day NE. Classical methods of analysis of matched data. In: Davis W, ed. The Analysis of Case-Control Studies. 6th ed. Lyon, France: International Agency for Research in Cancer; 1980:162. 19. Townsend P, Phillimore P, Beattie A. Health and Deprivation: Inequality and the North. London United Kingdom: Croom Helm; 1988. 20. Edwards YH, Potter J, Hopkinson DA. Human FAD-dependent NAD(P)H diaphorase. Biochem J. 1980;187:429[Medline] [Order article via Infotrieve].
21.
Rothman N, Smith MT, Hayes RB, et al.
Benzene poisoning, a risk factor for hematological malignancy, is associated with the NQO1 609C
22.
Ben-Yehuda D, Krichevsky S, Caspi O, et al.
Microsatellite instability and p53 mutations in therapy-related leukemia suggest mutator phenotype.
Blood.
1996;88:4296
23.
Zhu YM, Das-Gupta EP, Russell NH.
Microsatellite instability and p53 mutations are associated with abnormal expression of the MSH2 gene in adult acute leukemia.
Blood.
1999;94:733 24. Rimsza LM, Kopecky KJ, Ruschulte J, et al. Microsatellite instability is not a defining genetic feature of acute myeloid leukemogenesis in adults: results of a retrospective study of 132 patients and review of the literature. Leukemia. 2000;14:1044[CrossRef][Medline] [Order article via Infotrieve]. 25. Gillert E, Leis T, Repp R, et al. A DNA damage repair mechanism is involved in the origin of chromosomal translocations t(4;11) in primary leukemic cells. Oncogene. 1999;18:4663[CrossRef][Medline] [Order article via Infotrieve]. 26. Difilippantonio MJ, Zhu J, Chen HT, et al. DNA repair protein Ku80 suppresses chromosomal aberrations and malignant transformation. Nature. 2000;404:510[CrossRef][Medline] [Order article via Infotrieve]. 27. Smith MT. The mechanism of benzene-induced leukemia: a hypothesis and speculations on the causes of leukemia. Environ Health Perspect. 1996;104(suppl 6):1219.
28.
Smith MT.
Benzene, NQO1, and genetic susceptibility to cancer [comment].
Proc Natl Acad Sci U S A.
1999;96:7624
29.
Brownson RC, Chang JC, Davis JR.
Cigarette smoking and risk of adult leukemia.
Am J Epidemiol.
1991;134:938 30. Korte JE, Hertz-Picciotto I, Schulz MR, Ball LM, Duell EJ. The contribution of benzene to smoking-induced leukemia. Environ Health Perspect. 2000;108:333[Medline] [Order article via Infotrieve]. 31. Pasqualetti P, Festuccia V, Acitelli P, Collacciani A, Giusti A, Casale R. Tobacco smoking and risk of haematological malignancies in adults: a case-control study. Br J Haematol. 1997;97:659[CrossRef][Medline] [Order article via Infotrieve]. 32. McDonald TA, Holland NT, Skibola C, Duramad P, Smith MT. Hypothesis: phenol and hydroquinone derived mainly from diet and gastrointestinal flora are causal factors in leukemia. Leukemia. In press. 33. Ross JA. Maternal diet and infant leukemia: a role for DNA topoisomerase II inhibitors? Int J Cancer Suppl. 1998;11:26[CrossRef][Medline] [Order article via Infotrieve].
34.
Siegel D, Bolton EM, Burr JA, Liebler DC, Ross D.
The reduction of alpha-tocopherolquinone by human NAD(P)H: quinone oxidoreductase: the role of alpha-tocopherolhydroquinone as a cellular antioxidant.
Mol Pharmacol.
1997;52:300
35.
Moran JL, Siegel D, Ross D.
A potential mechanism underlying the increased susceptibility of individuals with a polymorphism in NAD(P)H:quinone oxidoreductase 1 (NQO1) to benzene toxicity [Comment appears in Proc Natl Acad Sci U S A. 1999;96:7624].
Proc Natl Acad Sci U S A.
1999;96:8150
© 2001 by The American Society of Hematology.
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  K. Iskander, R. J. Barrios, and A. K. Jaiswal Disruption of NAD(P)H:Quinone Oxidoreductase 1 Gene in Mice Leads to Radiation-Induced Myeloproliferative Disease Cancer Res., October 1, 2008; 68(19): 7915 - 7922. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. Bolufer, M. Collado, E. Barragan, J. Cervera, M.-J. Calasanz, D. Colomer, J. Roman-Gomez, and M. A. Sanz The potential effect of gender in combination with common genetic polymorphisms of drug-metabolizing enzymes on the risk of developing acute leukemia Haematologica, March 1, 2007; 92(3): 308 - 314. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Begleiter, D. Hewitt, A. W. Maksymiuk, D. A. Ross, and R. P. Bird A NAD(P)H:Quinone Oxidoreductase 1 Polymorphism Is a Risk Factor for Human Colon Cancer Cancer Epidemiol. Biomarkers Prev., December 1, 2006; 15(12): 2422 - 2426. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. S. Fenske, C. McMahon, D. Edwin, J. C. Jarvis, J. M. Cheverud, M. Minn, V. Mathews, M. A. Bogue, M. A. Province, H. L. McLeod, et al. Identification of candidate alkylator-induced cancer susceptibility genes by whole genome scanning in mice. Cancer Res., May 15, 2006; 66(10): 5029 - 5038. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. M. Korashy and A. O. S. El-Kadi TRANSCRIPTIONAL REGULATION OF THE NAD(P)H:QUINONE OXIDOREDUCTASE 1 AND GLUTATHIONE S-TRANSFERASE YA GENES BY MERCURY, LEAD, AND COPPER Drug Metab. Dispos., January 1, 2006; 34(1): 152 - 165. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. H. Wilson and K. Olden The Environmental Genome Project: Phase I and Beyond Mol. Interv., June 1, 2004; 4(3): 147 - 156. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Rollinson, J. M. Allan, G. R. Law, P. L. Roddam, M. T. Smith, C. Skibola, A. G. Smith, M. S. Forrest, K. Sibley, R. Higuchi, et al. High-Throughput Association Testing on DNA Pools to Identify Genetic Variants that Confer Susceptibility to Acute Myeloid Leukemia Cancer Epidemiol. Biomarkers Prev., May 1, 2004; 13(5): 795 - 800. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Seedhouse, R. Faulkner, N. Ashraf, E. Das-Gupta, and N. Russell Polymorphisms in Genes Involved in Homologous Recombination Repair Interact to Increase the Risk of Developing Acute Myeloid Leukemia Clin. Cancer Res., April 15, 2004; 10(8): 2675 - 2680. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. T. Bowen, M. E. Frew, S. Rollinson, P. L. Roddam, A. Dring, M. T. Smith, S. E. Langabeer, and G. J. Morgan CYP1A1*2B (Val) allele is overrepresented in a subgroup of acute myeloid leukemia patients with poor-risk karyotype associated with NRAS mutation, but not associated with FLT3 internal tandem duplication Blood, April 1, 2003; 101(7): 2770 - 2774. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Anwar, D. Dehn, D. Siegel, J. K. Kepa, L. J. Tang, J. A. Pietenpol, and D. Ross Interaction of Human NAD(P)H:Quinone Oxidoreductase 1 (NQO1) with the Tumor Suppressor Protein p53 in Cells and Cell-free Systems J. Biol. Chem., March 14, 2003; 278(12): 10368 - 10373. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. K. Bauer, B. Faiola, D. J. Abernethy, R. Marchan, L. J. Pluta, V. A. Wong, K. Roberts, A. K. Jaiswal, F. J. Gonzalez, B. E. Butterworth, et al. Genetic Susceptibility to Benzene-induced Toxicity: Role of NADPH: Quinone Oxidoreductase-1 Cancer Res., March 1, 2003; 63(5): 929 - 935. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. T. Smith, Y. Wang, C. F. Skibola, D. J. Slater, L. L. Nigro, P. C. Nowell, B. J. Lange, and C. A. Felix Low NAD(P)H:quinone oxidoreductase activity is associated with increased risk of leukemia with MLL translocations in infants and children Blood, December 15, 2002; 100(13): 4590 - 4593. [Abstract] [Full Text] [PDF]
|
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|
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C. Seedhouse, R. Bainton, M. Lewis, A. Harding, N. Russell, and E. Das-Gupta The genotype distribution of the XRCC1 gene indicates a role for base excision repair in the development of therapy-related acute myeloblastic leukemia Blood, November 15, 2002; 100(10): 3761 - 3766. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. Asher, J. Lotem, L. Sachs, C. Kahana, and Y. Shaul Mdm-2 and ubiquitin-independent p53 proteasomal degradation regulated by NQO1 PNAS, October 1, 2002; 99(20): 13125 - 13130. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. J. Long II, A. Gaikwad, A. Multani, S. Pathak, C. A. Montgomery, F. J. Gonzalez, and A. K. Jaiswal Disruption of the NAD(P)H:Quinone Oxidoreductase 1 (NQO1) Gene in Mice Causes Myelogenous Hyperplasia Cancer Res., June 1, 2002; 62(11): 3030 - 3036. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. Hamajima, T. Saito, K. Matsuo, and K. Tajima Competitive Amplification and Unspecific Amplification in Polymerase Chain Reaction with Confronting Two-Pair Primers J. Mol. Diagn., May 1, 2002; 4(2): 103 - 107. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Anwar, D. Siegel, J. K. Kepa, and D. Ross Interaction of the Molecular Chaperone Hsp70 with Human NAD(P)H:Quinone Oxidoreductase 1 J. Biol. Chem., April 12, 2002; 277(16): 14060 - 14067. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. L. Winski, Y. Koutalos, D. L. Bentley, and D. Ross Subcellular Localization of NAD(P)H:quinone Oxidoreductase 1 in Human Cancer Cells Cancer Res., March 1, 2002; 62(5): 1420 - 1424. [Abstract] [Full Text] [PDF]
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G. Asher, J. Lotem, R. Kama, L. Sachs, and Y. Shaul NQO1 stabilizes p53 through a distinct pathway PNAS, February 20, 2002; (2002) 52706799. [Abstract] [Full Text] [PDF]
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J. M. Allan, C. P. Wild, S. Rollinson, E. V. Willett, A. V. Moorman, G. J. Dovey, P. L. Roddam, E. Roman, R. A. Cartwright, and G. J. Morgan Polymorphism in glutathione S-transferase P1 is associated with susceptibility to chemotherapy-induced leukemia PNAS, September 5, 2001; (2001) 191211198. [Abstract] [Full Text] [PDF]
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G. Asher, J. Lotem, R. Kama, L. Sachs, and Y. Shaul NQO1 stabilizes p53 through a distinct pathway PNAS, March 5, 2002; 99(5): 3099 - 3104. [Abstract] [Full Text] [PDF]
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J. M. Allan, C. P. Wild, S. Rollinson, E. V. Willett, A. V. Moorman, G. J. Dovey, P. L. Roddam, E. Roman, R. A. Cartwright, and G. J. Morgan Polymorphism in glutathione S-transferase P1 is associated with susceptibility to chemotherapy-induced leukemia PNAS, September 25, 2001; 98(20): 11592 - 11597. [Abstract] [Full Text] [PDF]
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Top
Abstract
Introduction
T) substitution polymorphism at
nucleotide 609 of the NQO1 complementary DNA (NQO1
C609T) results in a lowering of NQO1 activity. Individuals homozygous for this mutation have no NQO1 activity, and
heterozygotes have low to intermediate activity compared with people
with wild type. DNA samples from 493 adult de novo acute leukemia patients and 838 matched controls were genotyped for NQO1 C609T. The majority of cases were diagnosed as acute
myeloid leukemia (AML) (n = 420); 67 as acute lymphoblastic leukemia
(ALL); and 6 as other forms of acute leukemia. The frequency of cases with low or null NQO1 activity (heterozygote + homozygous mutant) was significantly higher among total acute leukemia case subjects compared with their matched controls (odds ratio [OR] = 1.49; 95%
confidence interval [CI], 1.17-1.89). Both ALL (OR = 1.93; 95% CI,
0.96-3.87) and AML case subjects (OR = 1.47; 95% CI, 1.13-1.90) exhibited a higher frequency of low or null NQO1
genotypes than controls. For de novo AML, the most significant effect
of low or null NQO1 activity was observed among the 88 cases harboring translocations and inversions (OR = 2.39; 95% CI, 1.34-4.27)
and was especially high for those harboring inv(16) (OR = 8.13; 95% CI, 1.43-46.42). These findings were confirmed in a second group of 217 de novo AML cases with known cytogenetics. Thus, inheritance of
NQO1 C609T confers an increased risk of de novo acute
leukemia in adults, implicating quinones and related compounds that
generate oxidative stress in producing acute leukemia.
(Blood. 2001;97:1422-1426)
5/5q
phenol, hydroquinone,
catechol, and trihydroxybenzene