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Prepublished online as a Blood First Edition Paper on December 5, 2002; DOI 10.1182/blood-2002-01-0228.
NEOPLASIA
From the Department of Molecular and Cellular
Pathology, University of Dundee, Dundee, United Kingdom; Academic Unit
of Hematology and Oncology, University of Leeds, Leeds, United Kingdom;
School of Public Health, University of California, Berkeley, CA;
Department of Hematology, University College London, London,
United Kingdom.
The etiology of acute myeloid leukemia (AML) is largely
unknown. Biologic and epidemiologic data implicate exogenous toxicants, including cytotoxic drugs, benzene, radiation, and cigarette smoking. Allelic variation in genes encoding enzymes such as
NADP(H) quinone oxidoreductase (NQO1) and
glutathione S-transferase T1 (GSTT1) that
metabolize environmental toxicants predispose to subtypes of AML,
including therapy-related AML. We assayed NRAS oncogene mutation and FLT3 internal tandem duplication in 447 AML
patients with an abnormal karyotype treated in Medical Research Council (MRC) AML clinical trials. Functional allelic variant
frequencies in genes encoding carcinogen-metabolizing enzymes
GSTT1, GSTM1, CYP1A1,
CYP2D6, CYP2C19, SULT1A1,
and NQO1 were previously determined for this
cohort. FLT3 internal tandem duplication (ITD)
frequency was 17%, and NRAS mutation 12% for the entire
cohort. The 2 mutations were found together in only 4 patients. No association was found between enzyme allelic
variant frequencies and the presence of FLT3 ITD for the
entire cohort or within cytogenetic subgroups. CYP1A1*2B
(Val) high-inducibility variant allele was overrepresented in patients with NRAS mutation compared with no mutation,
for (1) the entire AML cohort (n = 8/53 vs 26/371; odds ratio [OR] = 2.36; 95% confidence interval [CI] 1.01-5.53) and (2) the poor-risk karyotype group (n = 6/14 vs 4/89; OR = 15.94; 95% CI 3.71-68.52) comprising patients with partial/complete deletion of chromosome 5 or
7, or abnormalities of chromosome 3. The CYP1A1*2B allele may predispose to the development of these subgroups of AML by augmented phase 1 metabolism to highly reactive intermediates of CYP1A1
substrates, including polycyclic aromatic hydrocarbons, or by
generation of oxidative stress as a metabolic by-product.
(Blood. 2003;101:2770-2774) The etiology of acute myeloid leukemia (AML)
is unknown for the majority of cases. The identification of
biologically well-defined subgroups on the basis of cytogenetic
analysis has improved prognostic power and led to risk-directed
therapeutic strategies. It is increasingly clear that the etiologic
mechanisms underlying the "good-risk" translocational karyotypes
t(15:17), inv(16), and t(8:21), which predominate in younger patients,
will differ from the largely deletional abnormalities seen in
"poor-risk" disease, which are more common in older
patients. The karyotypic similarities between therapy-related AML
(t-AML) and poor-risk de novo AML1 suggest that an
environmental etiology is more likely in the latter group than in the
de novo good-risk group. Questionnaire-based case-control studies have
suggested associations between exposure to specific environmental
toxicants and the development of AML, but cannot define mechanisms of
leukemogenesis.2,3
The cytochrome P450 enzymes are expressed predominantly in the
liver and function to detoxify many environmental toxicants (xenobiotics). These phase 1 metabolic enzymes transfer electrons onto
substrate toxicants to create highly reactive intermediates, which are
then available for detoxification by a variety of phase 2 enzymes
including glutathione S-transferases and sulfotransferases.
Several carcinogen-metabolizing genes with functional allelic variants
are now known to predispose to t-AML4,5 and also to de
novo AML.6-8 Furthermore, this predisposition may be
greater or less in subgroups of AML defined by specific genomic damage at the karyotypic level. The paradigm for an AML-predisposition gene encoding a carcinogen-metabolizing enzyme is
NADP(H) quinone oxidoreductase (NQO1). The
C609T polymorphic variant, which confers reduced
phase 2 metabolism, is associated with a predisposition to
therapy-related AML4 and selected cytogenetic subgroups of
de novo AML.6 Reduced phase 2 metabolism has the potential to result in an accumulation of reactive intermediates, which in turn
oxidize DNA and protein, leading to DNA mutation and/or cell death.
Phase 1 enzymes with functionally relevant allelic variants are also
predisposition genes for AML and include cytochrome P450 2C19
(CYP2C19) and CYP2D6.8 The proposed mechanism of predisposition for these 2 genes is a consequence of reduced
phase 1 metabolism, presumably allowing the accumulation of
nonmetabolized toxic carcinogens.
We selected functional polymorphic variants in specific
carcinogen-metabolizing enzymes for study. Enzymes were selected on the
basis of an established role in the metabolism of known leukemogenic compounds (eg, benzene, cytotoxic chemotherapeutic drugs). We then
selected only patients with well-characterized karyotypic abnormalities, to include abnormalities known to occur
following genotoxic insult (eg, chromosome 5 and 7 abnormalities) and
also good-prognosis translocations for which an environmental etiology may be less likely. Finally, we assayed the 2 most common molecular abnormalities in AML, namely, FLT3 internal tandem
duplication (ITD) and NRAS mutation; each of which is likely
to arise from a different mechanism.
We demonstrate that the *2B high-inducibility variant of
CYP1A1 is overrepresented in a subgroup of
poor-risk AML patients with NRAS mutation and may represent
a predisposition allele for these specific forms of genomic damage in AML.
Patients
Cytogenetic classification
Carcinogen-metabolizing enzyme gene allelic variant analysis Assays for allelic variants at the following loci have been previously described: GSTM1 (null), GSTT1 (null),7 CYP2D6 (poor/extensive metabolizer), CYP2C19*2 (681G A; aberrant splice),
CYP1A1*2B allele (2455AG,
IleVal),8 and NQO1
(609CT; ProSer).6 In addition, a polymorphism in SULT1A1 (*2, 213G A;
ArgHis) was assayed by allelic discrimination by means of
the polymerase chain reaction (PCR)-based TaqMan technology
(PE Applied Biosystems, Foster City, CA). Primer and probe
sequences for this assay were as follows: forward primer,
5'-GGTTGAGGAGTTGGCTCTGC-3' (300 nM); reverse primer, 5'-ACGTGTGCTGAACCATGAAGT-3' (300 nM) (annealing temperature, 62°C); wild-type (WT) probe, 5'-AGTTTGTGGGGCGCTCCCTG-3' (100 nM) (Tet labeled); variant probe 5'-AGTTTGTGGGGCACTCCCTGC-3' (200 nM) (Fam labeled).
FLT3 internal tandem duplication assay Genomic DNA was amplified from exons 12 and 13 of the FLT3 gene.13 This produced a wild-type fragment of 328 bases plus a higher-molecular weight fragment containing internal tandem duplicated sequences (when present) of varying length as previously described.13,14 Bands with higher molecular weight than wild type were cut from the gel and directly sequenced by means of a fluorescent primer adapted chain-termination method15 on an ABI 3100 sequencer (PE Applied Biosystems) to determine the start site and size of each duplication.NRAS mutational analysis Mutation screen.
Separate assays were developed for mutation detection at "hot
spots" in codons 12/13 (exon 1) and codon 61 (exon 2).
Oligonucleotide primers amplifying short fragments (241 base pair
[bp], exon 1; 201 bp, exon 2) were designed for PCR as follows:
N12/13 assay: forward, 5'-GACTGAGTACAAACTGGTGG-3'; reverse,
5'-TGCATAACTGAATGTATACCC-3'. N61 assay: forward,
5'-CAAGTGGTTATAGATGGTGAAACC-3'; reverse,
5'-AAGATCATCCTTTCAGAGAAAATAAT-3'. PCR products were then subjected
to denaturing heteroduplex high-pressure liquid chromatography
(HPLC) analysis (dHPLC) (Transgenomic WAVE, Crewe, United
Kingdom). PCR conditions were as follows: (1) Exon 1, HotStarTaq (Qiagen, Valencia, CA), 0.625 U. Primers (12.5 pmol), N12/13 forward, N12/13 reverse. Denaturing, 95°C for 15 minutes and 94°C for 30 seconds; annealing, 55.5°C for 1 minute;
extension, 72°C for 1 minute for 35 cycles; final cycle at 72°C for
10 minutes. (2) Exon 2, HotStarTaq (Qiagen), 0.625 U. Primers (12.5 pmol), N61F forward, N61R reverse. Denaturing, 95°C for 15 minutes;
94°C for 30 seconds; annealing, 55.5°C for 1 minute; extension,
72°C for 1 minute for 35 cycles; final cycle at 72°C for 10 minutes. Heteroduplexes were then generated by means of a thermal
cycler as follows: 95°C for 5 minutes; 95°C, reducing at 1°C per
22 seconds, for 70 cycles. Then, 10 µL heteroduplexed PCR product per
well was loaded from 96-well plates and analyzed by dHPLC under the following conditions: flow, 0.9 mL/min, 47% to 52% buffer
(B) in 0.1 minutes, to 60% B in 4 minutes at 61°C.
Representative dHPLC plots are shown in Figure
1.
Mutation confirmation. Samples exhibiting an abnormal dHPLC profile were confirmed as mutant by direct sequencing and/or PCR-restriction fragment length polymorphism mutation-sensitive digestion analysis for codons 12 and 13.16,17 If these assays were insufficiently sensitive to confirm mutation, PCR products were cloned (Original TA Cloning Kit; Invitrogen, Groningen, the Netherlands) and sequenced.15 The sensitivity of the dHPLC is such that 15% mutant DNA can be confidently detected in a sample containing wild-type and mutant sequence (M.E.F., manuscript in preparation). Statistical analysis CYP1A1 allellic variants were analyzed as dichotomous variables (Ile/Val plus Val/Val, versus Ile/Ile). Odds ratios (ORs) and 95% confidence intervals were calculated from 2 × 2 tables for mutant versus nonmutant (NRAS or FLT3) and Ile/Val plus Val/Val, versus Ile/Ile. Logistic regression was used to test these associations within the entire cohort and also between the 3 cytogenetic risk groups. Power calculations were prospectively computed to inform sample size for the case-control study reported elsewhere6 and were based upon expected enzyme variant polymorphism frequencies. These prospective calculations were not done for NRAS or FLT3 ITD frequency within the patient cohort alone. Retrospective power calculations were performed with the assumption of an expected CYP1A1*2B allele variant frequency (Ile/Val plus Val/Val) of 11%,8 an FLT3 ITD mutant frequency of 25%,14 and an NRAS mutant frequency of 15%. The sample size of 427 patients was sufficient to provide 80% power at a P value less than .05 to detect an OR of 2.5 for the difference in CYP1A1*2B variant frequency between FLT3 ITD mutant versus no ITD, and an OR of 2.9 for NRAS mutation versus no NRAS mutation.
FLT3 ITD frequency was 17% (77 of 447) and NRAS mutation was 12% (53 of 443) for the entire cytogenetically selected AML cohort. The 2 mutations were found together in only 4 patients, confirming previous observations.18 Presence of FLT3 ITD is not associated with variant allele frequency in carcinogen-metabolizing enzymes No differences in carcinogen-metabolizing enzyme variant allele frequency were found for GSTT1, GSTM1, CYP2D6, CYP2C19, CYP1A1, SULT1A1, or NQO1, either for the presence versus absence of FLT3 ITD (data for CYP1A1 variant alleles shown in Table 1) or in relation to start site or duplication size (data not shown).
CYP1A1*2B allele is overrepresented in AML with NRAS mutation Patients with NRAS-mutant AML had a higher frequency of the CYP1A1*2B allele (combined Ile/Val plus Val/Val) compared with nonmutant AML cases (z = 2.0; P < .045) (Table 2). When the cohort was subdivided by cytogenetic risk group, this association was confined to the poor-risk karyotype group (Table 2), which was in turn statistically significantly different (logistic regression) from the good-risk group alone (z = 2.78; P < .005); the intermediate-risk group alone (z = 2.0; P < .045); and the combined good- plus intermediate-risk groups (z = 3.026; P < .005).
The poor-risk group comprised patients with abnormalities of chromosomes 5 and/or 7 (5q/7q) and also patients with abnormalities of 3q. The frequency of the *2B allele in patients with 5q/7q abnormalities was 4 of 7 for patients with NRAS mutation versus 4 of 79 for patients without the mutation. Corresponding frequencies for the 3q group were 2 of 7 for patients with the NRAS mutation versus 0 of 10 for those without. No difference in variant allele frequency was found for GSTT1, GSTM1, CYP2D6, CYP2C19, SULT1A1, or NQO1 when patient groups with and without the NRAS AML mutation were compared. The CYP1A1*2B allele is not associated with a specific NRAS signature mutation The NRAS mutation spectrum for patients with the CYP1A1*2B allele is presented in Table 3. Codon 12 mutations were most frequent; 6 of 7 of those mutations were at hot-spot sites, compared with 24 of 45 mutations at codon 12 among patients lacking the *2B allele (not significant). The other base change at codon 33 is a novel NRAS mutation in a patient with trisomy 8.
We have previously observed that the allele frequency for the CYP1A1*2B variant is no different in AML patients than in controls8 and cannot therefore be considered a predisposition allele for the development of all types of AML. We now show that the CYP1A1*2B allele may indeed predispose patients to develop a subgroup of AML characterized by specific genomic damage, namely, NRAS mutation and poor-risk karyotype. CYP1A1 is a phase 1 detoxification enzyme, expressed predominantly in extrahepatic tissue and with a wide variety of substrates, including the carcinogenic polycyclic aromatic hydrocarbons (PAHs). Baseline cellular expression of CYP1A1 is usually low, but high inducibility is mediated through the binding of inducers such as TCDD (2,3,7,8-tetrachlorodibenzo-p-dioxin) and PAH to a cellular protein, the aryl hydrocarbon receptor (AhR). AhR is in turn bound to heat-shock protein 90 (Hsp90) and releases this before translocation to the nucleus to associate with another protein, the Ah receptor nuclear translocator (Arnt). This complex binds an enhancer sequence activating transcriptional induction of CYP1A1 mRNA.19 Thus, phase 1 detoxification capacity of CYP1A1 is influenced at 3 levels: baseline expression level, expression induction, and enzymatic activity. Several polymorphic allelic variants have now been described within the
CYP1A1 gene (reviewed in Wormhoudt et
al20). The most common variant allele, designated
*2A, introduces an Msp1 restriction site in the
3' end of the gene. The next most common, and potentially functionally
more significant, variant is a single nucleotide polymorphism in exon 7 (A The high concentration of PAH in cigarette smoke has led to extensive studies of CYP1A1 allelic variant frequencies in smoking-associated cancers. Although most studies are small, the *2B allele may be overrepresented in smokers developing lung,23 breast,24 and colorectal25 cancers. Several studies provide plausible epidemiologic support for the association between AML and substrates and inducers of CYP1A1. A cohort of subjects exposed accidentally to the potent CYP1A1 inducer TCDD have shown a 3.8-fold increased risk of myeloid leukemia with a latency of 15 years.26 Exposure to cigarette smoke is a weak but reasonably consistent risk factor for AML in large case-control studies.27,28 Smoking history data were unfortunately not available for most subjects in our study. NRAS mutations in our patients with the CYP1A1*2B
allele show no signature mutation, and this is perhaps not surprising
given the diversity of putative environmental carcinogens in the
etiology of AML. It is of note, however, that in those patients
reported here and in our extended cohort of AML samples (data not
shown), most NRAS mutations are transitions, as has
previously been reported in AML and other hematologic
malignancies.29 Thus, although PAHs are the most
attractive candidate carcinogenic substrate of CYP1A1 in the etiology
of AML, on the basis of the mutation spectrum in our study, it is
likely that the other substrates are involved. This
may indeed be the case in other tumors, including lung cancer. Although
a signature p53 mutation spectrum is evident in cohorts of smokers with
lung cancer,30 a recent study found a higher prevalence of
p53 mutation in lung cancers from heavy smokers (compared with
nonsmokers) with variant CYP1A1 alleles (*2A/*2B), but the usual signature mutation spectrum was not
found in this subgroup.31 This suggests that the mutation
signature may be less evident in patients with variant
CYP1A1 alleles. Also in this study, smokers with a variant
CYP1A1 allele had an increased frequency of KRAS
mutation but the authors do not comment upon the mutation spectrum.
Cigarette smoke contains a multitude of carcinogenic compounds in
addition to both TCDD and PAHs. Exposure to combinations of CYP1A1
inducers and substrates may therefore exacerbate the potential for
genomic damage on the background of inheritance of the
high-inducibility *2B allele. A final alternative hypothesis
is that reactive oxygen species known to be generated as a byproduct of
CYP1A1-mediated carcinogen metabolism32,33 may oxidize
DNA. Oxidative DNA damage may generate a more diverse mutation
spectrum, including transitions (eg, 5OH-cytosine G It remains unclear why the association between the CYP1A1*2B variant allele and NRAS mutation should be confined to the poor-risk karyotype groups. In the context of therapy-related AML, however, point mutations in critical regulatory genes are more common within the "deletional" karyotypes, namely, p53 mutation associated with chromosome 5 deletion,34 and RAS mutation associated with chromosome 7 deletion.1 These data suggest that genomic instability leads to AML through different pathways,1 and in the context of de novo AML, CYP1A1 variant allele status may represent one determinant of this instability. It is not surprising that FLT3 ITD is not associated with the CYP1A1*2B allele within these cytogenetic subgroups, as the ITD most likely arises from a mechanism different from that of point mutation, perhaps aberrant recombination or defective double-strand DNA repair. In conclusion, our data suggest that the variant CYP1A1*2B allele may predispose to the development of a subgroup of AML patients characterized by poor-risk karyotypes and NRAS mutation. Epidemiologic data also suggest that substrates and inducers of CYP1A1 represent candidates for environmental carcinogens with potential to cause AML, but alternative mechanisms such as CYP1A1-induced oxidative stress are also proposed.
We wish to thank Mrs Helen Walker for her assistance in characterizing the DNA bank samples and Dr Simon Ogston for statistical advice. We also wish to thank Professors Alan Burnett (Chairman, MRC Adult Leukemia Working Party) and David Linch for initiating, administering, and providing access to the DNA bank. Finally, we wish to thank David Baty and Dot Mechan for assistance with dHPLC assays, and Professor Roland Wolf for access to the ABI 7700 TaqMan.
Submitted January 25, 2002; accepted November 13, 2002.
Prepublished online as Blood First Edition Paper, December 5, 2002; DOI 10.1182/blood-2002-01-0228.
Supported by Leukemia Research Fund grant no. 98/35. The AML DNA bank has been supported by the Medical Research Council, the Leukemia Research Fund, and the Kay Kendall Leukemia Fund.
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: David T. Bowen, Molecular and Cellular Pathology, Ninewells Hospital, Dundee, DD1 9SY United Kingdom; e-mail: d.t.bowen{at}dundee.ac.uk.
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D. T. Bowen, M. E. Frew, R. Hills, R. E. Gale, K. Wheatley, M. J. Groves, S. E. Langabeer, P. D. Kottaridis, A. V. Moorman, A. K. Burnett, et al. RAS mutation in acute myeloid leukemia is associated with distinct cytogenetic subgroups but does not influence outcome in patients younger than 60 years Blood, September 15, 2005; 106(6): 2113 - 2119. [Abstract] [Full Text] [PDF]
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Top
Abstract
Introduction
, +21, 20q
T polymorphism in the NAD(P)H:quinone oxidoreductase (NQO1) gene in patients with primary and therapy-related myeloid leukemia.
Blood.
1999;94:803-807