|
|||||||||
|
|
|
|
|
|
|
|
|
|
|
Prepublished online as a Blood First Edition Paper on July 18, 2002; DOI 10.1182/blood-2002-04-1152.
NEOPLASIA
From the Division of Haematology, School of Clinical
Laboratory Sciences, University of Nottingham, and Nottingham City
Hospital, Nottingham, United Kingdom.
Polymorphisms in several DNA repair genes have been described.
These polymorphisms may affect DNA repair capacity and modulate cancer
susceptibility by means of gene-environment interactions. We
investigated DNA repair capacity and its association with acute myeloblastic leukemia (AML). We studied polymorphisms in 3 DNA repair
genes: XRCC1, XRCC3, and XPD. We
also assessed the incidence of a functional polymorphism in the
NQO1 gene, which is involved in protection of cells from
oxidative damage. We genotyped the polymorphisms by using polymerase
chain reaction-restriction fragment-length polymorphism analysis in
134 patients with de novo AML, 34 with therapy-related AML
(t-AML), and 178 controls. The distributions of the
XRCC3 Thr241Met and NQO1 Pro187Ser genotypes
were not significantly different in patients and controls. However, the
distribution of the XRCC1 Arg399Gln genotypes was
significantly different when comparing the t-AML and control groups
( Acute myeloblastic leukemia (AML) is a clonal
hemopoietic disorder that is frequently associated with genetic
instability characterized by a diversity of chromosomal and molecular
changes. Most cases of AML arise de novo, with no known exposure to
leukemogenic substances. However, approximately 10% to 20% of all
cases of AML arise after therapy, most often chemotherapy, used to
treat other malignant diseases (therapy-related AML
[t-AML]1).
Many genes encode proteins that function to protect cells against
genetic instability by means of many mechanisms, including DNA repair
pathways and protection against oxidative stress. DNA repair pathways
play a vital role in maintaining genetic integrity, and it is becoming
clear that defects in repair pathways are connected to many different
types of diseases, including leukemia and cancer. It is now thought
that an individual's DNA repair capacity is genetically determined and
is the result of combinations of multiple genes that may display subtle
differences in their activity (see Mohrenweiser and Jones2
for review). Inactivating mutations in DNA repair genes are rare,
resulting in embryonic death or serious genetic diseases and reflecting
the importance of the gene products; however, polymorphisms have been
identified in several DNA repair genes.3 Many of these
polymorphisms result in amino acid substitutions and hence may alter
wild-type (WT) protein function and affect cellular ability to repair
endogenous and exogenous DNA damage, thereby contributing to disease susceptibility.
XRCC1, XRCC3, and XPD are polymorphic
genes belonging to 3 of the major DNA repair pathways. XRCC1
is involved in base excision repair (BER) and the repair of
single-strand breaks. The XRCC1 gene product plays an important role in
the pathway by acting as a scaffold for other DNA repair proteins, such
as DNA polymerase Several variants of XRCC1 have been described, including one affecting
codon 399 in exon 10 that results in an arginine (Arg) to methionine
(Met) substitution3 and one affecting codon 194 in exon 6 that results in an Arg to tryptophan (Trp) substitution. Both codon 194 and codon 399 are conserved across species. Codon 194 resides in a
linker region connecting the domains that interact with PARP and DNA
polymerase The XRCC3 protein functions in the homologous DNA double-strand break
(DSB) repair pathway and directly interacts with and stabilizes
Rad51,10 one of the key components of the pathway. The
homologous DNA DSB repair pathway uses the second, intact copy of a
chromosome as a template to copy the information lost at the DSB site
on the first chromosome, resulting in a high-fidelity process that has
a vital role in preventing chromosomal aberrations. The threonine (Thr)
to Met polymorphism at codon 241 of XRCC3 is a nonconservative change.
Little is known about the functional consequence of this amino acid
change, although positive associations between the variant allele and
cancer have been observed in various investigations, including studies
of bladder cancer11 and melanoma skin
cancer.12
The XPD protein, a 5' to 3' DNA helicase involved in the nucleotide
excision repair pathway, functions to remove bulky damage adducts from
DNA. The XPD lysine (Lys) 751-glutamine (Gln) polymorphism does not
reside in a known functional domain of XPD and was initially thought to
be unlikely to result in an altered DNA repair
capacity.3,13 However, additional studies produced
contrasting results, linking the XPD 751Gln variant allele to both
reduced14 and elevated15 nucleotide excision
repair capacity. Thus, more work is warranted to establish whether this
polymorphism is clinically relevant.
Nicotinamide adenine dinucleotide phosphate:quinone oxidoreductase 1 (NQO1) functions to protect cells from oxidative stress by detoxifying
several compounds. The enzyme reduces reactive quinones to the less
reactive hydroquinones and so prevents accumulation of reactive oxygen
species that may then go on to damage DNA. A polymorphism has been
identified in NQO1 at codon 187.16 This polymorphism
converts a proline (Pro) to a serine (Ser) residue and has been shown
to result in inactivation of NQO1.17 The incidence of this
polymorphism was found to be significantly increased both in patients
with de novo AML18 and in those with t-AML, particularly
those with chromosome 5/7 abnormalities.19
In the current study, we investigated the genotype distributions of the
XRCC1 Arg399Gln, XRCC3 Thr241Met, and NQO1 Pro187Ser polymorphisms in
patients with AML, particularly those with t-AML, and in controls. We
also studied the distribution of the XRCC1-194 and XPD-751 genotypes.
In addition, because a malignant phenotype is likely to result from the
accumulation of many minor genotypes, we assessed whether there was an
association between DNA repair gene polymorphisms (XRCC1 and
XRCC3) and a polymorphism in a protein involved with
minimizing the effects of oxidative stress (NQO1).
Study subjects
Polymerase chain reaction (PCR)-restriction fragment-length
polymorphism (RFLP) genotyping analysis
The XRCC1 Arg399Gln polymorphism was amplified in a 616-bp fragment by using the following primers: xrcc1-399F 5'-TTGTGCTTTCTCTGTGTCCA-3' and xrcc1-399R 5'-TCCTCCAGCCTTTACTGATA-3'21 with 2 mM/L MgCl2. The PCR product was digested with 10 U MspI (Helena Biosciences, Sunderland, United Kingdom) in the manufacturer's buffer at 37°C overnight. The recognition site for the MspI restriction endonuclease is present only in the Arg (WT) allele; hence, digestion of the Arg allele results in products of 376 bp and 240 bp, whereas the Gln allele remains undigested. A segment of the XRCC1 gene containing the Arg194Trp polymorphism was amplified by using the primer pairs xrcc1-194F 5'-GGTAAGCTGTACCTGTCACTC-3' and xrcc1-194R 5'-GACCCAGGAATCTGAGCC-3' with 1.5 mM/L MgCl2. The PCR products were digested at 37°C overnight with 10 U MspI. The PCR product contains an internal MspI site, and products with the 194Arg genotype contain an additional MspI site, resulting in 20-, 117-, and 167-bp products. The 194Trp allele is digested only at the internal MspI site, resulting in 137- and 167-bp products. XRCC3 Thr241Met was amplified in a 415-bp product by using the primers xrcc3-241F 5'-GGTCGAGTGACAGTCCAAAC-3' and xrcc3-241R 5'-CTACCCGCAGGAGCCGGAGG-3'3 with 2 mM/L MgCl2. The PCR products were digested at 37°C overnight with 10 U NlaIII (New England Biolabs, Hitchin, United Kingdom) in 1 × buffer supplied with the enzyme and supplemented with 100 ng/µL bovine serum albumin. All XRCC3 PCR products contain an internal NlaIII site, and the presence of the Met polymorphism also generates an additional NlaIII site, resulting in 104-, 141-, and 170-bp products for the polymorphic allele and 141- and 274-bp products for the WT Thr allele. The XPD Lys751Gln polymorphism was amplified in a 344-bp fragment by using the following primers: xpd-751F 5'-TCAAACATCCTGTCCCTACT-3' and xpd-751R 5'-CTGCCGATTAAAGGCTGTGGA-3'3 with 2 mM/L MgCl2. The PCR product was digested with 10 U PstI (Helena Biosciences) at 37°C overnight. All PCR products contain an internal PstI site, resulting in 110- and 234-bp products in the 751Lys allele. In addition, an extra PstI site is present in the Gln allele, resulting in 63-, 110-, and 171-bp products. The NQO1 Pro187Ser polymorphism was amplified in a 304-bp fragment by using the primers nqo1F 5'-AAGCCCAGACCAACTTCT-3' and nqo1R 5'-TCTCCTCATCCTGTACCTCT-3'15 with 1.5 mM/L MgCl2. The PCR products were digested overnight at 37°C with 10 U HinfI (New England Biolabs) in the manufacturer's buffer. All PCR products contain an internal HinfI site, and the Ser polymorphism also introduces an additional HinfI site, resulting in 33-, 120-, and 151-bp digested fragments, whereas the WT allele results in 33- and 271-bp products. The digested products were resolved on 3% agarose gels (Helena Biosciences), stained with ethidium bromide and analyzed under UV light. Two reviewers independently scored all genotypes, and samples that could not be scored were sequenced. Sequencing was also carried out on a 10% random sample population of control and AML PCR products. Sequencing reactions Sequencing reactions were set up with approximately 200 ng purified PCR product and 10 mM primer by using a Thermo Sequenase II dye terminator cycle sequencing premix kit according to the manufacturer's instructions (Amersham Biosciences). The primers used for sequencing were the same as those used for the PCR amplifications. The reactions were electrophoresed by using an ABI 377 automated DNA sequencer (PE Applied Biosystems, Foster City, CA) as recommended by the manufacturer.Statistical analysis The observed genotype frequencies of the 3 polymorphisms in the control cohorts were compared with those calculated by using the Hardy-Weinberg equilibrium (p2 + q2 + 2pq = 1; where p is the variant allele frequency). The distribution of genotypes in AML populations compared with the control population was assessed for significance by 2 testing, and odds ratios (ORs) and
95% confidence intervals (CIs) were calculated by logistic regression
analysis and adjusted for the effect of age. P values of
less than or equal to .05 were considered to represent significance.
All analyses used the statistical package SPSS for Windows (version 9;
SPSS, Chicago, IL).
XRCC1 Arg399Gln, XRCC3 Thr241Met, and NQO1 Pro187Ser polymorphisms We examined the frequency of 3 polymorphisms in 134 patients with de novo AML (median age, 63 years) and 178 controls (median age, 51.5 years). We also analyzed a subgroup of 34 patients with t-AML (median age, 61.5 years). Because of an inadequate amount of DNA in some cases, several samples did not generate complete information for all 3 polymorphisms. Among the controls, the variant allele frequencies were 0.48 for XRCC1 399Gln, 0.30 for XRCC3 241Met, and 0.22 for NQO1 187Ser. All genotype frequencies in the control population were consistent with those expected from the Hardy-Weinberg equilibrium (XRCC1 Arg399Gln,2 = 1.93 and P = .38; XRCC3 Thr241Met,
2 = 1.22 and P = .54; and NQO1 Pro187Ser,
2 = 0.94 and P = .63). The distributions
of the frequencies of the polymorphisms in AML cases and controls are
shown in Table 1. The results for the
XRCC1 Arg399Gln polymorphism showed that the proportion of AML and
t-AML patients homozygous for the WT Arg allele was higher than in the
control group, with the difference in the distribution of genotypes
reaching statistical significance in the t-AML group
(P = .03 on 2 testing). Neither the
XRCC3-241 nor the NQO1 genotype distributions showed any differences in
either the de novo AML or t-AML group compared with the control group.
The adjusted ORs for the individual genotypes are shown in Table
2. The XRCC1 399 homozygous variant genotype is a protective factor in both the de novo AML and t-AML patient groups. When the presence of at least one Gln allele is considered, it becomes apparent that the variant allele is
significantly protective against the development of t-AML (OR, 0.46;
95% CI, 0.20-0.93).
XRCC1 Arg194Trp and XPD Lys751Gln polymorphisms We also studied 2 additional polymorphisms, XRCC1 Arg194Trp and XPD Lys751Gln, in a smaller cohort of patients and controls. Among the controls, the variant allele frequencies were 0.07 for XRCC1 194Trp and 0.38 for XPD 751Gln. The genotype distributions among the control population were consistent with those expected from the Hardy-Weinberg equilibrium (XRCC1 Arg194Trp,2 = 2.49 and
P = .29; and XPD Lys751Gln, 2 = 0.25 and
P = .88). The distributions of the frequencies of the
polymorphisms in AML patients and controls are shown in Table 1;
adjusted ORs are shown in Table 2. No significant differences were
observed between the AML patient cohort and the controls.
Combined analysis of polymorphisms Table 3 shows the combined analysis for either the XRCC1 Arg399Gln or XRCC3 Thr241Met genotypes with the NQO1 Pro187Ser genotype. Because of the small numbers of t-AML samples available, these were grouped with the samples from the de novo AML cases for this analysis. The DNA repair gene polymorphisms did not show an interaction with the detoxification NQO1 Pro187Ser polymorphism.
Although it has been established that mismatch repair is important in a subset of patients with AML,22-24 little is known about the role of the other DNA repair pathways in this disease. In this study, we found that a polymorphism in a DNA repair gene belonging to the BER pathway, XRCC1 Arg399Gln, is associated with a protective effect against the development of AML, particularly t-AML. Hence, patients in whom AML develops as a result of therapy for a primary malignant disease are more likely to have the WT XRCC1 399 Arg allele. It is possible that differences between the cases and controls may have contributed to the observed association, but we believe that this is unlikely. Both populations were from the same small geographical area in the United Kingdom and had the same age range. Sex has been shown not to have any influence on the XRCC1 Arg399Gln genotype,20 and although race was previously found to be an important factor in the distribution of the XRCC1 Arg399Gln genotype,25,26 all our patients and controls were white. We did not find any differences between the distributions of the XRCC3 Thr241Met and NQO1 Pro187Ser genotypes. Others have observed a significant increase in the incidence of the variant NQO1 allele in patients with AML, particularly those with chromosome 5/7 abnormalities.19 This association was not evident in our AML groups, although the number of patients with chromosome 5/7 abnormalities in our cohort was small and that may have accounted for the difference from previous studies. We were able to obtain cytogenetic information for approximately 100 of our patients, and only 10 of them had chromosome 5/7 abnormalities. We combined the de novo AML and t-AML groups to examine possible associations between either the XRCC1 Arg399Gln or XRCC3 Thr241Met genotypes and the NQO1 Pro187Ser genotypes. No significant association was observed, suggesting that the phenotypes resulting from these proteins do not interact to increase the risk of AML. However, our number of t-AML samples was too small to allow us to conduct combined logistic regression analysis of this group alone. We also performed PCR-RFLP analysis of a smaller number of patients and controls to study the distribution of genotypes of an additional polymorphism in XRCC1 (XRCC1 Arg194Trp) and a polymorphism in XPD (XPD Lys751Gln), a gene involved in the nucleotide excision repair pathway. No significant differences were found between controls and patients with AML. Several previous studies assessed the functional relevance of polymorphisms in DNA repair genes. Lunn et al21 measured genotoxic end points of DNA damage and showed that the XRCC1 399Gln allele was associated with increased placental aflatoxin DNA adducts and increased glycophorin A mutations in erythrocytes. They suggested that the Arg to Gln change at codon 399 may alter the phenotype of the XRCC1 protein, resulting in deficient DNA repair. In addition, Duell et al27 measured DNA damage by using a sister chromatid exchange assay and also detected polyphenol DNA adducts. They found more damage in current smokers homozygous for the XRCC1 399Gln allele than in current smokers with the homozygous WT allele. A sister chromatid assay was also used by Abdel-Rahman and El-Zein,28 who found that a higher level of DNA damage after treatment with a tobacco-specific nitrosamine occurred in XRCC1 399Gln homozygotes. Several polymorphism studies have observed a positive association of the XRCC1 399 Gln allele with various malignant diseases, including cancer of the head and neck,20 breast,25 lung,26 and colon and rectum.29 The researchers suggested that these results correlated with the in vitro functional data and illustrated the adverse effects of deficient DNA repair systems. However, other studies, including ours, had conflicting results. We found that the presence of the XRCC1 399Gln allele is protective against the development of t-AML. The same protective effect has been observed in studies of bladder cancer30 and nonmelanoma skin cancer.31 This may indicate the presence of a strong gene-environment interaction that is tumor specific. There is a fine balance between deficient and functional DNA repair systems. Although it is important for damaged DNA to be recognized and repaired, it is also vital for the cell to be able to recognize when the damage is too extensive to be repaired and to allow the apoptotic pathway to be stimulated; this prevents cells from potentially misrepairing damage and surviving with mutations. This process may be particularly important in the development of t-AML. Chemotherapy and radiotherapy both induce immense amounts of DNA damage and have the aim of achieving cell death. Even subtle changes in DNA repair capacity are likely to be important when large external influences such as chemotherapy or radiotherapy are present. We hypothesize that when hematopoietic progenitor cells in the bone marrow are damaged by therapy, the cells with the XRCC1 399 Gln allele and resulting reduced DNA repair capacity are more likely to be driven toward apoptosis. This is contrary to what happens to cells with the WT genotype, which are more likely to repair their damage, possibly harbor mutations, and initiate clonal disease resulting in t-AML. Hence, we suggest the XRCC1 399 Gln allele is protective against the development of t-AML. A similar proposal was made by Nelson et al31 in their large study of nonmelanoma skin cancer. Our hypothesis can be extended to the opposite situation observed in many primary malignant diseases in which the XRCC1 399Gln allele has been shown to be a risk factor. Although DNA damage caused by "low-dose" exogenous sources (for example, smoking and diet) is considered to be an important contributory factor in many malignant diseases, the resulting oxidative burden on the cells is significantly smaller than that following chemotherapy or radiotherapy, which can be considered to cause "high-dose" damage. Hence, a BER pathway with a fully functional XRCC1 gene (XRCC1 399Arg) would be expected to repair the damage caused by low-dose damaging agents (smoking and diet), whereas a deficiency in the DNA repair pathway, such as an XRCC1 399Gln allele, would reduce the effectiveness of the pathway in repairing damage from low-dose sources and thus increase the risk of a primary malignant disease. Additional work is now required to determine whether polymorphisms do indeed lead to a reduced DNA repair capacity in vivo and to identify the consequences of these phenotypes in different environmental conditions. The identification of polymorphisms or mutations in many genes and the determination of their functional importance in AML will allow susceptibility-risk models to be designed for de novo and therapy-related disease. Intervention strategies and early detection approaches could then be targeted at those individuals genetically identified to be at higher risk of AML or t-AML.
We thank Tricia McKeever for assistance with the statistical analysis; Stephen Langabeer and the Kay Kendall Leukaemia Fund for t-AML DNA samples from the DNA/RNA banking facilities at University College Hospital, London; and the Medical Research Council (MRC) Acute Leukaemia Working Party for access to samples from patients with AML entered into MRC trials.
Submitted April 16, 2002; accepted July 1, 2002.
Prepublished online as Blood First Edition Paper, July 18, 2002; DOI 10.1182/blood-2002-04-1152.
Sponsored partly by a grant from the Leukaemia Research Fund, United Kingdom.
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: Claire Seedhouse, Department of Academic Haematology, Clinical Sciences Building, Nottingham City Hospital, Nottingham, NG5 1PB, United Kingdom; e-mail: claire.seedhouse{at}nottingham.ac.uk.
1.
Pedersen-Bjergaard J, Andersen MK, Christiansen DH, Nerlov C.
Genetic pathways in therapy-related myelodysplasia and acute myeloid leukemia.
Blood.
2002;99:1909-1912 2. Mohrenweiser HW, Jones IM. Variation in DNA repair is a factor in cancer susceptibility: a paradigm for the promises and perils of individual and population risk estimation? Mutat Res. 1998;400:15-24[Medline] [Order article via Infotrieve].
3.
Shen MR, Jones IM, Mohrenweiser H.
Nonconservative amino acid substitution variants exist at polymorphic frequency in DNA repair genes in healthy humans.
Cancer Res.
1998;58:604-608
4.
Kubota Y, Nash RA, Klungland A, Schar P, Barnes DE, Lindahl T.
Reconstitution of DNA base excision-repair with purified human proteins: interaction between DNA polymerase
5.
Caldecott KW, McKeown CK, Tucker JD, Ljungquist S, Thompson LH.
An interaction between the mammalian DNA repair protein XRCC1 and DNA ligase III.
Mol Cell Biol.
1994;14:68-76
6.
Caldecott KW, Aoufouchi S, Johnson P, Shall S.
XRCC1 polypeptide interacts with DNA polymerase
7.
Masson M, Niedergang C, Schreiber V, Muller S, Menissier-de Murcia J, de Murcia G.
XRCC1 is specifically associated with poly(ADP-ribose) polymerase and negatively regulates its activity following DNA damage.
Mol Cell Biol.
1998;18:3563-3571 8. Lamerdin JE, Montgomery MA, Stilwagen SA, et al. Genomic sequence comparison of the human and mouse XRCC1 DNA repair gene regions. Genomics. 1995;25:547-554[CrossRef][Medline] [Order article via Infotrieve].
9.
Shen MR, Zdzienicka MZ, Mohrenweiser H, Thompson LH, Thelen MP.
Mutations in hamster single-strand break repair gene XRCC1 causing defective DNA repair.
Nucleic Acids Res.
1998;26:1032-1037
10.
Bishop DK, Ear U, Bhattacharyya A, et al.
Xrcc3 is required for assembly of Rad51 complexes in vivo.
J Biol Chem.
1998;273:21482-21488 11. Matullo G, Guarrera S, Carturan S, et al. DNA repair gene polymorphisms, bulky DNA adducts in white blood cells and bladder cancer in a case-control study. Int J Cancer. 2001;92:562-567[CrossRef][Medline] [Order article via Infotrieve].
12.
Winsey SL, Haldar NA, Marsh HP, et al.
A variant within the DNA repair gene XRCC3 is associated with the development of melanoma skin cancer.
Cancer Res.
2000;60:5612-5616 13. Broughton BC, Steingrimsdottir H, Lehmann AR. Five polymorphisms in the coding sequence of the xeroderma pigmentosum group D gene. Mutat Res. 1996;15:209-211.
14.
Matullo G, Palli D, Peluso M, et al.
XRCC1, XRCC3, XPD gene polymorphisms, smoking and (32)P-DNA adducts in a sample of healthy subjects.
Carcinogenesis.
2001;22:1437-1445
15.
Lunn RM, Helzlsouer KJ, Parshad R, et al.
XPD polymorphisms: effects on DNA repair proficiency.
Carcinogenesis.
2000;21:551-555 16. 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;5:199-206[Medline] [Order article via Infotrieve]. 17. 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;9:113-121[Medline] [Order article via Infotrieve].
18.
Smith MT, Wang Y, Kane E, et al.
Low NAD(P)H:quinone oxidoreductase 1 activity is associated with increased risk of acute leukemia in adults.
Blood.
2001;97:1422-1426
19.
Larson RA, Wang Y, Banerjee M, et al.
Prevalence of the inactivating 609C
20.
Sturgis EM, Castillo EJ, Li L, et al.
Polymorphisms of DNA repair gene XRCC1 in squamous cell carcinoma of the head and neck.
Carcinogenesis.
1999;20:2125-2129
21.
Lunn RM, Langlois RG, Hsieh LL, Thompson CL, Bell DA.
XRCC1 polymorphisms: effects on aflatoxin B1-DNA adducts and glycophorin A variant frequency.
Cancer Res.
1999;59:2557-2561
22.
Ben-Yehuda D, Krichevsky S, Caspi O, et al.
Microsatellite instability and p53 mutations in therapy-related leukemia suggest mutator phenotype.
Blood.
1996;88:4296-4303
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;94:733-740 24. Das-Gupta EP, Seedhouse CH, Russell NH. Microsatellite instability occurs in defined subsets of patients with acute myeloblastic leukaemia. Br J Haematol. 2001;14:307-312.
25.
Duell EJ, Millikan RC, Pittman GS, et al.
Polymorphisms in the DNA repair gene XRCC1 and breast cancer.
Cancer Epidemiol Biomarkers Prev.
2001;10:217-222 26. Divine KK, Gilliland FD, Crowell RE, et al. The XRCC1 399 glutamine allele is a risk factor for adenocarcinoma of the lung. Mutat Res. 2001;461:273-278[Medline] [Order article via Infotrieve].
27.
Duell EJ, Wiencke JK, Cheng TJ, et al.
Polymorphisms in the DNA repair genes XRCC1 and ERCC2 and biomarkers of DNA damage in human blood mononuclear cells.
Carcinogenesis.
2000;21:965-971 28. Abdel-Rahman SZ, El-Zein RA. The 399Gln polymorphism in the DNA repair gene XRCC1 modulates the genotoxic response induced in human lymphocytes by the tobacco-specific nitrosamine NNK. Cancer Lett. 2000;159:63-71[CrossRef][Medline] [Order article via Infotrieve]. 29. Abdel-Rahman SZ, Soliman AS, Bondy ML, et al. Inheritance of the 194Trp and the 399Gln variant alleles of the DNA repair gene XRCC1 are associated with increased risk of early-onset colorectal carcinoma in Egypt. Cancer Lett. 2000;159:79-86[CrossRef][Medline] [Order article via Infotrieve].
30.
Stern MC, Umbach DM, van Gils CH, Lunn RM, Taylor JA.
DNA repair gene XRCC1 polymorphisms, smoking, and bladder cancer risk.
Cancer Epidemiol Biomarkers Prev.
2001;10:125-131
31.
Nelson HH, Kelsey KT, Mott LA, Karagas MR.
The XRCC1 Arg399Gln polymorphism, sunburn, and non-melanoma skin cancer: evidence of gene-environment interaction.
Cancer Res.
2002;62:152-155
© 2002 by The American Society of Hematology.
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
 |
|
 |
|
  M. Voso, E Fabiani, F D'Alo', F Guidi, A Di Ruscio, S Sica, L Pagano, M Greco, S Hohaus, and G Leone Increased risk of acute myeloid leukaemia due to polymorphisms in detoxification and DNA repair enzymes Ann. Onc., September 1, 2007; 18(9): 1523 - 1528. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M Jawad, G Giotopoulos, C Cole, and M Plumb Target cell frequency is a genetically determined risk factor in radiation leukaemogenesis Br. J. Radiol., September 1, 2007; 80(Special_Issue_1): S56 - S62. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. Kuptsova, K. J. Kopecky, J. Godwin, J. Anderson, A. Hoque, C. L. Willman, M. L. Slovak, and C. B. Ambrosone Polymorphisms in DNA repair genes and therapeutic outcomes of AML patients from SWOG clinical trials Blood, May 1, 2007; 109(9): 3936 - 3944. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Jawad, C. H. Seedhouse, N. Russell, and M. Plumb Polymorphisms in human homeobox HLX1 and DNA repair RAD51 genes increase the risk of therapy-related acute myeloid leukemia Blood, December 1, 2006; 108(12): 3916 - 3918. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. Matullo, A.M. Dunning, S. Guarrera, C. Baynes, S. Polidoro, S. Garte, H. Autrup, C. Malaveille, M. Peluso, L. Airoldi, et al. DNA repair polymorphisms and cancer risk in non-smokers in a cohort study Carcinogenesis, May 1, 2006; 27(5): 997 - 1007. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. J. Hung, J. Hall, P. Brennan, and P. Boffetta Genetic Polymorphisms in the Base Excision Repair Pathway and Cancer Risk: A HuGE Review Am. J. Epidemiol., November 15, 2005; 162(10): 925 - 942. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. Matullo, S. Guarrera, C. Sacerdote, S. Polidoro, L. Davico, S. Gamberini, M. Karagas, G. Casetta, L. Rolle, A. Piazza, et al. Polymorphisms/Haplotypes in DNA Repair Genes and Smoking: A Bladder Cancer Case-Control Study Cancer Epidemiol. Biomarkers Prev., November 1, 2005; 14(11): 2569 - 2578. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Z. Hu, H. Ma, F. Chen, Q. Wei, and H. Shen XRCC1 Polymorphisms and Cancer Risk: A Meta-analysis of 38 Case-Control Studies Cancer Epidemiol. Biomarkers Prev., July 1, 2005; 14(7): 1810 - 1818. [Abstract] [Full Text] [PDF]
|
|
Top
Abstract
Introduction
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