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implicating the precautionary principle.
8 american medical association house of delegates.

« implicating people in the process of change:
"implicating people in the process of change:

evidence implicating nymphal ixodes pacificus(acari:
evidence implicating nymphal ixodes pacificus (acari:

criteria and procedures for implicating clostridium perfringens in food-borne outbreaks.
criteria and procedures for implicating clostridium perfringens in foodborne outbreaks.

philippa roddam, raymond cartwright, and gareth morgan nad(p)h:quinone oxidoreductase 1 (nqo1) is an enzyme that detoxifies quinones and reduces oxidative stress. a cysteine￾to-threonine (c 3 t) substitution poly￾morphism at nucleotide 609 of the nqo1 complementary dna (nqo1 c609t ) re￾sults in a lowering of nqo1 activity. indi￾viduals homozygous for this mutation have no nqo1 activity, and heterozy￾gotes 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 5 420); 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 1 homozy￾gous mutant) was significantly higher among total acute leukemia case sub￾jects compared with their matched con￾trols (odds ratio [or] 5 1.49; 95% confi- dence interval [ci], 1.17-1.89). both all (or 5 1.93; 95% ci, 0.96-3.87) and aml case subjects (or 5 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 5 2.39; 95% ci, 1.34-4.27) and was especially high for those harboring inv(16) (or 5 8.13; 95% ci, 1.43-46.42). these findings were con- firmed in a second group of 217 de novo aml cases with known cytogenetics. thus, inheritance of nqo1 c609t con￾fers an increased risk of de novo acute leukemia in adults, implicating qui￾nones and related compounds that gen￾erate oxidative stress in producing acute leukemia. (blood. 2001;97:1422-1426) © 2001 by the american society of hematology introduction 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 crucifer￾ous vegetables4,5 and protects cells against oxidative stress. a single nucleotide polymorphism (cysteine-to-threonine, [c 3 t]) at position 609 in the nqo1 gene has been identified in a human colon cancer cell line with very low nqo1 activity.6 this variant produces a proline-to-serine substitution that inactivates the enzyme. people who are homozygous for the variant allele completely lack nqo1 activity, and heterozygotes have low to intermediate activity compared with people with the wild type.7 the incidence of the polymorphism varies widely by race,8 and associations have been made between the presence of variant alleles and lung and urological cancers.9-11 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 pre￾sented.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 individu￾als 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 polymor￾phism (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. patients and methods case-control study population and sample collection this study was based on subjects participating in a population-based case-control study of adult acute leukemia conducted by the leukaemia research fund’s centre for clinical epidemiology in the united kingdom. details of the study are published elsewhere.15 briefly, patients recruited into the study were aged 16 to 69 years and had received a new diagnosis of acute leukemia between april 1, 1991, and december 31, 1996, while resident in parts of the north and southwest of england. all diagnoses were pathologically confirmed, and cytogenetics were obtained from cytogenetic laboratories. for each case subject, 2 controls matched on gender, year of 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. submitted june 12, 2000; accepted october 31, 2000. supported by the national foundation for cancer research and the leukaemia research fund of great britain. 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@uclink4.berkeley.edu. 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. © 2001 by the american society of hematology
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