REVIEW

Markers of DNA Repair and Susceptibility to Cancer in Humans: an Epidemiologic Review

Marianne Berwick, Paolo Vineis

Affiliations of authors: M. Berwick, Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, NY; P. Vineis, Unit of Cancer Epidemiology, University of Torino, and Ospedale S. Giovanni Battista, Torino, Italy.

Correspondence to: Marianne Berwick, Ph.D., Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, 1275 York Ave., Box 588, New York, NY 10021 (e-mail: berwickm{at}mskcc.org).


    ABSTRACT
 Top
 Notes
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Conclusion
 References
 
DNA repair is a system of defenses designed to protect the integrity of the genome. Deficiencies in this system likely lead to the development of cancer. The epidemiology of DNA repair capacity and of its effect on cancer susceptibility in humans is, therefore, an important area of investigation. We have summarized all of the published epidemiologic studies on DNA repair in human cancer through 1998 (n = 64) that addressed the association of cancer susceptibility with a putative defect in DNA repair capacity. We have considered study design, subject characteristics, potential biases, confounding variables, and sources of technical variability. Assays of DNA repair capacity used, to date, can be broadly grouped into five categories: 1) tests based on DNA damage induced with chemicals or physical agents, such as the mutagen sensitivity assay, the G2-radiation assay, induced micronuclei, and the Comet assay; 2) indirect tests of DNA repair, such as unscheduled DNA synthesis; 3) tests based on more direct measures of repair kinetics, such as the host cell reactivation assay; 4) measures of genetic variation associated with DNA repair; and 5) combinations of more than one category of assay. The use of such tests in human populations yielded positive and consistent associations between DNA repair capacity and cancer occurrence (with odds ratios in the range of 1.4–75.3, with the majority of values between 2 and 10). However, the studies that we have reviewed have limitations, including small sample size, "convenience" controls, the use of cells different from the target organ, and the use of mutagens that do not occur in the natural environment. The evolving ability to study polymorphisms in DNA repair genes may contribute to new understandings about the mechanisms of DNA repair and the way in which DNA repair capacity affects the development of cancer.



    INTRODUCTION
 Top
 Notes
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Conclusion
 References
 
Interindividual variability in human responses to carcinogens has been described repeatedly. Much attention has been devoted to heritable polymorphisms in genes involved in carcinogen metabolism. Another potentially important source of interindividual variability in relation to the development of cancer is DNA repair capacity, including the genetic instability syndromes (1). These are rare, recessive traits that include ataxia-telangiectasia (A-T), Fanconi anemia, and Bloom's syndrome (all of which are characterized by both chromosomal instability and high risk of cancer) as well as xeroderma pigmentosum (XP), a disease caused by a deficiency in nucleotide excision repair that is characterized by extreme susceptibility to ultraviolet (UV) light-associated skin cancer (1). Apart from these rare syndromes, individuals differ widely in their capacity to repair DNA damage from both exogenous agents, such as tobacco smoke and sunlight exposure, and endogenous reactions, such as oxidations (2). At least some of such interindividual difference is likely to have a genetic origin. A number of epidemiologic studies have been conducted to compare measures of DNA repair capacity between cancer case subjects and healthy control subjects to assess the role of repair in the development of human cancer. Such studies have used a variety of measures of DNA repair capacity. However, DNA repair capacity is extremely complex; at this time, the current assays do not measure specific aspects of repair but rather assess more global effects.

Most assays are based on an approach that compares induced DNA damage to circulating lymphocytes from subjects with cancer with induced DNA damage to circulating lymphocytes from subjects without cancer with quantitation of subsequent "repair" in both groups. Damage is usually delivered in the form of a "pulse" of carcinogen applied to cell culture (e.g., {gamma}-rays, UV radiation, benzo[a]pyrene diol epoxide [BPDE], or hydrogen peroxide [H2O2]) or to fresh or cryopreserved lymphocytes. A period of time is allowed to elapse for repair to occur, and then damage is measured in a variety of ways (e.g., as unrepaired single- or double-strand breaks or the rate of incorporation of a radioisotope).

We have attempted a formal evaluation of the published studies of DNA repair capacity in the etiology of human cancer and have considered their design, methods, and results. In addition, we have assessed the results and the limitations of such studies. We use the term "DNA repair capacity" to describe a variety of different techniques and manifestations, not all of which are necessarily a direct expression of actual repair of DNA damage but are often a measure of unrepaired DNA damage.


    METHODS
 Top
 Notes
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Conclusion
 References
 
From personal archives and from a MEDLINE® search, we have identified all peer-reviewed studies published through December 1998 on DNA repair and human cancer (366) (Tables 1 and 2GoGo). The studies that we reviewed included only those published through 1998. We have tried to be widely inclusive; however, we realize that some studies may have been inadvertently left out. During 1999, there has been an explosion of new studies published in which DNA repair has been used as an end point. We are in the process of establishing a web site to track all DNA repair studies.


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Table 1. Design of studies of DNA repair and susceptibility to cancer in humans by type of assay*
 

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Table 2. Results of studies on DNA repair and cancer in humans by type of assay*
 
We have included case series in which no standard control group was used but where second primary cancers or family history of cancer were the major focus of the investigation. We excluded other studies without control groups or studies that examined only healthy subjects, except, in the text, to illustrate a principle (such as confounding). We have considered the design, the characteristics of the patients and control subjects, potential biases, confounding variables, and sources of technical variability. Covariates have been noted when they were considered in the design. The coefficient of variation (CV) has been computed as the ratio between the standard deviation (SD) and the mean in control subjects (whenever possible); when the SD was not available, it was computed from the standard error (SE). When possible (i.e., when DNA repair was categorized), we have reported the odds ratios (ORs) with their associated 95% confidence intervals (CIs) as a measure of association and sometimes calculated the ORs from the data presented. All P values that we calculated were two-sided.

Characteristics of Tests

In most assays currently used, it is not possible to make a distinction between DNA damage and repair. The test developed by Athas and collaborators (20,28) has the advantage of relying on a plasmid that is damaged and then transfected into the host cell rather than on direct damage to the host cell. This technique minimizes the cytotoxic effects of damaging agents that might indirectly compromise the repair mechanisms of the cell. However, an important limitation of this assay is the fact that repair of DNA damage (e.g., adducts) in a plasmid transfected into cells has been shown to differ substantially from the process of repair of genomic damage [e.g., (67)]. There is greater overlap between damage and repair in the other assays. For example, one of the commonly reported tests, the mutagen sensitivity assay developed by Hsu et al. (6), is based on the induction of chromosome damage in lymphocytes by bleomycin. This is a relatively simple test in which a higher number of bleomycin-induced chromatid breaks is assumed to express higher "mutagen sensitivity" and lower DNA repair (an assumption that has not been tested directly). Wei et al. (68) compared the mutagen sensitivity assay with the host cell reactivation assay and found a correlation of r = -.70 (P<.01) with 4-nitroquinoline-1-oxide (4NQO)-induced mutagen sensitivity, although the authors suggested that each assay is actually measuring a different function. On the other hand, although Miller et al. (61) found no clear association between mutagen sensitivity and the host cell reactivation assay within case or control subjects, we calculated among all subjects a smaller but statistically significant correlation between the host cell reactivation assay and 4NQO-induced mutagen sensitivity (r = -.43; P = .01) but not bleomycin-induced mutagen sensitivity (r = -.12; P = .48).

Wu et al. have shown that BPDE-induced (69) and bleomycin-induced (70) chromatid breaks in the lymphocytes of lung cancer patients have nonrandom distributions and occur more frequently in chromosomes 2, 3p21, 4, and 5, with a statistically significant gradient of increasing risk with increasing number of aberrations. What this means for the interpretation of DNA repair capacity measurements is unclear. It does suggest that mutagen sensitivity may be more prevalent in chromosomes previously identified as critical in the pathway of development of specific cancers.

Hall et al. (31) analyzed in detail the sources of variation for the test based on the host cell reactivation assay, and Scott et al. (71) discussed sources of variation for the G2-phase X-ray-induced chromosome damage. We have assembled the papers that described any of the variation in DNA repair capacity among these studies (Table 3Go).


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Table 3. Measures of variability in studies of DNA repair capacity*
 
Sources of Potential Confounding or Bias

Inducibility. Some DNA repair genes seem to be inducible (e.g., the nucleotide excision repair genes by UV radiation) (1). In fact, there is wide overlap among mammalian genes induced by UV radiation and those induced by phorbol ester promoters or by growth factors [p. 601 in (1).]. Such inducibility can occur as a result of exposure to many different agents, indicating a biologic cross-reactivity. This leads to the potential for epidemiologic confounding when assessing causal pathways; induction by one agent can be wrongly attributed to another agent. However, investigators may not measure that agent; therefore, variation in repair activity due to the measured exposure may be confounded or spurious.

The repair of some types of lesions is inducible, e.g., cyclobutane pyrimidine dimers produced by UV radiation. Repair of other lesions, such as 6-4 pyrimidine dimers repaired by XPA-G (i.e., complementation groups of XP), is not inducible. Preferential repair (repair that occurs more quickly than overall genome repair and on the transcribing strand of DNA) is not inducible (1). Induction of DNA repair by different exposures may be an important source of unmeasured confounding for studies of DNA repair and cancer.

Other potential confounders. Age, smoking habits, sex, dietary habits, sunlight exposure, and exposure to pro-oxidants appear to influence some assays. These, too, should be regarded as potential confounders.

With regard to age, Wei et al. (28) have shown that the repair capacity of a UV-damaged plasmid cat (i.e., chloramphenicol acetyltransferase) gene inserted into human lymphocytes declined with increasing age at a rate of about 0.61% per year, as did Moriwaki et al. (72), among others. Stierum et al. (73) observed a decrease in BPDE-induced unscheduled DNA synthesis with increasing age, and Barnett and King (74) found a higher level of single-strand breaks in older individuals, aged 65–69 years, than in younger individuals, aged 35–39 years.

In in vitro experiments with cultured lymphocytes, antioxidants such as {alpha}-tocopherol, N-acetyl-L-cysteine, and ascorbic acid inhibited bleomycin-induced chromosome damage in a dose-dependent manner (75,76). In a study of 25 healthy individuals, Kucuk et al. (77) found strong inverse correlations between plasma nutrients and the mutagen sensitivity assay based on bleomycin-induced chromatid breaks. Correlations were as follows: r = -.76 (P<=.01) with ß-carotene and r = -.72 (P<.05) with total carotenoids (monthly mean levels). In contrast, a positive correlation was found with triglyceride levels (r = .60; P<.01).

In contrast, Cloos et al. (44) found that N-acetylcysteine supplementation did not modify DNA repair capacity, as measured by bleomycin-induced mutagen sensitivity. King et al. (78) found no association between supplemental ascorbic acid and mutagen sensitivity. In a crossover design, Goodman et al. (79) were unable to find an effect of either {alpha}-tocopherol or ß-carotene on mutagen sensitivity values. One problem with the mutagen sensitivity assay, pointed out by the authors, is that the 3-day culture of cells required is likely to dilute the circulating antioxidants in the plasma and, thus, diminish the antioxidant's ability to inhibit damage. However, the ability of humans to modify DNA damage/repair by short-term ingestion of supplements is cast into further doubt by the data of Hu et al. (80). In a randomized, double-blind trial of {alpha}-tocopherol, Hu et al. did not find any association between supplementation and DNA repair activity when they used two different measures of DNA repair capacity, adenosine diphosphate polyribosyl transferase (ADPRT) and unscheduled DNA synthesis.

There is fairly good evidence that caffeine inhibits DNA repair. p53 null cells (i.e., those in which both p53 alleles were disrupted) were more sensitive to UV light only in the presence of caffeine (81), and a comet assay study indicated that a caffeine-mediated increase in radiation risk of embryos is due to inhibition of DNA repair (82). Caffeine inhibited gene-specific repair of UV-induced damage in hamster cells and in human XP cells (83). The relevance of these observations to human cancer is still unclear.

Sunlight exposure can actually induce DNA repair, as measured by unscheduled DNA synthesis. In one study (54), DNA damage and repair were statistically significantly affected by the season of testing, with unscheduled DNA synthesis tending to be higher in the summer than in the winter.

Pero et al. (84) studied 40 healthy volunteers for ADPRT- and N-acetoxy-2-acetylaminofluorene (NA-AAF)-induced unscheduled DNA synthesis after exposure of mononuclear lymphocytes to pro-oxidants. They found that repair of DNA lesions induced by NA-AAF was inhibited in a dose-dependent manner by exposure to H2O2 and other pro-oxidants. In another study, ethanol at high doses (in cultured lymphocytes) interfered with the repair of bleomycin-induced chromosome breaks (mutagen sensitivity assay), and the researchers (85) suggested that it might inactivate enzymes involved in DNA repair.

Population Stratification

DNA repair defects are presumed to have a genetic origin and to be associated with polymorphic alleles in subgroups of the population. Extreme examples are represented by conditions like XP or A-T; genetic polymorphisms in DNA repair genes have been proposed to be responsible for other, less dramatic, DNA repair deficiencies (86). Altschuler et al. (87) have raised some concerns about potential confounding related to population admixture that has the potential to cause an artificial association if a study includes genetically distinct subpopulations, one of which coincidentally displays a higher frequency of disease and allelic variants. As Mark (88) has shown, population admixture can give rise to spurious associations and can mask a true association. If two genotypes have a beneficial joint effect but neither is effective alone, measuring only one of them in two populations with different allele frequencies can result in completely different results (including a beneficial effect in one population and not in the other).

Alternative Explanations

Effects of therapeutic agents. Most studies have compared patients diagnosed with cancer with subjects without a cancer diagnosis. This method is quite appropriate for early transitional studies. The use of cancer patients, however, may introduce a bias due to treatment. Patients undergoing chemotherapy or radiation therapy may have reduced DNA repair in lymphocytes (although the tumor itself may have increased repair). A study of 41 cancer patients (9) indicated that the [3H]thymidine incorporation into UV-damaged DNA was affected by chemotherapy or radiotherapy. There is a substantial body of literature [e.g., (89)] indicating that drug-resistant tumors have enhanced DNA repair capacity. This potential source of confounding has not been well studied.

In addition, immunologic status may be relevant. Interferon may stimulate repair processes and may reduce chromosome aberrations. In a study of 14 breast cancer patients treated with Iscador, an extract of Viscum album (mistletoe) that is a known immunomodulator, DNA repair increased 2.7 times over baseline (18).

Tamoxifen has been suggested to enhance immune cell responsiveness by increasing the activity of ADPRT, an enzyme involved in DNA repair, in lymphocytes (22). Therefore, comparisons of subjects who have received treatment with healthy control subjects can yield biased comparisons and may misrepresent the constitutive or unstimulated repair capacity of the individual.

Effect of cancer itself. Tumor burden is a potentially important confounding factor in the measurement of DNA repair capacity. Its role in terms of repair in lymphocytes (thought to express germline genetic tendencies) versus repair in the tumor itself is unclear at present. On the one hand, the tumor itself may have a substantially enhanced DNA repair capacity, which is sometimes a cause of drug resistance and therapeutic failure. On the other hand, however, tumor burden might suppress or decrease DNA repair activity through high metabolic rate and excessive endogenously generated oxidative stress, which might affect lymphocytes and their repair values (13). In the light of such uncertainties, it would be preferable to have measures of DNA repair capacity that are unaffected by cancer status. Germline genetic measures are one approach that would avoid this problem because they are static. However, to our knowledge, definitive studies relating genetic polymorphisms with functional measures of repair have not yet been published. To date, the data on polymorphisms in repair genes and their functions are extremely scant. The specific DNA repair genes and the polymorphisms in alleles of these genes are still very poorly understood. An important alternative, that of a cohort study that measures repair prior to the development of cancer, has not yet been published.


    RESULTS
 Top
 Notes
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Conclusion
 References
 
The analytic design of the studies is shown in Table 1Go, while the results are given in Table 2Go. Table 2Go also gives the CV of the repair assays among control subjects from individual studies, and Table 3Go reports data on the published variability and reproducibility of the tests. The results can be broadly grouped into five categories, depending on the tests used.

Category 1 includes tests based on DNA damage to cells (usually chromatid breaks in lymphocytes) induced with a chemical (e.g., bleomycin or BPDE) or with physical agents (e.g., ionizing radiation): the mutagen sensitivity assay, the G2-radiation assay, the micronucleus assay, and the comet assay (also known as the single-cell gel electrophoresis assay). The mutagen sensitivity assay is generally thought to measure strand breaks, although its specificity is as yet undetermined. As currently performed, it could simply be indirectly measuring the scavenging of free radicals generated by ionizing radiation or bleomycin, resulting in altered levels of DNA damage. Both the micronucleus assay and the comet assay have been used most often in studies as markers of DNA damage. However, recent investigations have assessed these end points as repair, either after a single time period has elapsed for repair or at multiple end points to estimate the rate and extent of repair.

Category 2 includes indirect tests of DNA repair, such as unscheduled DNA synthesis, and activity of the repair enzyme ADPRT. These assays are usually conducted on isolated lymphocytes that have been damaged by UV radiation or by a chemical. The level of enzyme activity or of DNA synthesis is measured in radiolabeled cells, usually by scintillation counting but also by radiography.

Category 3 encompasses tests based on more direct measures of repair kinetics, such as the plasmid host cell reactivation assay. In the host cell reactivation assay, separate sets of fresh or cryopreserved lymphocytes are transfected with both a damaged plasmid and an undamaged plasmid. Repair is then measured as a "rate," i.e., the amount of radiation or fluorescence at specific points in time. Usually, the chloramphenicol acetyltransferase gene, or cat, has been incorporated into the plasmid. (More recently, the Luciferase gene has been used because it gives better precision and does not require radioactivity.)

Category 4 includes measurement of genetic variation, usually as polymorphisms in the genes associated with DNA repair. In addition to the four broad categories used in epidemiology studies, a number of methods have been used in one or two studies only. Category 5 includes studies that examined more than one category of DNA repair.

In category 1, DNA repair capacity is inferred from unrepaired damage: the number of chromatid breaks, the numbers of micronucleated cells, or the length of the "tail" of a comet, after treatment for a standard period of time; there is not an actual measure of DNA repair capacity. Category 2 includes tests in which the cellular incorporation of activity is measured by scintillation counting or visualization. In category 3, the kinetics of repair are measured, i.e., the rate at which lymphocytes from a cancer patient or from a healthy control repair a damaged plasmid. In category 4, polymorphisms in repair genes are assessed to estimate the distribution of polymorphic alleles, and differences between case and control subjects are measured through tests of association. And, finally, in category 5, it is sometimes possible to examine the correlation between assays conducted on the same individuals.

With the use of these five categories, as indicated in Table 2Go, 31 of the 38 studies based on tests belonging to category 1 (i.e., tests based on induced DNA damage) showed statistically significant results. (Note that, in each category, there are one to three studies that appear in category 5 [multiple tests] and overlap categories. Thus, the number of studies within each category will actually include more studies than are counted under each category.) Two studies did not report statistically significant findings: One was a randomized intervention with antioxidants (44), and the other belonged to category 5. That study (61) investigated both the mutagen sensitivity assay (with the use of both bleomycin and 4NQO) and the host cell reactivation assay. The mutagen sensitivity assays showed increased ORs that were not statistically significant, whereas the host cell reactivation assay did have statistically significant results (OR = 14.0; 95% CI = 2.1–591.3). As noted previously, we conducted a correlation analysis on the data given and found that there was an inverse correlation between the host cell reactivation assay and the mutagen sensitivity assay using 4NQO (r = -0.43; P = .01) but not the mutagen sensitivity assay using bleomycin (r = -.12; P = .48). Another five studies (6,12,26,43,54) did not report significance levels for the relationship between cancer case and control subjects, or they could not be calculated from the data given. When ORs were available or could be calculated, they ranged between 1.4 (12) and 38.4 (59).

With regard to category 2, indirect tests of DNA synthesis, 11 of the 15 studies showed statistically significant results. Two (7,48) of the 15 studies did not attain statistical significance, and two (21,37) did not report significance levels. The ORs available ranged from 1.2 (48) to 73.5 (13).

In category 3, tests based on repair kinetics, 10 of 11 studies were statistically significant; one (31) of 11 investigations did not find a statistically significant association between the results of the host cell reactivation assay and cancer—in this instance, basal cell carcinoma. The ORs in these 10 investigations with positive results ranged from 1.9 (28) to 14.0 (61). Finally, of the four studies based on genotyping, one study (48) did not find a statistically significant association with breast cancer occurrence, although the phenotypic expression, i.e., oligonucleotide-induced poly(ADP-ribose)polymerase (PARP) activity, showed a statistically nonsignificant OR of 3.4 (95% CI = 0.7–19.5). A second study (57) found a statistically significant association between the PARP genotype and lung cancer among Mexican-Americans (OR = 3.2; 95% CI = 1.0–10.3) but not among African-Americans (OR = 2.3; 95% CI = 0.7–8.0). A third study (51) found statistically significant associations between polymorphisms in two DNA repair genes and both cancer status and clinical radiosensitivity. The fourth study (52), examining mismatch repair gene expression, found varied levels of reduced expression among case subjects with head and neck cancer compared with control subjects, with low expression of hMLH1 (a human mismatch repair gene) 4.4 times more likely (95% CI = 2.1–9.1) among case subjects than among control subjects.

In category 5, multiple measures, positive correlations between two or more assays were evident in two (54,61) of the four studies, but in the other two studies (48,57) insufficient data were presented for conclusions to be drawn.


    DISCUSSION
 Top
 Notes
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Conclusion
 References
 
Design

All of the studies that we have examined were case–control studies, except for four prospective investigations designed to study second primary cancers, recurrence, or survival (16,32 [an extension of (16)],60,62). In most of the studies, it was difficult or impossible to judge whether cases were newly diagnosed (incident) or prevalent. The exact source of control subjects was not always clear, although most were based on "convenience" samples.

Selection Bias

Selection bias might be a problem in many of the studies, although seldom is sufficient detail presented to judge the comparability of case and control subjects. Control subjects were typically blood donors, hospital personnel, and other types of convenience samples. The extent of their comparability to case subjects is difficult to evaluate, even though they were often frequency matched on sex, age, and ethnicity.

Only one study (31) had a population-based design; ironically, this was the only clearly negative study. However, reasons for this negative result have been listed below, and these are separate considerations from selection bias. It is hard to imagine that selection bias has affected all of the positive studies (which are the vast majority), since they were based on different series of subjects and sampled from different populations. It is unlikely that the same type of bias in sampling has occurred in all of these studies. In addition, to explain ORs with a magnitude of 4 or higher, the bias would have to be quite strong.

Confounding

Confounding describes the possibility that some exposure or characteristic of the patients is associated with both DNA repair capacity and risk of cancer, creating a spurious relationship between DNA repair capacity and the disease. Repair enzymes can be induced in several ways by stresses that damage DNA, e.g., oxidative stress. According to recent investigations based on microchip technology (90), in yeast treated with an alkylating agent, the expression of more than 300 gene transcripts was increased, while that of approximately 75 gene transcripts was decreased. However, no information is available on the persistence of gene induction.

In human studies, several assays for DNA repair were affected by characteristics, such as age, sunlight exposure, dietary habits (with an inverse relationship between carotenoids and mutagen sensitivity), exposure to pro-oxidants, and cancer therapies. While age and therapies were usually controlled for, dietary habits might have acted as confounders, since both the intake and the plasma levels of carotenoids and other antioxidants have been shown to be lowered in cancer patients compared with those in healthy control subjects [e.g., (91)]. The extent of such potential confounding is hard to estimate because it is not clear that this is a confounding effect, since DNA repair might be one of the mechanisms by which antioxidants and other constituents of fruits and vegetables affect the risk of cancer. In this case, controlling for such constituents in the analysis might lead to inaccurate conclusions because DNA repair would be an intermediate step between exposure and cancer risk. In one study (49), dietary habits were not associated with mutagen sensitivity in control subjects; rather, vitamins seem to act as effect modifiers, not as confounders.

How persistent the effect of potential confounders could be is unknown. In fact, we know little about the duration of DNA damage induced by different agents. It has been suggested (92) that DNA damage induced by coal tar treatment of psoriasis could persist for more than 3 months.

Strength of Association, Internal-Coherence, Dose–Response Relationship

The reported ORs of DNA repair measures and cancer range from 1.4 to 75.3, with the majority of point estimates ranging between 2 and 10. When stratified by exposure groups, the ORs are often quite high, over 30 in several instances. Few studies were able to examine dose–response relationships, although Bondy et al. (27) found increased ORs with an increased number of family members with cancer.

Consistency of Results

The one study by Hall et al. (31) that did not find an association between DNA repair capacity and the occurrence of basal cell carcinoma used a test based on a damaged plasmid transfected into the subject's lymphocytes and not on direct damage to the host cell. This technique minimizes cytotoxic effects from damaging agents that might indirectly compromise the repair mechanisms of the cell. The authors attribute the negative finding to a number of factors, including delayed transportation of samples, with a resultant impaired viability of lymphocytes, and variability between the two technicians conducting the assay. Finally, of course, there may not be an association between DNA repair and the occurrence of basal cell carcinoma in this population. All of the other studies were positive, although with the differences in the strength of association discussed above.

Test Reliability

Few authors (11 of 64) included measures of variability or reliability of assays (Table 3Go). Several studies (6,21,28,31,44) reported on technical variability, i.e., the same sample measured more than once. Four studies (6,11,13,31) measured variability due to different observers. Intraindividual variation was also rarely reported and was relatively high when assessed, ranging from 3% to 43% (see Table 3Go). Several authors [e.g., (28)] did comment on measures that might affect the reliability of their results, using characteristics such as rank order, range of bias, and variance of the outcome measure. In no study was the intraclass correlation coefficient reported.

Publication Bias

We plotted the log of the OR by the inverse of the SE for the studies for which this information was available or could be calculated (Fig. 1Go). This plot represents the precision in estimating the underlying true associations (i.e., between DNA repair deficiency and the development of cancer) in relationship to the size of the sample. We also calculated the Begg–Mazumdar test for publication bias (93), which was not significant (P = .93), indicating no observable publication bias. On the basis of this plot and the statistical test, we found no evidence of publication bias in this selection of studies.



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Fig. 1. Funnel plot showing the inverse of the standard error (SE) (of the odds ratio) plotted by the odds ratios. This funnel plot has no particular pattern and shows no evidence of publication bias.

 
Time Sequence and Biologic Plausibility

Most studies had a case–control design; i.e., DNA repair was evaluated in a cross-sectional fashion among case subjects with cancer and control subjects. In addition, with few exceptions (48,51,52,57), the studies were based on phenotypic expression of repair that the cancer process itself or the use of cellular damaging agents might impair. Only one study (60) was prospective, where mutagen sensitivity was measured at the time of patient recruitment and recurrence rate was determined. This study, however, was aimed at evaluating the ability of the mutagen sensitivity results to predict clinical outcome, not its relationship to disease risk.

With regard to biologic plausibility, a major limitation of many tests (particularly those belonging to category 1 discussed above) is that DNA repair capacity is only indirectly inferred from cellular DNA damage remaining after exposure to mutagens for a specific time period. In many of these studies, the mutagen used to induce damage is not known to initiate tumors and, methodologically, it would be extremely useful to extend this assay to carcinogens specific to tumor types, such as N-ethylnitrosourea.

We have learned from Table 2Go, in fact, that most of the studies based on tests belonging to category 1 showed statistically significant results. Those belonging to category 2, indirect tests of DNA repair, were often not statistically significant. This result could be due to a high background level when using scintillation counting that is not amenable to chemical damping by such agents as hydroxyurea.

The results of studies based on category 3, assessing the kinetics of repair, were mixed. Studies in category 4, those based on genotyping, were limited in number and were, unfortunately, small with limited power, similar to many studies of metabolic polymorphisms. It is not clear that conducting these studies without concomitant studies of expression and/or function will be fruitful.

To draw firm conclusions about a cause–effect relationship, therefore, we need more evidence about the biologic meaning of the current tests. In particular, evidence has not been provided that tests belonging to category 1 really express DNA repair. They do appear to express unrepaired DNA. One possible interpretation is that category 1 tests refer to a general and nonspecific impairment of the DNA repair machinery, while tests belonging to categories 2 and 3 explore more specific aspects of DNA repair capacity. This working hypothesis, however, requires further evidence.


    CONCLUSION
 Top
 Notes
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Conclusion
 References
 
We have summarized what we believe to be all of the relevant human epidemiologic studies that have addressed the role of a defect in DNA repair capacity in the development of cancer. That is, many of the assays are measuring a response of phytohemagglutinin-stimulated lymphocytes to a mutagenic agent and, as stated in the "Discussion" section under the subheading entitled "Confounding," we do not know the extent to which the results may depend on responses to unmeasured endogenous sensitizing or protective agents rather than on intrinsic DNA repair capacity. However, it must be stressed that the results shown in the tables represent the state of the art for measurements of DNA repair (through 1998) in human epidemiology studies. While associations with cancer risk have been observed in the assays described, the specificity of these assays as measures of DNA repair and, more importantly, as repair of carcinogenic or even mutagenic lesions in DNA is as yet undetermined.

We hope that a presentation of these studies will stimulate the field to develop definitive molecular assays that may define not only the potential genetic defects themselves but also the repair pathways that might be affected by such defects. Although a firm conclusion cannot be drawn, there are a few aspects that are worth noting: (a) The vast majority of studies show a difference between cancer case subjects and control subjects; (b) although this observation is compatible with a chromosomal instability due to cancer itself (with an inversion of the cause–effect relationship), it is notable that impaired mutagen sensitivity was also observed in healthy relatives of cancer case subjects; (c) there are a variety of functional tests that only indirectly address DNA repair and that show high variability in their expression; and (d) the issue of confounding is almost totally unexplored, although many of the observed associations are too strong to be attributable to confounders.

As new functional assays are developed and the current assays are made more precise, the role of DNA repair capacity will be clarified, particularly as more relevant mutagens specific to particular cancers are employed. All such studies should evaluate and report the variability of the assay used and the intraindividual and interindividual variabilities. Prospective studies will be critical and should eliminate concern over the role of cancer itself leading to associations. New studies are appearing on the DNA repair genotypes. Those that compare genetic polymorphisms with functional assays will likely be valuable. It is likely that the study of interindividual variability in DNA repair will greatly contribute to our knowledge of human carcinogenesis.


    NOTES
 
Supported by a grant (to P. Vineis) from the Associazione Italiana per le Ricerche sul Cancro and by Public Health Service grant K07CA16230 (to M. Berwick) from the National Cancer Institute, National Institutes of Health, Department of Health and Human Services.


    REFERENCES
 Top
 Notes
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Conclusion
 References
 

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Manuscript received July 27, 1999; revised March 7, 2000; accepted March 23, 2000.


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