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Epidemiology and Prevention |
Department of Environmental Epidemiology, Istituto Nazionale per la Ricerca sul Cancro, I-16132 Genova, Italy [S. B.]; Department of Occupational and Environmental Medicine, Lund University, S-221 85 Lund, Sweden [L. H., U. S., H. T.]; Centro Nacional de Condiciones de Trabajo, Instituto Nacional de Seguridad e Higiene en el Trabajo, ES-08034 Barcelona, Spain [A. H. M.]; Dipartimento di Medicina del Lavoro, Clinica del Lavoro "Luigi Devoto," Milan University, I-20122 Milan, Italy [A. F.]; Finnish Institute of Occupational Health, FIN-00250 Helsinki, Finland [P. H., H. N.]; Department of Occupational and Evironmental Medicine, Telemark Central Hospital, N-3710 Skien, Norway [S. W., I-L. H.]; and Danish National Institute of Occupational Health, DK-2100 Copenhagen, Denmark [P. W., L. E. K.]
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ABSTRACT |
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INTRODUCTION |
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TopABSTRACTINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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A relationship between chromosomal damage and cancer development has been suggested since the beginning of the 20th century (5) , but only since 1960 have extensive data been gathered on the frequency of CAs in PBLs of humans exposed to known or suspected genotoxic carcinogens. The idea of a causal association between CAs and cancer risk is based on the concept that genetic damage in lymphocytes reflects similar damage in cells undergoing carcinogenesis. However, only recently have prospective cohort studies performed in the Nordic countries (Denmark, Finland, Norway, and Sweden) and in Italy shown that CA frequency measured in PBLs of healthy individuals is predictive of cancer risk (6, 7, 8) . Despite the marked interlaboratory variability and the different outcomes investigated (cancer incidence and cancer mortality), results were consistent. Subjects with the highest level of CAs showed an incidence ratio of 2.08 (95% CI, 1.26–3.40) and a mortality ratio of 2.56 (95% CI, 1.35–4.86) in the Nordic countries and Italy, respectively, compared with subjects with the lowest level. These findings did not appear to be modified by sex, age, country, or time since CA test (6, 7, 8) . The contribution of exposure to carcinogens was not evaluated in those studies because of the requisite information concerning occupation and lifestyle was lacking. Therefore, it was impossible to ascertain whether CAs predicted cancer because they were the result of past exposure to carcinogens or because they were an intermediate end point in the pathway leading to disease, perhaps reflecting inherent genetic susceptibility. This is a crucial issue; the demonstration of a causal role for chromosomal damage in carcinogenesis has important and obvious implications for the study of mechanisms, as well as for public health purposes. To test whether CAs are associated with cancer risk, we conducted a case-control study nested within the two above-mentioned cohorts. The nested design allowed restricting the assessment of carcinogen exposure to cancer cases identified during the follow-up of the cohorts and, likewise, to a sample of subjects who were free of cancer during the period when the cancer cases occurred.
Exposure to carcinogens could modify the prediction of cancer risk
based on CA frequency in different ways. Three models seem most
plausible: (a) exposures early in life induce persistent
chromosome damage or genomic instability, causing an increase in cancer
incidence; (b) recent exposures induce CAs in the target
organs (and in PBLs) and increase the risk of cancer; and
(c) exposures close to cancer onset may modify the effect of
earlier events, such as CAs. The role of exposure was evaluated by
assessing exposure to occupational carcinogens and cigarette smoke in
each of these three periods, as illustrated in Fig. 1
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SUBJECTS AND METHODS |
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Cases and Controls.
In the Nordic cohorts, information on malignant tumors diagnosed from
the date of CA testing until the end of 1993 (Denmark), 1994 (Sweden
and Norway), or 1995 (Finland) was obtained from national cancer
registries. Overall, the Nordic cohorts comprised 93 incident cancer
cases [2 more Swedish cases were included than in the cohort analysis
(8)
due to an additional year of follow-up]. In the
Italian cohort, the specific causes of death until April 30, 1996, were
obtained from the municipality of residence. In total, the Italian
cohort comprised 62 deceased cancer cases (two cases included in the
cohort analysis were excluded because their tumors had been diagnosed
before the date of CA testing). The distribution of subjects in the
whole database by major cancer site and by the other variables
considered in the analysis is given in Table 1
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For each case, our aim was to select four controls from the cohort (11) . Controls were retrospectively and randomly selected from the subjects in the cohort who were at risk for the outcome event in the calendar year of each case occurrence (12) . Controls were matched with their corresponding case by country (only the Nordic data), sex, year of birth, and year of CA test. The maximum differences permitted between the matched subjects’ year of birth and year of CA test were ±15 and ±5 years, respectively. Thus, the matched sets generally consisted of one case and four controls, except for eight Nordic and three Italian sets, which had three controls.
Ascertainment of Occupational Exposure and Smoking Habits.
Occupational hygienists performed partly structured telephone
interviews with cases and controls or, if deceased, with next-of-kin
(widows, widowers, children, parents, or siblings). Exposure
measurements performed for the original cytogenetic studies or for
other purposes were used. Other information sources included contacts
with companies at which the subjects had been employed, former
co-workers, company records, and medical records. In some instances,
when the medical or company records were reliable and covered the whole
occupational history, the subjects were not interviewed. Exposure data
for 4 cases and 10 controls in the Nordic countries and for 2 cases and
20 controls in Italy were missing or were too poor for exposure
classification. Subjects who had quit smoking were classified as
nonsmokers when the available data implied that the subject had quit
smoking cigarettes more than 5 years before the CA test year. Eight
cases and 13 controls in the Nordic countries and 10 cases and 30
controls in Italy lacked smoking data.
Occupational Exposure Matrix.
Scientific publications and other information on all original
cytogenetic studies from which the cohorts were recruited were
scrutinized for occupational exposures of potential interest (6
, 7
, 13)
. A matrix comprising 22 categorized exposure indices was
constructed (Table 2)
. Exposure assessment was semiquantitative except for three categories
classified as exposed versus nonexposed.
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. Group A: exposures
evaluated in the original cytogenetic study to agents classified by the
IARC as human carcinogens (class 1); Group B: exposures to other IARC
class 1 agents not described in the original papers and revealed by the
exposure assessment process, and Group C: all other agents in the
matrix. Occupational exposure was assessed annually starting from the year the subject left school until the end of follow up. Only exposure periods exceeding 1 year were assessed.
For subjects classified as nonexposed, an accuracy assessment of their exposure information was performed. Subjects for whom occupational exposure to any agent in the matrix was unlikely, either because of the nature of their reported job or because information available totally excluded any such exposure, were classified as high-accuracy nonexposed. The rest of the subjects, for whom exposure had been possible although not likely, were classified as moderate-accuracy nonexposed.
Quality Control of Occupational Exposure Assessment.
After the first national exposure assessments, a description of working
histories, including types and levels of exposures, was sent to an
independent occupational hygienist. Based on those descriptions, the
hygienist selected 27 histories to be used in the harmonization
procedure (5% of the whole study group). Discrepancies were discussed
at a meeting, and consensus on all assessments was reached, which
resulted in a harmonization of the exposure categorization. The final
exposure assessments were thereafter performed on a national basis. At
the end of the assessment, a quality control round testing
interassessor repeatability was carried out. The round included 55
(10%) randomly selected subjects evenly distributed among the
countries. For the occupational exposure classification presented in
Table 4
, three different classifications were possible. All five
occupational hygienists were in agreement for 33 subjects (60%), and
four of five were in agreement for 13 subjects (23.6%). For the
remaining nine subjects (16.4%), a lower degree of agreement was
reached, although for eight of nine subjects, the disagreement was
restricted to contiguous exposure classifications.
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. The threshold of 5 years
before CA test, which discriminates recent from past exposures, was
chosen in consideration of the half-life of PBLs (16)
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Moreover, subgroup analyses among nonexposed subjects and among
nonsmokers were performed by means of unconditional logistic
regression. |
RESULTS |
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TopABSTRACTINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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. These estimates did not differ substantially from the crude ORs and
were not significantly modified by country (only considered for the
Nordic countries), sex, age at test, or time since test (all
P > 0.11; likelihood ratio test).
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did not change
noticeably, when occupational exposure level was included in the
conditional logistic regression models. Table 4
shows the data for the period of 5 years or less before CA test;
results from the other two periods were similar. No marked confounding by occupational exposure was found when the analysis was restricted to cases (and their controls) occurring within a limited period of time after the CA test (7 and 10 years, median values for Nordic countries and Italy, respectively).
An informative data subset is represented by those subjects classified as nonexposed during the whole assessment period. Crude ORs of 1.22 (0.30–5.22) for the medium versus low CA group and 2.86 (0.85–9.66) for the high versus low CA group were found for Nordic countries (18 cases and 80 controls). The estimates were not noticeably changed when adjustment was made for the matching factors and the accuracy scoring of the nonexposed subjects. For Italy, the corresponding subgroup analysis could not be performed due to the small number of cases (n = 4) and controls (n = 20).
Table 5
shows the maximum occupational exposure levels of the cases and
controls assessed for different time periods relative to the time of CA
testing. For most individuals, the exposure classification remained the
same during all three time periods. Regression models considering
changes of exposure status between time periods or based on alternative
definitions of exposure (duration of occupational exposure and
different time periods relative to the CA test) were performed. None of
these models revealed any evidence of modification or confounding
effect.
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5 years before CA testing was
included in the conditional logistic regression models (Table 6)
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The crude ORs within each stratum of the cigarette smoking variable
revealed no obvious modification of the total cancer predictivity of
the CA biomarker (P = 0.6 for the Nordic
countries; P = 1.0 for Italy; likelihood
ratio test; Table 6
). The group of Nordic subjects (28 cases and 134
controls) classified as nonsmokers during the whole assessment period
(including non-pipe- and non-cigar-smokers) showed crude ORs of 1.28
(CI, 0.47–3.49) for medium versus low CA group and
2.52 (CI, 0.92–6.94) for high versus low CA group. These
estimates were not markedly changed when adjustment was made for the
matching factors. For Italy, the corresponding subgroup analysis was
not performed because of the small number of cases classified as
nonsmokers during the whole assessment period (8 cases and 63
controls).
Finally, ORs adjusted for matching factors and both occupational exposure and smoking habit were 0.86 (CI, 0.45–1.66) for medium versus low CA group and 2.25 (CI, 1.24–4.09) for high versus low CA group for the Nordic countries and 1.59 (CI, 0.72–3.48) and 2.56 (CI, 1.18–5.56), respectively, for Italy.
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DISCUSSION |
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TopABSTRACTINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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The potential effect of occupational exposure on the association
between CA frequency and cancer risk was estimated separately for each
of the three time periods (Fig. 1)
. The overlapping results of all
regression models made unlikely the hypothesis that the cancer
predictivity of CAs would differ with extent or intensity of exposure.
This conclusion was upheld by the subgroup analysis of subjects who had
never to their knowledge been exposed to any occupational carcinogen
during their lifetime. The ORs of cancer associated with high CA
frequencies in this subgroup were close to those observed among the
carcinogen-exposed subjects.
Like occupational exposure, smoking habit showed no evidence of being a confounder or a modifier of the association between CAs and cancer risk. This finding, too, was upheld by the restricted analyses performed in the subgroup of those who had never smoked (possible only in the Nordic cohort).
Due to limited numbers, diagnosis-specific analyses could only be performed for respiratory tract cancer within the Italian cohort (23 cases). Even within this group of smoking-associated cancer cases, smoking habits did not appear to modify CA predictivity.
It should be noted that in the present study, we evaluated the effect of carcinogen exposure on the association between cancer risk and level of CAs. The ORs shown in the tables estimate relative risks between groups, and ORs between different groups cannot be directly compared. No inference is made about the absolute risk of cancer, which might be higher in smokers as well as in subjects occupationally exposed to carcinogens.
The present results, as well as those of the cohort analysis (8) , gave no evidence that the prediction of cancer risk by CA frequency is dependent on the time interval after CA testing. Different hypotheses have been suggested to interpret this finding. Exposure may have continued after the CA test for a large portion of the exposed subjects, or different induction-latency periods for different cancers and exposures may account for the lack of modifying effect of time since test. Both of these hypotheses are based on the role of carcinogen exposure, which was shown not to affect the CA-cancer association. The results may be interpreted instead as evidence of proneness to develop cancer due to individual susceptibility factors, such as genetic instability or DNA repair deficiencies.
Our finding that the association between CAs and cancer was not attributable to exposure to carcinogens is consistent with the idea of increased CA frequency as a cancer-prone state. The results are provocative and have obvious ramifications for the understanding of the role played by high levels of chromosome damage in the origin of neoplasia-associated chromosome aberrations. The presence of recurrent and specific chromosome abnormalities, which characterize all neoplastic disorders that have been studied sufficiently to permit conclusions (17) , provides strong evidence that they have a causal role in carcinogenesis. The mechanisms involved are unknown, but at least one breakage event is a prerequisite.
The present study no doubt underestimates the true frequency of chromosome breakage because the results are based on conventional cytogenetic analyses of unbanded metaphase preparations of PBLs. Future studies of interphase cells by fluorescent in situ hybridization and spectral karyotyping (18) should clarify the association between the frequency and type of chromosome damage in PBLs and other, perhaps more relevant, cell types and tumor-associated chromosome aberrations.
An increasing amount of data has shown that some individual characteristics associated with cancer risk, such as differences in metabolizing enzymes or DNA repair capacity, also have an effect on CA occurrence (16 , 19, 20, 21, 22, 23, 24, 25) . These findings raise the obvious question of whether the association between CAs and cancer risk depends on individual metabolism and DNA repair capability, so that CAs would better predict cancer risk in people with as yet unknown predisposing genes. Some polymorphisms of carcinogen-metabolizing enzymes, such as N-acetyltransferase 2, also appear to affect baseline CAs, which may reflect interaction with genotoxic exposures common to most people or involvement of such enzymes in metabolism affecting CAs (23) . CA levels may also be affected by nutritional conditions such as folate deficiency (26) . The role of genetic and other individual factors remains open, even if the framework of this study could be used to test the hypothesis.
The generalization of our results to all carcinogen exposures depends on how complete our exposure survey was. Because tobacco smoke is one of the most important carcinogens and occupational carcinogen exposures are usually higher than nonoccupational, we believe that substantial exposure was taken into account. Probably the most important exposures that we could not evaluate were those from food and beverages, a limitation that should be kept in mind.
Some factors limiting the use of CAs as a marker of cancer risk should be considered, such as the relatively low increase in risk or the impossibility of controlling subsequent steps of carcinogenesis that might modify the validity of the prediction. The evidence of a causal association between chromosomal damage and cancer occurrence, however, is well substantiated by theoretical and epidemiological data, and preventive policies and measures are always recommended when an increase of CAs is found in a group of exposed subjects.
In conclusion, the results of this study contribute to the validation of CAs as an intermediate end point in carcinogenesis. Occupational exposures and smoking did not modify the association between CA level and cancer. Although genotoxic carcinogens induce CAs and cancer, the cancer predictivity of high CA rate does not require such exposure. Individual characteristics not identified in the present study are probably behind the CA-cancer risk association, and may include polymorphisms of genes involved in carcinogen metabolism and DNA repair, genetic instability, and nutritional status.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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1 This study was supported by the European Union
Biomed 2 Program (Contract BMH4-CT96–0874), the Swedish Medical
Research Council, the Swedish Cancer Society, the Swedish Council for
Work Life Research, the Academy of Finland, the Associazione Italiana
per la Ricerca sul Cancro, the Italian Ministry of Health, and the
Italian Ministry of the University and of Scientific and Technological
Research. Other members of European Study Group on Cytogenetic
Biomarkers and Health include Anton Brøgger, Norwegian Radium
Hospital, Oslo, Norway; Benkt Högstedt, Department of
Occupational Medicine, Central Hospital, Halmstad, Sweden; Christina
Reuterwall, National Institute of Work Life, Solna, Sweden; Bo Lambert,
Department of Biosciences, CNT/Novum, Karolinska Institute, Stockholm,
Sweden; Felix Mitelman, Department of Clinical Genetics, Lund
University, Sweden; Ingrid Nordenson, National Institute of Work Life,
Umeå, Sweden; Sisko Salomaa, Finnish Centre for Radiation and Nuclear
Safety, Helsinki, Finland; and Staffan Skerfving, Department of
Occupational and Environmental Medicine, Lund University, Sweden. 
2 To whom requests for reprints should be
addressed, Department of Environmental Epidemiology, Istituto Nazionale
per la Ricerca sul Cancro, Largo Rosanna Benzi 10,
I-16132 Genova, Italy. Phone: 39-010-5600924; Fax: 39-010-5600501.
3 The abbreviations used are: CA, chromosomal
aberration; OR, odds ratio; CI, confidence interval; PBL, peripheral
blood lymphocyte.
Received 8/27/99. Accepted 1/19/00.
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R. Julian Preston Quantitation of Molecular Endpoints for the Dose-Response Component of Cancer Risk Assessment Toxicol Pathol, January 1, 2002; 30(1): 112 - 116. [Abstract] [PDF]
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M. G. Andreassi, E. Picano, S. Del Ry, N. Botto, M. G. Colombo, D. Giannessi, V. Lubrano, C. Vassalle, and A. Biagini Chronic long-term nitrate therapy: possible cytogenetic effect in humans? Mutagenesis, November 1, 2001; 16(6): 517 - 521. [Abstract] [Full Text] [PDF]
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M. L. Bondy, L.-E. Wang, R. El-Zein, M. de Andrade, M. S. Selvan, J. M. Bruner, V. A. Levin, W. K. Alfred Yung, P. Adatto, and Q. Wei {gamma}-Radiation Sensitivity and Risk of Glioma J Natl Cancer Inst, October 17, 2001; 93(20): 1553 - 1557. [Abstract] [Full Text] [PDF]
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J. W. Crott, S. T. Mashiyama, B. N. Ames, and M. Fenech The Effect of Folic Acid Deficiency and MTHFR C677T Polymorphism on Chromosome Damage in Human Lymphocytes in Vitro Cancer Epidemiol. Biomarkers Prev., October 1, 2001; 10(10): 1089 - 1096. [Abstract] [Full Text] [PDF]
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J. Crott, P. Thomas, and M. Fenech Normal human lymphocytes exhibit a wide range of methionine-dependency which is related to altered cell division but not micronucleus frequency Mutagenesis, July 1, 2001; 16(4): 317 - 322. [Abstract] [Full Text] [PDF]
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J. W. Crott, S. T. Mashiyama, B. N. Ames, and M. F. Fenech Methylenetetrahydrofolate reductase C677T polymorphism does not alter folic acid deficiency-induced uracil incorporation into primary human lymphocyte DNA in vitro Carcinogenesis, July 1, 2001; 22(7): 1019 - 1025. [Abstract] [Full Text] [PDF]
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J. Crott and M. Fenech Preliminary study of the genotoxic potential of homocysteine in human lymphocytes in vitro Mutagenesis, May 1, 2001; 16(3): 213 - 217. [Abstract] [Full Text] [PDF]
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M. Kirsch-Volders and M. Fenech Inclusion of micronuclei in non-divided mononuclear lymphocytes and necrosis/apoptosis may provide a more comprehensive cytokinesis block micronucleus assay for biomonitoring purposes Mutagenesis, January 1, 2001; 16(1): 51 - 58. [Abstract] [Full Text] [PDF]
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