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Molecular Epidemiology Section, Laboratory of Human Carcinogenesis, Division of Basic Science, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892–4255
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONCARCINOGENESISCARCINOGEN METABOLISM AND...GENETIC POLYMORPHISMS FOR...DIET, CARCINOGENESIS AND...CONCLUSIONSREFERENCES |
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KEY WORDS: • carcinogenesis • epidemiology • carcinogen metabolism • genetic polymorphism • nutrition
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONCARCINOGENESISCARCINOGEN METABOLISM AND...GENETIC POLYMORPHISMS FOR...DIET, CARCINOGENESIS AND...CONCLUSIONSREFERENCES |
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).
Several types of biomarkers are used in molecular epidemiology studies.
These include markers of exposure (e.g., serum levels of nutrients),
DNA damage (e.g., carcinogen-DNA adducts), early pathobiological
effects (e.g., mutations in tumor suppressor genes, structural
chromosomal changes or changes in morphology) and inherited
susceptibilities (inheritance of germline mutations and genetic
polymorphisms). The use of biomarkers can help elucidate causal
mechanisms of carcinogenesis (Vineis and Porta 1996
).
Biomarkers of DNA damage can improve exposure assessments (e.g.,
characterizing low dose exposures or low risk populations), provide a
relative contribution of individual chemical carcinogens from complex
mixtures (e.g., tobacco-specific N-nitrosamines in cigarette smoke) and
estimate total burden of a particular exposure for which there are
numerous sources [e.g., benzo(a)pyrene from air, tobacco, diet and
occupation] (Vineis and Porta 1996
). Although the
incorporation of biomarkers into molecular epidemiologic studies should
strengthen statistical associations, enhancing both exposure assessment
and measurement outcome, there are also new opportunities for bias and
confounding (Boffetta 1995
, Hall et al. 1994
).
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CARCINOGENESIS |
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TOPABSTRACTINTRODUCTIONCARCINOGENESISCARCINOGEN METABOLISM AND...GENETIC POLYMORPHISMS FOR...DIET, CARCINOGENESIS AND...CONCLUSIONSREFERENCES |
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), although overlap clearly exists for some genes. This
concept of caretaker and gatekeeper genes acknowledges their respective
roles in maintenance of genomic integrity (e.g., DNA repair) and
cellular proliferation, respectively. Some examples of caretaker genes
are those that are involved in either DNA repair, carcinogen activation
or carcinogen detoxification, whereas examples of gatekeeper genes are
those involved in cell cycle control and DNA replication.
Dysfunctional caretaker genes increase the probability of mutations in
gatekeeper genes, initiating and promoting the molecular pathogenesis
of cancer. |
CARCINOGEN METABOLISM AND INTERINDIVIDUAL VARIATION |
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TOPABSTRACTINTRODUCTIONCARCINOGENESISCARCINOGEN METABOLISM AND...GENETIC POLYMORPHISMS FOR...DIET, CARCINOGENESIS AND...CONCLUSIONSREFERENCES |
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), for example, inherited capacities for
carcinogen metabolism and DNA repair. Many of these differences occur
because of variations in genetic sequence, which code for enzymes with
different functions. A single base change may result in a different
amino acid sequence, which might substantially affect activity. Some
genetic variants result in the complete absence of a gene. If a genetic
variant occurs in >1% of the population, then it is considered a
genetic polymorphism. Carcinogen exposures generally require metabolic activation to become harmful; this occurs as part of natural processes that serve to excrete foreign compounds. The processes of activation and conjugation are governed by phase I and II enzymes, respectively. In general, phase I enzymes convert relatively inert chemicals into electrophilic intermediates via oxidation reactions. Phase II enzymes remove the activated intermediates from the body via conjugation reactions to carriers such as glutathione. The role of carcinogen metabolism in carcinogenesis is shown in Figure 1.
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GENETIC POLYMORPHISMS FOR CARCINOGEN METABOLISM AND CANCER RISK |
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TOPABSTRACTINTRODUCTIONCARCINOGENESISCARCINOGEN METABOLISM AND...GENETIC POLYMORPHISMS FOR...DIET, CARCINOGENESIS AND...CONCLUSIONSREFERENCES |
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, Okada et al. 1995
),
in which the combination of the homozygous minor allele and smoking
yielded odds ratios similar to having one of the other genotypes and a
greater smoking history. There is also one report that associates this
polymorphism with increased stages of disease (Okada et al. 1995
); recent data suggest that CYP1A1 genetic polymorphisms
predict the presence of mutations in the p53 tumor suppressor gene
(Kawajiri et al. 1996
). Nonetheless, an association of
CYP1A1 polymorphisms and lung cancer risk has been identified only in
Japanese subjects, and most Western studies have been negative.
The presence of a homozygous deletion of the glutathione-S-transferase
gene (GSTM1) results in the loss of function and the ability to
conjugate and detoxify carcinogens. An association of increased bladder
cancer risk and GSTM1 null genotypes has been shown, as has one for
lung cancer. The null genotype also is associated with the presence of
p53 mutations (Ryberg et al. 1994
). Interestingly, data
have suggested that GSTM3 levels in the lung are related to the GSTM1
genetic polymorphism (Anttila et al. 1995
,
Nakajima et al. 1995
), and that the GSTM1 null genotype
was associated with CYP1A1 transcription (Vaury et al. 1995
); thus the effects of GSTM1 might be to detoxify
carcinogenic intermediates directly and to induce other genes involved
in carcinogen metabolism.
There are several recently described phenotypic DNA repair assays that
are in the process of being validated. For example, by using a
carcinogen-modified plasmid DNA with a chloramphenical
acetyltransferase reporter gene transfected into cultured lymphocytes
and assessing the repair of these lesions, a prediction of an increased
risk of basal cell skin cancers can be made (Wei et al. 1994
). However, these assays are technically difficult and not
all studies are positive (Hall et al. 1994
). A less
specific assay, but one much less difficult to perform, has been
labeled "mutagen sensitivity." Here, bleomycin or radiation are
used as a mutagen in cultured lymphocytes, and chromosomal aberrations
are counted. This assay has been associated with oral cavity cancers
(Ankathil et al. 1996
, Cloos et al. 1994 and 1996
, Pandita and Hittelman 1995
, Spitz et al. 1994
), with
multiple primary cancers (Cloos et al. 1994
) and an
interaction with smoking and alcohol use (Cloos et al. 1994 and 1996
).
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DIET, CARCINOGENESIS AND INTERINDIVIDUAL VARIATION |
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TOPABSTRACTINTRODUCTIONCARCINOGENESISCARCINOGEN METABOLISM AND...GENETIC POLYMORPHISMS FOR...DIET, CARCINOGENESIS AND...CONCLUSIONSREFERENCES |
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).
Well-done cooking of meats and fish provides significant exposures to
heterocyclic amines, formed from the pyrolysis of creatines and amino
acids (Felton et al. 1986
, Sinha and Rothman 1997
). These compounds are suspected to be colon and breast
carcinogens (Kadlubar et al. 1995
, Sinha and Rothman 1997
, Snyderwine 1994
). By using
phenotypic assays to assess CYP1A2 and NAT2, an increased risk of colon
cancer was identified in persons who consume red meat (Badawi et al. 1996
). Additional studies are in progress, including those
for colonic polyps as early markers.
Several studies have focused on an interaction for
carcinogen-metabolizing enzymes or DNA repair and antioxidants. Using
blood-DNA polycyclic aromatic hydrocarbon (PAH) adducts as an
intermediate marker of cancer risk, it has been reported that in
persons who are GSTM1, there is an inverse relationship between vitamin
E levels and adducts, and for smoking-related adducts and vitamin C
(Grinberg-Funes et al. 1994
). It has been reported that
micronuclei formation was highest in persons with the lowest blood
levels of folate and B-12 (Hong and Sporn 1997
); this
was confirmed by another study (Bourhis et al. 1996
).
However, increasing dietary folate in deficient subjects did not
improve the micronucleus score (Bourhis et al. 1996
).
Increased alcohol consumption is a risk factor for oral cavity, liver,
esophagus and breast cancer. The carcinogenic components of alcoholic
beverages are not known, but acetaldyde, which is metabolically
converted by the liver from ethanol is suspected. This oxidation is
governed primarily by alcohol dehydrogenases (ADH). In Caucasians, the
ADH3 is polymorphic (Xu et al. 1988
), and the activity
has been associated with oral cavity cancer (Harty et al. 1997
). An interesting interaction of decreased folate and
alcohol consumption increases colon cancer risk in persons with a
variant in the methylenetetrahydrofolate reductase gene (Ma et al. 1997
), but this has not yet been studied in relation to
ADH2 genotypes. In Japanese subjects, for whom ADH2 rather than ADH3 is
polymorphic, as is the detoxifying aldehyde dehydrogenase
(Bosron and Li 1986
, Yoshida 1992
), an
increased risk of liver cancer occurs (S. Kato, unpublished
data).
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CONCLUSIONS |
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TOPABSTRACTINTRODUCTIONCARCINOGENESISCARCINOGEN METABOLISM AND...GENETIC POLYMORPHISMS FOR...DIET, CARCINOGENESIS AND...CONCLUSIONSREFERENCES |
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FOOTNOTES |
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1 Presented at the symposium "Interactions of
Diet and Nutrition with Genetic Susceptibility in Cancer" as part of
Experimental Biology 98, April 18–22, 1998, San Francisco, CA. The
symposium was sponsored by the American Society for Nutritional
Sciences. Published as a supplement to The Journal of
Nutrition. Guest editors for the symposium publication were Jo L.
Freudenheim, State University of New York, Buffalo, NY and Rashmi
Sinha, National Cancer Institute, Bethesda, MD.
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REFERENCES |
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TOPABSTRACTINTRODUCTIONCARCINOGENESISCARCINOGEN METABOLISM AND...GENETIC POLYMORPHISMS FOR...DIET, CARCINOGENESIS AND...CONCLUSIONSREFERENCES |
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