Background
Summary of Evidence
Significance
        Cytochrome p450 Enzymes
        N-acetyl transferase 1 and N-acetyl transferase 2
        Glutathione S-transferase

Background

The search for genetic markers for breast cancer susceptibility has led to an increasing number of epidemiologic studies of relatively common genetic markers referred to as genetic polymorphisms.[1] These polymorphically expressed genes code for enzymes that may have a role in the metabolism of estrogens or detoxification of drugs and environmental carcinogens. Although the clinical significance and causality of associations with breast cancer reported to date is unclear, genetic polymorphisms may account for why some women are more sensitive than others to environmental carcinogens such as replacement estrogens or cigarette smoke.

Evidence of associations between genetic polymorphisms and breast cancer risk in women has been obtained from case-control or cohort (nested case-control) analytic studies, usually with just a single center or research group (level of evidence: 3). The endpoint in these studies has sometimes been prevalent breast cancer rather than the more satisfactory endpoint of incident breast cancer. In several studies of genetic polymorphisms and breast cancer, convenience samples of cases and controls have been used. However, some studies have been population based, with incident cases of breast cancer and with adequate control of confounding factors. Results to date have largely been inconsistent, and none of the markers so far has clinical applications.

Cytochrome p450 enzymes are members of a multiple gene “superfamily” that play an important role in steroidogenesis and detoxification of xenobiotics such as polycyclic aromatic hydrocarbons, benzo(a)pyrene, arylamines, and heterocyclic amines.[2] The p450 cytochromes provide a line of defense against exposure to environmental chemicals. However, carcinogens may be activated by p450 metabolism. Cytochrome p450 enzymes are expressed primarily in the liver and in other tissues.

Molecular epidemiology studies of cancer of the breast (as well as lung, bladder, colon, and other sites) have examined associations with p450 cytochrome genotypes such as CYP1A1, CYP2D6, and CYP17. Earlier studies, carried out before the availability of DNA tests for CYP1A1 and CYP2D6, examined the activity of the corresponding polymorphically expressed enzyme.

The CYP1A1 gene, located on chromosome 15q, codes for aryl hydrocarbon hydroxylase (AHH). AHH, which catabolizes polycyclic aromatic hydrocarbons and arylamines, has been found in breast tumor tissue. AHH is strongly inducible, i.e., greater enzymatic activity is seen with greater exposure to substrates. AHH catalyzes the mono-oxygenation of polycyclic aromatic hydrocarbons to phenolic products and epoxides that may be carcinogenic. AHH is also involved in the conversion of estrogen to hydroxylated conjugated estrogens such as 2-hydroxyestradiol.

Three polymorphisms of this p450 gene that code for AHH have been identified so far: an MspI RFLP of the 3’ end of the gene (MspI); an adenine-to-guanine mutation in exon 7 of this gene, which causes an isoleucine to valine substitution (Ile-Val); and a polymorphism of the CYP1A1 gene identified among African Americans (AA). The frequencies of the MspI and Ile-Val polymorphisms vary considerably by race; the frequencies are higher among Japanese and Hawaiian populations as compared with Caucasians and African Americans.

The CYP2D6 gene is located on chromosome 22q and codes for debrisoquine hydroxylase, which metabolizes a variety of drugs and other xenobiotics. Like other polymorphically expressed p450 enzymes, debrisoquine hydroxylase may activate procarcinogens or, conversely, detoxify carcinogens. A number of alleles have been characterized at the CYP2D6 locus. The “poor metabolizer” phenotype (CYP2D6 mutant/mutant genotype), which is rare in Asians, occurs in about 5% to 10% of Caucasians and in 2% of African Americans.

Relatively few molecular epidemiology studies of the CYP2D6 genotype and breast cancer risk have been reported. Based upon genotype assays in breast cancer cases and controls, negative results have been reported in Great Britain [3,4] and in the United States.[5]

The N-acetyl transferase-1 (NAT1) and N-acetyl transferase-2 (NAT2) genes are located on chromosome 8q. Both are polymorphically expressed in a variety of tissues. NAT2 detoxifies or, conversely, activates aromatic amines such as 4-aminobiphenyl found in tobacco smoke.[5] Both phenotypic assays and genotypic assays for NAT2 can be used to classify individuals as rapid or slow acetylators. Genetic variants of the NAT2 gene have been cloned, and 6 alleles at this locus have been identified; the F1 allele confers the fast acetylator phenotype. The distribution of NAT1 and NAT2 alleles differs widely between racial and ethnic groups. Studies of the NAT2 genotype and breast cancer susceptibility have reported inconsistent results.[6-9]

The glutathione S-transferase-M1(GSTM1) gene is located on chromosome 1, and the gene for glutathione S-transferase-T1 (GSTT1) is located on chromosome 11q. A glutathione S-transferase-P1 (GSTP1) gene has also been identified. The glutathione S-transferase genes may play a role in susceptibility to cancer. Glutathione S-transferases detoxify a variety of carcinogens and cytotoxic drugs (for example, benzo(a)pyrene, monohalomethanes such as methyl chloride, ethylene oxide, pesticides, and solvents used in industry) by catalyzing the conjugation of a glutathione moiety to the substrate. Individuals who are homozygous carriers of deletions in the GSTM1, GSTT1, or GSTP1 genes may have a higher risk of cancer of the breast and other sites because of their impaired ability to metabolize and eliminate carcinogens.[10-12]

GSTM1 is polymorphically expressed and 3 alleles at the GSTM1 locus have been identified: GSTM1-0 (homozygous deletion genotype), GSTM1a, and GSTM1b. The null allele (GSTM1-0) is present in about 38% to 67% of Caucasians and 22% to 35% of African Americans. GSTM is not expressed in breast tissue at high levels. Two functionally different genotypes at the GSTT1 locus have been described: GSTT1-0 (homozygous deletion genotype) and GSTT1-1 (genotypes with 1 or 2 undeleted alleles).[9] A polymorphism of the GSTP1 gene, A313G (changing codon 105 from Ile to Val), has been identified.

Glutathione S-transferase genotypes have also been examined in relation to age at breast cancer diagnosis in women with a positive family history. One study examined 185 breast cancer cases ascertained through hereditary breast cancer clinics in the United States and found no association between GSTM1 genotypes and breast cancer penetrance. However, the GSTT1-0 allele was associated with accelerated age of first breast cancer diagnosis as compared with the GSTT1-1 allele. Approximately 40% of the subjects were diagnosed before age 40 years.[9]

References

1. Nathanson KL, Weber BL: "Other" breast cancer susceptibility genes: searching for more holy grail. Hum Mol Genet 10 (7): 715-20, 2001.  [PUBMED Abstract]
   
   
2. Strong LC, Amos CI: Inherited susceptibility. In: Schottenfeld D, Fraumeni JF Jr, eds.: Cancer Epidemiology and Prevention. 2nd ed. New York, NY: Oxford University Press, 1996, pp 559-583. 
   
   
3. Wolf CR, Smith CA, Gough AC, et al.: Relationship between the debrisoquine hydroxylase polymorphism and cancer susceptibility. Carcinogenesis 13 (6): 1035-8, 1992.  [PUBMED Abstract]
   
   
4. Smith CA, Moss JE, Gough AC, et al.: Molecular genetic analysis of the cytochrome P450-debrisoquine hydroxylase locus and association with cancer susceptibility. Environ Health Perspect 98: 107-12, 1992.  [PUBMED Abstract]
   
   
5. Buchert ET, Woosley RL, Swain SM, et al.: Relationship of CYP2D6 (debrisoquine hydroxylase) genotype to breast cancer susceptibility. Pharmacogenetics 3 (6): 322-7, 1993.  [PUBMED Abstract]
   
   
6. Ambrosone CB, Freudenheim JL, Graham S, et al.: Cigarette smoking, N-acetyltransferase 2 genetic polymorphisms, and breast cancer risk. JAMA 276 (18): 1494-501, 1996.  [PUBMED Abstract]
   
   
7. Agúndez JA, Ladero JM, Olivera M, et al.: Genetic analysis of the arylamine N-acetyltransferase polymorphism in breast cancer patients. Oncology 52 (1): 7-11, 1995 Jan-Feb.  [PUBMED Abstract]
   
   
8. Millikan RC, Pittman GS, Newman B, et al.: Cigarette smoking, N-acetyltransferases 1 and 2, and breast cancer risk. Cancer Epidemiol Biomarkers Prev 7 (5): 371-8, 1998.  [PUBMED Abstract]
   
   
9. Morabia A, Bernstein M, Heritier S, et al.: NAT2-smoking interaction with respect to breast cancer in menopausal women. Am J Epidemiol 147: A179, S45, 1998. 
   
   
10. Rebbeck TR: Molecular epidemiology of the human glutathione S-transferase genotypes GSTM1 and GSTT1 in cancer susceptibility. Cancer Epidemiol Biomarkers Prev 6 (9): 733-43, 1997.  [PUBMED Abstract]
    
    
11. Maugard CM, Charrier J, Pitard A, et al.: Genetic polymorphism at the glutathione S-transferase (GST) P1 locus is a breast cancer risk modifier. Int J Cancer 91 (3): 334-9, 2001.  [PUBMED Abstract]
    
    
12. Mitrunen K, Jourenkova N, Kataja V, et al.: Glutathione S-transferase M1, M3, P1, and T1 genetic polymorphisms and susceptibility to breast cancer. Cancer Epidemiol Biomarkers Prev 10 (3): 229-36, 2001.  [PUBMED Abstract]
    
    

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