Breast cancer is the most common form of cancer among women worldwide.  The American Cancer Society reported 192,200 new cases of invasive breast cancer in 2001 (1).  Several genetic factors have been related to breast cancer in various studies (2).  Results have largely conflicted between studies.  Risk estimates for individual polymorphisms in various proposed susceptibility genes are generally moderate overall, possibly because of incomplete penetrance, study population diversity, low population prevalence of various alleles, and gene-gene or gene-environment interactions.  Many of the host of environmental risk factors for breast cancer are related to cumulative lifetime exposure to endogenous or exogenous estrogens (3).   This has led to intensive study of genetic factors involved in estrogen metabolism, including the study of polymorphisms in the glutathione-S-transferase (GST) genes and of catechol-O-methyl-transferase (COMT) polymorphisms (4,5).  Results from these studies also have been discrepant within and among laboratories (4-6).  Furthermore, hormone replacement therapy (HRT) has been shown to be associated with a slight increase in breast cancer risk (3).

The Finding

Mitrunen et al. performed a well-designed case-control study in an ethnically homogenous population of Finnish women to elucidate the breast cancer risk associated with various combinations of GST polymorphisms, COMT polymorphisms, and HRT.  All GST polymorphisms previously suspected of a positive association were included.  The COMT polymorphisms studied included those resulting in low enzyme activity, which could in result in mutagenic by-products of incomplete estrogen metabolism.  The study tested the hypothesis that certain polymorphisms in both the GST gene and the COMT gene synergistically increase susceptibility to breast cancer and that HRT, in the presence of these mutations, interacts to augment the increased risk.

Risks were significantly higher for women with HRT who were carrying the low-activity COMT-L allele or COMT-LL genotype together with either the GSTP1 Ile/Ile or the GSTT1 null genotypes.  Although based on small numbers, a clear tendency of increased risk by increasing duration of HRT use and increased number of at-risk alleles was observed.  This effect was dose-dependent with respect to length of HRT use.  No overall modifying effect was found in breast cancer risk for combinations of COMT and GST genes alone or of HRT alone.  Thus, increased overall breast cancer risk for users of HRT may be at least partly explained by differences in genetic susceptibility. 

Public Health Implications

The study demonstrates how an environmental factor, i.e., drug therapy, modifies gene-gene interactions affecting breast cancer risk in this Finnish population.  Conclusions in the highest risk groups are based on low sample numbers, and confidence intervals are wide.  The paper adds to the scientific knowledge base of breast cancer risk mechanisms.  However, these results alone do not indicate the need for population screening or genetic testing for these mutations in improving the overall public health risk for breast cancer.  Thus, confirmatory studies need to be done to predict public health value.

References

1. American Cancer Society. Cancer facts and figures 2001.  Atlanta: American Cancer Society; 2001.
2. Dunning AM, Healey CS, Pharoah PDP, et al. A systematic review of genetic polymorphisms and breast cancer risk.  Cancer Epidemiol Biomark Prev   1999; 8: 843–53.
3. Feigelson HS, Henderson BE. Estrogens and breast cancer. Carcinogenesis 1996;17: 2279–84.
4. Millikan R, Pittman G, Tse C-K, et al.  Glutathione S-transferases M1, T1, and P1 and breast cancer.  Cancer Epidemiol Biomark Prev  2000;9:567–73.
5. Lavigne JA, Helzlsouer KJ, Huang H-Y, et al. An association between the allele coding for a low activity variant of catechol-O-methyltransferase and the risk for breast cancer.  Cancer Res 1997;57:5493–97.
6. Mitrunen K, Jourenkova N, Kataja V, et.al. Gluathione S-transferases, M1, M3, P1, and T1 genetic polymorphisms and susceptibility to breast cancer. Cancer Epidemiol Biomark Prev 2001;10:229–36.
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