Association Between the T29®C Polymorphism in the Transforming Growth Factor b1 (TGF-b1) Gene and Breast Cancer Among Elderly White Women
Association Between the T29®C Polymorphism in the Transforming Growth Factor b1 (TGF-b1) Gene and Breast Cancer Among Elderly White Women
Abstract & commentary
Synopsis: TGF-b1 genotype is associated with risk of breast cancer in white women aged 65 years and older. Because the T allele is common and confers risk, it may be associated with a large proportion of breast cancer cases.
Source: Ziv E, et al. JAMA. 2001;285:2859-2863.
Tgf-b1 has been shown to inhibit cellular
proliferation, suppress inflammatory response, stimulate angiogenesis, and increase production of the extracellular matrix. In vitro studies have shown that increased activity in the TGF-b1 pathway is a potent inhibitor of most mammary cells lines. Transgenic mice with single gene deletion of TGF-b1 are more susceptible to lung, breast, and liver cancers induced by carcinogens. Since the activities of TGF-b1 play a role in the development and progression of cancer, Ziv and colleagues sought to determine if common allelic variants conferred risk for, or protection from, breast cancer. The answer is apparently "yes" for the population studied. The study group consisted of 3075 white women older than age 65. The allelic variant that was most common was T/C at 48.6%. The allelic variant that conferred protection was least common at 14.9%. The allelic variant T/T, present in 36.7%, did not give more risk than the T/C variant. Adjusting for age, age at menarche, age at menopause, parity, hormone use, body mass index, and bone mass did not change the associations. Ziv et al note that roughly 60% of women carry either the T/T or T/C genotype, so if this association holds, then this genotype might be responsible for far more excess risk for breast cancer than high-penetrance genotypes such as BRCA1. A limitation of the study is that so few women in any category developed breast cancer when followed for almost 10 years. In the T/C group, the rate was 5.8 per 1000 person-years and 80 cases of breast cancer. In the T/T group, the rate was 5.4 per 1000 person-years and 56 cases. In the C/C group, the rate was only 2.3 per 1000 person-years and only 10 cases of breast cancer. Therefore, Ziv et al consider their findings preliminary. Of note, there was no difference in stage or estrogen receptor status in those who did develop breast cancer.
COMMENT by Sarah L. Berga, MD
It is commonplace to attribute causality to things we can control. It gives us a sense of order. However, to the extent that we are mislead by our attributions, then we stand to pay a price for this longing. This is what I worry about when we blame breast cancer on postmenopausal hormone use. On the other hand, we often wink at habits that we know are unhealthy, such as tobacco smoking, because we know the behavior is difficult to stop. It is obviously our job, as physicians, to help patients distinguish between behaviors that are unhealthy and those that are not. Do we really think that estrogen causes breast cancer? What if it does not? My greatest fear is that many women will be denied the benefits of hormone use because we cannot provide an unequivocal answer that it is largely safe. Our hesitation results from the constant trickle of studies purporting to find an association. But what if breast cancer is generally NOT related to a personal behavior such as hormone use or vitamin intake, but, instead, due to some kind of bad luck, such as a genetic factor? Enter the present study.
In this article, Ziv et al find that a common genetic allele for the protein TGF-b1 confers risk for breast cancer. What is an allelic variant? It just means that for any one gene, there are variations in the coding sequence that show up as minor variations in the resulting gene product. In this study there is a single change, so instead of being cytosine, there is thymine at the 29th nucleotide of the coding sequence. The apparent effect of this change is to increase the amount of TGF-b1 that is made and released into the circulation. Is an allelic variant a mutation? This is a matter of perspective, I suppose. In this study, the excess risk is conferred by the 2 most common variants. It is difficult to call them mutations when they are so prevalent. The effect size if one has either the T/T or T/C variant is about a tripling of risk for breast cancer, far more than has ever been suggested for ERT or HRT use. Not addressed by this study is whether there might be an interaction between this genetic risk factor and behavioral risk factors, such as alcohol intake or tobacco use. Should we screen for this allelic variant? Ziv et al say that more work is needed to confirm this association, but their hope is that work of this type will make prediction of breast cancer risk more accurate.
While there is clearly much work to be done in identifying and understanding how various cellular products regulate cell growth and risk for cancer, it is becoming much easier to do genotyping. Let’s say that there are 200 genes that appear to confer a moderate to high risk for breast cancer. Can we easily screen for these? The answer is yes. This is what gene microassay technology promises. The polymorphisms in the genes are found, the associations are found, and then a "gene chip" is developed for easily detecting in one assay all of these 200 high-risk polymorphisms for breast cancer. Instead of literally chipping away at an individual’s genotype one gene at a time, if we know what we are looking for, then we can make the chip for the "worst" genes. Using the "gene chip," we can find out how many of the 200 or so genes that might confer risk a given individual has. Screening for gene polymorphisms with microassay technology gets increasingly easier. Figuring out which ones to screen for is still hard, but increasingly feasible with molecular epidemiology. So don’t forget to donate your blood to the next molecular epidemiologist who asks. We will need large numbers, and lots of public good will, to figure out these associations. Once found, then we will need to figure out how to explain this to our patients. I have 2 hopes about this process of discovery. First, I hope that we learn what is and what is not high-risk behavior so that we can wisely advise our patients. Second, since it is likely that we will all have some high-risk genes, I hope that we as a society will learn to be a lot less judgmental and stop blaming patients for illnesses that are linked to genes.
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