Vol. 04 Issue 4, Late Fall 1999
Research Commentary: Genetically-Influenced Susceptibility to Ionizing Radiation
The Ribbon
Think about recommending routine screening for a large number of healthy people for early detection of some dreaded disease like breast cancer. What criteria would you consider appropriate for this recommendation? You would surely want the screening to be effective at saving lives, reasonably accurate (i.e. not miss real cancers and minimize false positives), and reasonably safe. This article is about general population screening of healthy women by annual mammograms; it is not relevant to those with personal or strong family histories of cancer or to patients who have detected a lump or other abnormality.
Is general population screening by mammography effective at saving lives?
- Eight large scale randomized controlled studies have shown that such screening for women over 50 can reduce breast cancer deaths in this population by 25 to 30% within five to six years.
- It is widely agreed that there is no benefit for screening women under 40.
- There is great controversy about such screening for women between 40 and 49. Premenopausal women have much lower risk of breast cancer and they have denser breasts, which make it harder to interpret their mammograms. With one exception, controlled trials have shown that the rate of death from breast cancer was the same in the screened group as in the control group for seven to nine years following initiation of screening.
Is general population screening by mammography reasonably accurate?
- 80% to 90% of women with known breast cancer show positive results on mammograms. This means that 10 to 20% of breast cancers go undetected by mammograms.
- About one in five to one in ten biopsies done on the basis of suspicious mammograms reveal cancer. This means that 80% to 90% of biopsies are done on women who do not have breast cancer.
What are the risks of mammographic screening?
One of the harmful consequences of routine mammograms relates to the high rate of false positives. Since 80%-90% of biopsies are done on women who do not have breast cancer, thousands of healthy women have biopsies and some of them have medical complications. The other major harmful consequence, DNA damage, is the focus of the rest of this article.
The X-rays used to make mammographic images also cause some small amount of damage to your DNA. Most people have wonderful repair systems that are capable of repairing the damaged DNA. Moreover most cells have a surveillance system that prevents a cell from copying its DNA if it is damaged. However, a small percentage of the population have inherited deficiencies in their repair systems and/or their surveillance systems. For these individuals the unrepaired damage increases their risk of cancer of all types.
An example of an inherited defect in DNA repair
Ataxia telangiectasia (AT) is a rare genetic disease characterized by neuromuscular degeneration, immune system dysfunction, and a 100 times greater risk of cancer than the general background rate. The elevated cancer risk results from an extreme sensitivity of AT patients to X-rays and the fact that they continue making new DNA even when their DNA is damaged.
To inherit AT disease you must inherit a bad copy of the gene from both your parents. If you inherit just one bad copy of the gene, you are a carrier. Although individuals having the full blown AT disease are rare, about 1% of the population are carriers. It is significant that AT carriers are sensitive to radiation-not as sensitive as those of AT patients but more so than most people. Their cells are more damaged by radiation than non-AT cells and the repair system in their cells is three times slower. AT carrier women have about a three- to four-fold increased risk of breast cancer compared to women without this mutated gene. Exposure to X irradiation, for example from diagnostic X-rays or from occupational exposure, probably increases the risk of breast cancer in carrier women. It has been suggested that more cases of breast cancer may occur in women with mutated AT genes than to women with altered BRCA 1 and 2 genes. Most importantly, for the 1% of women who are carriers of an AT mutation, mammography may significantly increase their risk of breast cancer.
It is likely that in the next 10 years clinical tests will become available that will identify AT carriers and perhaps women with other genetic susceptibilities to X-rays. Such women will be advised to avoid routine mammograms. Even though they will represent only a few percent of the population, since there are 32 million American women between 40 and 79 we are talking about hundreds of thousands of women who in the future may be advised
not to have routine mammograms.
Conclusion
For women over 50 at average risk of breast cancer, routine mammograms are probably worthwhile. Since the benefit of routine screening for women under 50 has not been documented and since at least several percent of the population are genetically sensitive to damage by X-irradiation, it seems advisable for premenopausal women to consult their doctors as to their personal risk factors before deciding whether to have routine mammograms.
References
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Elmore, J. et al. Ten-Year Risk of False Positive Screening Mammograms and clinical Breast Examinations. New Eng. J Med. 338:1089-1096. 1998.
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Jatoi, I. Breast cancer screening. Am J Surg 177(6):518-24. 1999.
Kastan, M. Ataxia telangiectasia - broad implications for a rare disorder. New Eng. J Med. 333:662-3. 1995.
Kerlikowske, K. Efficacy of screening mammography among women aged 40 to 49 years and 50 to 69 years: comparison of relative and absolute benefit. J Natl. Cancer Inst. Monogr. 22:79-86. 1997
Shigeta, T., Takagi, M., Delia, D., Chessa, L., Iwata, S., Kanke, Y., Asada, M., Eguchi, M., Mizutani, S. Defective control of apoptosis and mitotic spindle checkpoint in heterozygous carriers of ATM mutations. Cancer Res. 59: 2602-2607. 1999.
Sox, H. Benefit and harm Associated with Screening for Breast Cancer. New Eng. J Med. 338:1145-1146. 1998.
Taubes, G. The Breast-Screening Brawl. Sci. 275:1056-1059. 1997.
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Prepared by Rita Calvo, Ph.D., Senior Lecturer, Molecular Biology and Genetics,
Prof. Calvo teaches courses in Human Genetics and Genetics and Society, Cornell University
Program on Breast Cancer and Environmental Risk Factors