5. What were the findings of the 1996 study in Washington?

This study:

Supported previous studies testing the frequency of three BRCA1 and BRCA2 alterations in the general Jewish population: The frequencies reported in this study are consistent with those previously reported for the general Jewish population. The DNA analysis in this study showed that 120 of the 5,318 volunteers had one of the three alterations or about 1 person in 44 (2.3 percent). No individual carried more than one of the three alterations. By comparison, the frequency of all BRCA1 and BRCA2 alterations combined in the non-Jewish population is less than 1 percent.

Estimated the average risk of breast and ovarian cancer associated with three BRCA1 and BRCA2 alterations in the general Ashkenazi population: The researchers found that women carrying one of the three alterations have, on average, a 56 percent chance (a range of 40 percent to 73 percent) of getting breast cancer by the age of 70 (compared with a 13 percent chance without the alterations) and a 16 percent chance (a range of 6 percent to 28 percent) of getting ovarian cancer by age 70 (compared with a 1.6 percent chance for noncarriers). In other words, the researchers estimate that by the age of 70, slightly more than half of all women with an alteration will develop breast cancer, and about one out of every six carriers will develop ovarian cancer.

The researchers noted that the cancer risks in this study are likely to be overestimates because people with personal or family histories of breast cancer may have been more likely than others to volunteer for the study. They estimated, for example, that the true breast cancer risk for U.S. Ashkenazi women with an alteration may be 50 percent or lower.

Found breast and ovarian cancer risks well below previous estimates: Before this study, small studies of families with cancer in several generations had estimated that women with an alteration had a 76 percent to 87 percent chance of developing breast cancer; for ovarian cancer, the estimated risk ranged from 11 percent to 84 percent.

Further explored the link between prostate cancer and the alterations: Previous studies had suggested a link between BRCA1 and prostate cancer. This study found an association with and showed a significant excess of prostate cancer among men with the alterations. Based on these findings, the researchers estimated that men carrying one of the three alterations have, on average, a 16 percent chance of getting prostate cancer (compared with a 3.8 percent chance for noncarriers) by the age of 70. In other words, by age 70 the researchers estimate that about one out of every six men carrying an alteration will develop prostate cancer. However, the results of subsequent studies have been conflicting. Some studies have shown an association between BRCA1 or BRCA2 alterations and prostate cancer, while others have not.

Found the average risks for breast, ovarian, and prostate cancers: The study estimated the average risk of cancer for alteration carriers as a group. The cancer risk for an individual man or woman who carries one of the alterations may be higher or lower than the average.

Found no link with colon cancer: A previous report showed a link between BRCA1 alterations and colon cancer that was not confirmed in this study.

Found that each alteration carries a similar breast cancer risk: Previous reports suggested that the risk of getting breast cancer was different for two of the alterations studied. Specifically, in studies involving Jewish early-onset breast cancer patients, data suggested that the risk associated with the 6174delT mutation (in BRCA2) was considerably lower than the risk associated with 185delAG. In this study, the risk associated with the 6174delT was slightly lower, but the risks for the three alterations were not significantly different from each other.

Found that the three alterations account for only a small proportion of breast cancer cases in Jewish women: Of the women in this study who were breast or ovarian cancer survivors, only 9 percent had one of the alterations. In fact, only about 7 percent of breast cancer in Jewish women is due to the three alterations in BRCA1 and BRCA2.

6. How is inherited breast cancer different from other genetic diseases?

For many genetic diseases, such as Huntington's disease, everyone who inherits an alteration in the gene will develop the disease. This is called "complete penetrance." All cases of Huntington's disease are caused by alterations in the Huntington's disease gene. The situation with breast cancer appears to be quite different.

Breast cancer is a common disease, but only a small fraction of cases are due to the inheritance of an alteration in a single gene. In order to isolate cancer-predisposing genes such as BRCA1 and BRCA2, scientists initially studied families with many members affected by breast and ovarian cancer over several generations. Estimates of the risk of breast cancer within these families were often over 80 percent by age 70, and 90 percent to 100 percent over a lifetime. These estimates are similar to other genetic diseases like Huntington's disease, with nearly complete penetrance, but whether they applied to all carriers of BRCA1 and BRCA2 alterations was unknown.

Evidence from this study suggests that they do not apply to all carriers, and that, on average, the risk of breast cancer among carriers is closer to 50 percent. This is called "incomplete penetrance" and suggests that about half of the carriers will not develop breast cancer even if they live to age 70. Other factors, both genetic and nongenetic, are likely to affect whether someone with an alteration will develop cancer or not.

7. What are the chances that someone with one of these alterations in BRCA1 or BRCA2 will get breast, ovarian, or prostate cancer?

On average, by the age of 70, women with one of the alterations tested for in this study have between a 40 percent and 73 percent chance of being diagnosed with breast cancer and between an 8 percent and 28 percent chance of developing ovarian cancer. Men with an alteration have about a 16 percent chance of developing prostate cancer by the age of 70. However, for any individual with an alteration, a precise estimate of risk is not possible.

Family history helps to place an individual's cancer risk in perspective, but is also an imperfect tool. For example, family history will be most useful in determining risk if a carrier has multiple relatives affected with breast or ovarian cancer. In this case, a woman's risk of breast cancer may be higher than theer has little or no family history of breast and ovarian cancer, his or her risk will be much more difficult to assess. This is particularly true of women in small families with very few close female relatives.

Unless someone already has a strong family history of breast or ovarian cancer, it will be very difficult to know his or her precise risk until other risk factors for cancer are identified.

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