BRCA Mutations Don't Raise Breast Cancer Risk Equally

TUESDAY Jan. 8, 2008 -- Not all carriers of the BRCA1 and BRCA2 genetic mutations show the same risk for developing breast cancer.

In fact, a new study finds wide variation in risk among families carrying the mutations, indicating that the mutations are influenced by other genetic, and possibly environmental, factors.

"Risk among carriers varies considerably, and, if you accept that that's the case, there must be a reason why it varies, and the most plausible explanation is that there are other genetic factors affecting breast cancer risk that are being passed on through these families," said study author Colin Begg, chairman of the department of epidemiology and biostatistics at Memorial Sloan-Kettering Cancer Center in New York City.

And that's where more work needs to be done, said Begg, whose report was published in the Jan. 9/16 issue of the Journal of the American Medical Association.

"They're saying that not all BRCA mutations are created equal," added Dr. Len Lichtenfeld, deputy chief medical officer at the American Cancer Society.

It is known that the BRCA1 and BRCA2 gene mutations raise a woman's risk for developing breast cancer, so the degree of that risk is critical in helping a woman make choices about prevention.

But most previous studies have only looked at overall risk among mutation carriers, not individual risk or risk in specific groups.

"To some extent, people have traditionally perceived the risk as being a fixed thing," Begg said. "People have studied BRCA1 and 2 separately, but, other than that, there's the sense that if you're a carrier, you have a certain risk, and it's a high risk, and that's it."

Experts have hypothesized that there is variation in the risk of breast cancer in general due to other, as yet unknown, genetic factors, but there's scant evidence of such a variation. There has been no research on whether such variation exists among BRCA mutation carriers.

This study provides such evidence.

Begg and his colleagues genotyped more than 2,000 participants in the Women's Environmental Cancer and Radiation Epidemiology (WECARE) Study who had been diagnosed with breast cancer. Of the total, 1,394 women had unilateral breast cancer (one breast only), while 704 had contralateral breast cancer (an additional malignancy in the opposite breast).

This study focused on the 181 women who were shown to be mutation carriers.

First-degree relatives of BRCA1 and 2 carriers had a higher risk of developing breast cancer if their proband (the relative whose breast cancer diagnosis first brought the family history to light) was diagnosed at a younger age (35 or under). The overall study only looked at women who had been diagnosed under the age of 55.

There was also a non-statistically significant trend toward higher risk for first-degree relatives of women with contralateral breast cancer as opposed to unilateral breast cancer.

The results strongly indicate that factors other than the BRCA mutations influence risk.

"If everyone with a mutation has exactly the same risk, then the presence of the mutation is the only factor that influences risk in carriers, [and] there are no other factors that can influence risk," Begg explained. "The fact that we see that age at diagnosis in the proband influences risk in the relatives implies that there is something else about the carrier families with a "young" proband that must influence risk. The presumption is that these families are passing on other genetic characteristics that positively influence breast cancer risk."

Although the authors state there is no need for wide screening of women yet, future technological advances may make such screening feasible.

"Lots of research is being done on the whole genome to identify new risk factors for breast cancer, and there's a certain amount of debate as to whether this is a worthwhile exercise or not. There's only a point to searching if something is to be found there," Begg explained. "This kind of study suggests that there is something to be found, and that it is worthwhile doing these studies not just on mutation carriers but on people with breast cancer on the whole. Our premise is that the additional breast cancer risk factors that will be found will be applicable to carriers just like to anyone else."

"This is a very, very interesting article, and very important. These two genes represent about 7 percent of all breast cancers and usually account for breast cancer in families and in young women," said Dr. Jay Brooks, chairman of hematology/oncology at Ochsner Health System in Baton Rouge, La. "We're understanding more about how patients can accept the risk that has been assigned to them. This is a very important paper going forward."

More information

There's an overview of the genetics of breast cancer at the U.S. National Cancer Institute.

Posted: January 2008


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