BRCA Mutation Risk May Not Be as High as Thought

BETHESDA, Md--Women of Ashkenazi Jewish lineage appear to have a lowerrisk of breast and ovarian cancer from mutations in the BRCA1 and BRCA2genes than was first thought, a study from the National Institutes of Healthhas found.

Earlier studies suggested that women with a mutation in either genehad a 76% to 87% chance of developing breast cancer and an 11% to 84% likelihoodof developing ovarian cancer by age 70, compared with just an 8% risk ofbreast cancer and 2% risk of ovarian cancer for women as a whole. The newstudy suggests the risk for Ashkenazi carriers is 56% and 16%, respectively.

The mutation carrier rate among Ashkenazim is more than 2%--the highestknown in any ethnic group. Of the six million Jews in the US, about 90%trace their ancestry to eastern or central Europe, indicating Ashkenazidescent.

Jeffrey P. Struewing, MD, and his NIH colleagues saw the high Ashkenaziprevalence as an opportunity to begin to answer an important question:What percentage of the enhanced susceptibility to breast and ovarian cancerin those who carry mutations of BRCA1 or BRCA2 is actually due to the geneticalteration?

Speaking at a press briefing held to coincide with publication of thedata (New England Journal of Medicine 336:1401-1408, 1997), Dr. Struewing,senior investigator at the National Cancer Institute, said that the womenin the previous studies of these gene mutations--Jewish or not--had extensivefamily histories of breast cancer, ovarian cancer, or both, and many had,themselves, had these tumors.

Unknown, therefore, was whether their elevated risk was entirely explainedby BRCA mutations or whether some of it was due to other genes they andtheir afflicted relatives had in common or to environmental influences--dietarypatterns, for instance--they had shared.

Rationale for Studying Ashkenazim

The challenge, in other words, was to assess the degree of risk conferredby a BRCA mutation when women had little or no family history of thesecancers. In theory, that could have been done with studies of any populationthat might have the mutations in its midst. In reality, Dr. Struewing doubtsthat would have been useful.

"For one thing," he explained," more than 140 differentBRCA mutations have been identified to date because both genes are verylarge. Also, it was learned from the original studies--which were donewithout regard to ethnicity--that very rarely is a BRCA mutation in onecancer-prone family the same as in another such family."

By contrast, three specific mutations seem to be unique to AshkenaziJews: 185delAG and 5382insC in BRCA1, and 6174delT in BRCA2. It thus madesense to focus on this trio of mutations in this particular ethnic group.

A further rationale for this strategy was the suggestion from earlierdata that the mutations--besides predisposing women to breast and ovariancancer-- predispose men to prostate cancer and both sexes to colon cancer.By including Jews of both genders in their study, the researchers wouldbe able to get more information about those issues as well.

5,000 Volunteers

The researchers appealed to the Jewish community in and around Washington,DC, for 5,000 people who would fill out a questionnaire about their personaland family cancer histories and have blood drawn for BRCA analysis.

So enthusiastic was the response that it took only nine weeks to recruit5,318 volunteers. Nearly 30% were men, and 75% had no personal or familyhistory of breast cancer.

The testing showed that 120 of the volunteers (2.3%) were positive forone of the three BRCA mutations (none were positive for more than one mutation).The family histories of these volunteers were than compared with thoseof the noncarrier volunteers.

As family history is the single strongest predictor for many cancers--includingbreast cancer--this made it possible to compare the average risk, by age70, for carriers of the mutations and non-mutation carriers.

For breast cancer, that risk proved to be 56%; for ovarian cancer, 16%.Moreover, Lawrence C. Brody, PhD--a co-author of the study--cautions that"even those estimates may be inflated because there was a larger percentageof volunteers in the study with a family history of breast cancer thanthere is in the Jewish population overall."

Dr. Brody is senior investigator at the National Human Genome ResearchInstitute in its Laboratory of Gene Transfer.

By the researchers' calculations, in fact, BRCA mutations could accountfor only about 7% of all breast cancers in Jewish women. Still, as anotherof the study's co-authors, Margaret A. Tucker, MD, notes, "an individualcarrier's risk may be smaller or larger than the average risk of 56%."Dr. Tucker heads the NCI's Genetic Epidemiology Branch.

Risk for Other Cancers

For colon cancer, the study found that the estimated average risk wasnot significantly different between noncarriers and carriers of the mutation.Thus, it would seem that none of the three BRCA mutations examined is implicatedin that malignancy in either sex.

On the other hand, the study provided convincing evidence that the suspectedlink between BRCA mutations and an increased risk of prostate cancer isreal. For a man with any of the three mutations, the risk by age 70 was16%, the same as for ovarian cancer in female mutation carriers.

The study also found that none of the three Ashkenazi-specific mutationsstudied was associated with a significantly higher risk of cancer thanthe others.

There are as yet no data on the average risk for non-Jewish carriersof such mutations. Still, the researchers' educated guess is that justas Jewish carriers with little or no family history of breast, ovarian,and prostate cancer have a lower risk than those from cancer-ridden families,so will their counterparts in other population groups.

Follow-up Study Planned

Dr. Struewing and his colleagues are planning a follow-up study in thegreater Washington, DC, Jewish community. Its volunteers, like their predecessors,will be tested for BRCA mutations. Unlike them, however, volunteers inthe new study will be told the results of their tests if they so choose.For that reason, all participants will get genetic counseling before beingtested.

The new study will search for factors that modify a carrier's risk ofdeveloping cancer. Among the factors being considered for inclusion inthe search are hormonal influences and interactions between BRCA mutationsand mutations in other genes.