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Genes, Early Lifestyle Affect Onset of Breast Cancer
  
By Edward R. Winstead

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One of the most comprehensive studies to assess the risk of breast cancer among women who have mutations in the genes BRCA1 and BRCA2 reports that these women are extremely likely to develop the disease in their lifetimes, regardless of family history.


Women from families with a history of breast cancer are generally thought to be at greater risk for the disease than other women. But this is not the case among women who have BRCA1/2 mutations, according to a new study led by Mary-Claire King of the University of Washington in Seattle.

Women with these mutations have an 82 percent chance of developing breast cancer by age 80, the researchers found. A woman's risk was not affected by whether the disease runs in the family.

A second important finding of the study was that even among women carrying these genetic mutations, the onset of the disease was influenced by factors other than genes.

“This study says that both your genes and other factors together confer the overall risk,” says Sharon E. Plon, a researcher at Baylor College of Medicine in Houston, Texas, and co-author of a commentary accompanying the study in tomorrow's issue of Science.

“The mutations still have a big effect, but these other factors influence the risk,” Plon says.

Two non-genetic, or environmental, risk factors for these women were body weight and physical activity during the adolescent years. Women who exercised regularly and were not overweight as teenagers developed the disease later than women who were not physically active and were obese as teens.

Another significant factor was the year of birth. Women in the study born after 1940 were much more likely to develop breast cancer disease at a younger age than women in the same families born before 1940.

The cancer risk for BRCA1/2 carriers has increased significantly in recent generations, and environmental factors are increasingly being studied as explanations for this shift.

Last week the US National Institutes of Health announced funding for four new centers dedicated to investigating the roles of environmental factors and exposures in breast cancer.

The breast cancer risks for women in the study born after 1940 were significantly higher for those born in the same families before 1940.

In the new study, the researchers focused on 104 women who had breast cancer and carried one of three common BRCA1/2 mutations, and their families.

The researchers also estimated the lifetime risk among these women of ovarian cancer, which is less common than breast cancer but among the most deadly cancers. For women with BRCA1 mutations the lifetime risk was 54 percent; for women with BRCA2 mutations the risk was 23 percent.

The women were part of The New York Breast Cancer Study Group, which includes 1008 Jewish women of Ashkenazi descent. Ashkenazi Jews as a group are at a higher risk for breast cancer than other ethnic groups because of the prevalence of three common BRCA1/2 mutations.

Of the 104 women, half had no family history of breast cancer. In nearly all of these 52 women, the mutations came from the fathers.

Women who inherited the mutations from their fathers are just as likely to develop the disease as those whose mothers passed on the mutations. But mutations inherited from fathers may go undetected until the disease occurs, especially in small families.

“If you get breast cancer it's generally thought that you inherited the gene from your mother, but we've clearly shown that that's not the case,” says Joan A. Marks of the Graduate Program in Human Genetics at Sarah Lawrence College in Bronxville, New York.

The study evolved out of a conversation between Mary-Claire King and Marks when King spoke at Sarah Lawrence College about six years ago. King told Marks that the next phase of her research would require 1,000 Jewish women who had breast cancer, but she was not clear how such a group could be assembled.

“Consider it done,” Marks responded to King. For decades Marks had sent Sarah Lawrence genetic counseling students to train at dozens of medical centers in the New York area. She soon began contacting surgeons who would help recruit 1,000 women who survived breast cancer.

The study is unusual in the large role allotted to genetic counseling. At the 12 medical centers involved in the study, participants met with genetic counselors at every stage of the process to discuss whether to be tested and what the results might mean.

Genetic testing involves much more than getting a test result back, says Jessica Mandell, who coordinated the study's genetic counseling. The post-test counseling allowed women to process their reactions and included a detailed discussion of options for women who tested positive. Often a surgeon was present in those meetings.

“This study certainly underscores how high the risk is in the Ashkenazi Jewish population,” says Marks, who started the nation's first genetic counseling graduate program and is considered the founder of the field. “It says to these young women that they should begin routine medical care on a regular basis through mammography and exams.”

There are now genetic counseling facilities at all major hospitals in large cities so these professionals are easy to reach, she adds.

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King, M.C. et al. Breast and Ovarian Cancer Risks Due to Inherited Mutations in BRCA1 and BRCA2. Science 302, 643-646 (October 24, 2003).

 

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