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Senior Citizen Health & Medicine

Major Study Paints Most Complete Picture of Breast Cancer Gene Mutations

Finds older women can be mutation carriers; Jewish ancestry is predictor for BRCA1

August 15, 2006 - A large study funded by the National Institutes of Health today provided the clearest picture yet of the prevalence in the U.S. population of mutations in two genes associated with an increased risk of breast cancer. The genes are called Breast Cancer 1 (BRCA1) and Breast Cancer 2 (BRCA2) and are suspected of playing a role in up to 27 percent of breast cancers. This study identified key predictors for assessing which women are most likely to carry these genetic mutations and provides the first direct evidence that women diagnosed with breast cancer later in life also can be mutation carriers.

Each year, approximately 200,000 women in the United States are diagnosed with breast cancer. The majority of breast cancer cases are caused by genetic changes that occur during a woman's lifetime and not by genetic mutations inherited from her parents.

However, researchers estimate that inherited mutations play a role in anywhere from 5 to 27 percent of all breast cancer cases. In the mid 1990s, researchers found that mutations in the BRCA1 and BRCA2 genes are a major cause of the hereditary form of the disease.

Women inheriting these mutations have a 40 to 85 percent lifetime risk of developing breast cancer, as well as an increased risk of ovarian cancer.

Most research on BRCA1 and BRCA2 mutations, in relation to breast and ovarian cancer, has focused on rare, high-risk families and younger women. Until now, the impact of these genetic mutations among women in the population at large – particularly among African-Americans and those age 45 and older – has been understudied and, as a result, poorly understood, according to lead investigators Kathleen E. Malone, Ph.D. and  Elaine A. Ostrander, Ph.D.

The new study, published today in the journal Cancer Research, looked at the prevalence and predictors of BRCA1 and BRCA2 mutations in under-studied groups of women, such as African Americans, older women and even women of Jewish ancestry.

"Studies of any notable size have focused almost exclusively on white women and young women. This research clearly was needed to improve our means of assessing the likelihood of carrying BRCA1 and BRCA2 mutations in a wider spectrum of women," said Ostrander, Ph.D., chief of the Cancer Genetics Branch in the National Human Genome Research Institute's Division of Intramural Research.

Dr. Ostrander was previously head of the genetics program at the Fred Hutchinson Cancer Research Center, which is the institution that led the study.

"Clarifying the prevalence and predictors of these mutations in a wider spectrum of the general population, including understudied groups like African-Americans and older women, is important and long overdue," said epidemiologist Malone, a member of the Hutchinson Center's Public Health Sciences Division.

While this population-based study confirmed what previously has been observed in high-risk families -- that BRCA mutations are indeed most common in younger women with breast cancer – the research also provided the first direct evidence that women diagnosed with breast cancer later in life also can be mutation carriers, although the probability decreases with age. The prevalence of BRCA mutations fell to about 2 percent among breast-cancer cases diagnosed at ages 60 to 64.

According to the National Cancer Institute, more than 192,000 U.S. women are diagnosed with breast cancer every year. Among women who carry a mutation in BRCA1 or BRCA2, an estimated 36 percent to 85 percent (360 to 850 women out of 1,000) will get breast cancer. In addition, women with breast cancer who carry a mutation also face an increased risk for developing a second breast cancer or ovarian cancer.

In this study, the researchers examined the prevalence and predictors of BRCA1 and BRCA2 mutations in 1,628 women with breast cancer and 674 similar women without breast cancer, all of whom were participants in the National Institute of Child Health and Human Development's (NICHD's) Women's Contraceptive And Reproductive Experiences (CARE) study.

The women involved in the study were white and African American women, ages 35 to 64, who lived in the Atlanta, Detroit, Los Angeles, Philadelphia and Seattle metropolitan areas.

"The advantages of this study include its large sample size, inclusion of under-studied groups of women and the fact that the results are population based," said one of the study's co-authors, Robert Spirtas, Dr.P.H, former chief of NICHD's Contraception and Reproductive Health Branch and now retired.

  ● Researchers found that 2.4 percent of the breast cancer patients had BRCA1 mutations and 2.3 percent had BRCA2 mutations.

  ● BRCA1 mutations were more common among white breast cancer patients (2.9 percent) than among African American patients (1.4 percent).

  ● Breast cancer patients of Jewish ancestry were also significantly more likely to have BRCA1 mutations than non-Jewish patients – 10.2 percent compared to 2.0 percent.

  ● For BRCA2, African American patients were slightly more likely to have mutations, 2.6 percent, than were white patients, 2.1 percent.

Based on their findings, the researchers went on to calculate the prevalence of BRCA1 and BRCA2 mutations in the general U.S. population.

  ● Among white and African American women ages 35 to 64, the prevalence of BRCA1 mutations is 0.06 percent and the prevalence of BRCA2 mutations is 0.4 percent, the researchers estimated.

"These findings from our large, population-based study are compatible with earlier estimates made by extrapolating from smaller studies. However, we found a slightly lower frequency of BRCA1 mutations and a higher frequency of BRCA2 mutations," said Malone..

"We think the difference lies in the fact that earlier studies were confined mainly to whites, and that African American women carry BRCA2 mutations more often than white women."

The researchers also identified key predictors of whether a woman with breast cancer is likely to carry a BRCA1 or BRCA2 mutation. Such information is important because it can help to improve means of assessing which women may benefit the most from genetic testing, increased breast cancer screening and other measures aimed at early detection, treatment or prevention.

The most significant predictors for BRCA1 mutations were:

  ● Jewish ancestry,
  ● a family history of ovarian cancer and
  ● a family history of breast cancer occurring before age 45.

For BRCA2 mutations, researchers uncovered fewer predictors, and they had more modest effects. Among the breast cancer patients studied, the only significant predictors of a BRCA2 mutation were early age of onset (before age 45) in the patient herself or early onset of breast cancer in mother, sisters, grandmothers or aunts.

"These findings underscore why women need to learn as much as they can about their family health history and then share that information with their health-care professionals. However, it must be emphasized that the presence or absence of a predictive factor does not automatically equate with a high or low likelihood of carrying a breast cancer gene mutation," said NIH Director Elias A. Zerhouni, M.D.

"The majority of women with breast cancer – even those with a family history of the disease – do not carry mutations in these genes. These predictors need to be considered in the context of each woman's complete family health history."

Notes on study:

The research team included investigators from the University of Southern California in Los Angeles; Wayne State University in Detroit; the University of Pennsylvania in Philadelphia; Bay State Medical Center in Springfield, Mass.; the National Cancer Institute (NCI); the National Institute of Child Health and Human Development (NICHD); and the Centers for Disease Control and Prevention.

The NICHD and NCI funded the research.

They study was conducted at the Fred Hutchinson Cancer Research Center, which says its interdisciplinary teams of world-renowned scientists and humanitarians work together to prevent, diagnose and treat cancer, HIV/AIDS and other diseases. Our researchers, including three Nobel laureates, bring a relentless pursuit and passion for health, knowledge and hope to their work and to the world. For more information, visit fhcrc.org.

About NIH
The National Cancer Institute, the National Institute of Child Health and Human Development, and the National Human Genome Research Institute are among the 27 institutes and centers that make up the National Institutes of Health (NIH) - The Nation's Medical Research Agency. NIH is a component of the U. S. Department of Health and Human Services (HHS). It is the primary federal agency for conducting and supporting basic, clinical, and translational medical research, and it investigates the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit http://www.nih.gov.

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