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Other Genes Can Modify BRCA Breast Cancer Risk

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Other Modifiers of Breast Cancer Risk in Mutation Carriers

by Sue Friedman

While studies of risk modifiers in BRCA mutation carriers have great potential to improve our understanding of the causes of BRCA-associated cancer and improve risk prediction, this research is still in its infancy. Most studies have been small, making it difficult to draw definitive conclusions. The following factors may affect breast cancer risk in BRCA mutation carriers:

Diet
Although diet is thought to be a factor in breast cancer risk, there is little research linking specific foods to cancer risk or protection in BRCA carriers.

Weight
Studies show that a healthy weight is beneficial for BRCA mutation carriers. A study of BRCA1 mutation carriers from five countries suggests losing as few as 10 pounds between ages 18 and 30 may reduce the risk for breast cancer. A weight change at age 30 to 40 did not influence the risk of breast cancer.

Menarche
The older a woman with a BRCA1 or BRCA2 mutation is at the onset of menstruation, the lower her risk for breast cancer.

Oral Contraceptives
The effect of oral contraceptives on breast cancer risk is still uncertain. Oral contraceptives may increase breast cancer risk in women who begin taking the pill before age 30, and those who continue on contraceptives for three years or more. However, BRCA mutation carriers who take contraceptives for three or more years have a lower risk for ovarian cancer.

Pregnancy
Studies suggest that pregnancy affects BRCA1 and BRCA2 carriers differently. In BRCA2 carriers, more pregnancies are associated with higher breast cancer risk. However, the increased breast cancer risk is statistically significant only after four births. In BRCA1 carriers, more pregnancies are associated with lower risk for breast cancer risk. The decreased risk was statistically significant for breast cancer only after four births.

Over the next few years CIMBA will be looking at some of these factors as they affect risk for members of our community. Stay tuned for research results.

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by Margaret Snow, MD, Lisa Held and Sue Friedman

Since BRCA testing has been available, genetics experts have sought to better understand factors that affect the cancer risk for women who have a mutation. Breast cancer risk assessment has never been an exact science: some studies quote a lifetime risk as low as 40 percent, while others predict the lifetime risk to be as high as 87 percent. Because of these divergent estimates, genetic experts use a “risk range”—often estimated at 40-85 percent—when discussing the risk of developing breast cancer for a woman with a BRCA mutation.

Researchers believe other factors modify breast cancer risk in mutation carriers. Diet, weight, exercise, age at the time of pregnancy, number of pregnancies, use of birth control pills, and exposure to environmental factors may all influence breast cancer risk. But growing evidence suggests that other inherited genetic changes may also influence cancer risk among BRCA mutation carriers.

DNA changes and SNPs

DNA is the building block of genes. Genes tell our bodies what proteins to make. With the exception of identical twins, no two people inherit exactly the same DNA sequence; these DNA differences make each of us unique. Some of these differences are responsible for a person’s unique appearance, such as brown or blue eyes. Other DNA changes lead to disease or increased risk for disease, such as DNA mutations in the BRCA1 or BRCA2 genes that lead to increased cancer risk. About 10 percent of all breast cancers and about 14 percent of all ovarian cancers are caused by mutations in genes such as BRCA. But most women who develop breast and ovarian cancers have no identifiable BRCA mutation. Although environmental factors play a role in these cancers, research suggests that having specific combinations of genes might influence a person’s risk for developing cancer and other diseases.

Single Nucleotide Polymorphisms (SNPs) are particular changes that genetic researchers consider as single “spelling errors” in DNA. Each SNP represents a change of a single building block in our DNA code. SNPs may occur commonly in the general population, can be found in healthy individuals, and represent normal variations in certain genes. However, some SNP gene changes may increase the risk for certain diseases.

In 2007, two large published studies addressed SNP changes associated with breast cancer. When researchers in one of these studies examined the DNA of non-BRCA women—some had breast cancer and some did not—they associated four SNPs that alone or in combination resulted in a slightly higher lifetime risk for breast cancer. In general, a woman’s lifetime risk is about 13 percent; the risk for women who carried these SNPs was about 20 percent. This may explain why some women may be more susceptible to breast cancer because of their genetics, even if they do not have a BRCA mutation. It may also explain why many BRCA-negative families have a lot of breast cancer.

Following up on this research, a group of breast cancer researchers formed the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) to learn more about the factors that affect cancer risk in BRCA carriers. As new information emerged about genes linked to breast cancer risk in the general population, the CIMBA group tested previously obtained blood samples from known BRCA carriers to determine whether these same gene changes affected their breast cancer risk.

The CIMBA Consortium found that two SNPs that increase breast cancer risk in the general population may also provide more information about breast cancer risk in BRCA carriers. BRCA2 carriers with the less common form of genes known as FGFR2 and TNRC9 were more likely to develop breast cancer. BRCA1 carriers who had the less common form of the TNRC9 gene were also more likely to have breast cancer.

Among the women who carried normal copies of these genes, the risk for breast cancer appeared to be at the lower end of the risk range. Of the BRCA-positive women who had two abnormal copies of these SNPs, lifetime risk for breast cancer was estimated to be at the high end of the risk range. Women with one abnormal copy of the SNPs were estimated to have a risk in the intermediate range.

Significance of this research

Although this research is promising, more study is needed to learn how SNP tests can improve risk assessment and clinical care for BRCA carriers. SNPs may help explain why cancer runs in families who have no identifiable mutation. The research may also help BRCA carriers clarify their risk for breast cancer. Ultimately, SNP studies may provide the longawaited breakthrough that helps scientists understand why breast cancer develops. This is one study of many that is trying to identify other genes that effect cancer risk. Similar research is being conducted to identify SNPs associated with ovarian and other cancers.

Dr. Timothy Rebbeck of the University of Pennsylvania is lead investigator of PROSE, a large study on BRCA and risk management. He is also a member of the FORCE Advisory Board, participant in the CIMBA consortium, and one of the authors of the study outlined in this article. Dr. Rebbeck believes the promise of this research is what it may mean for BRCA-positive individuals: testing for these and other as yet unidentified modifier mutations will provide more specific information about their personal risk of developing breast cancer.

References

DF Easton, et al. Genome-wide association study identifies novel breast cancer susceptibility loci. Nature, 2007; 447: 1087-1095.

AC Antoniou, et al on behalf of CIMBA. Common Breast Cancer-Predisposition Alleles are Associated with Breast Cancer Risk in BRCA1 and BRCA2 Mutation Carriers. The American Journal of Human Genetics, 2008; 82: 937–948.

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