Combining Risk of Common Genetic Variants May Lead to Better Breast Cancer Risk Assessment

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Most inherited cases of breast cancer are associated with two abnormal genes: BRCA1 (BReast CAncer gene one) and BRCA2 (BReast CAncer gene two). Women with an abnormal BRCA1 or BRCA2 gene have up to an 85% risk of developing breast cancer by age 70. Their risk of ovarian cancer also is higher than average.

Researchers know that other genetic variants, called single nucleotide polymorphisms (SNPs), also are linked to breast cancer. Still, each SNP contributes only a tiny amount to a person’s overall risk of developing breast cancer.

SNPs are the most common type of genetic variant. Each SNP is a difference in a single building block of DNA (called a nucleotide). SNPs happen normally in our DNA – scientists estimate that a SNP happens once in every 300 nucleotides, which means there are about 10 million SNPs in the human genome. Most SNPs have no effect on health or development, but some, like the ones associated with breast cancer, may have health implications.

A study combined the risk of 77 SNPs associated with breast cancer into a single risk factor, called a polygenic score, to better estimate breast cancer risk.

The research was published in the April 2, 2015 issue of the Journal of the National Cancer Institute. Read the abstract of “The Contributions of Breast Density and Common Genetic Variation to Breast Cancer Risk.”

In the study, the researchers essentially added up information on 77 SNPs from 33,673 women diagnosed with breast cancer and 33,381 women who hadn’t been diagnosed.

They found that the polygenic risk score could put women into risk categories. Compared to women with an average polygenic risk score:

  • women with the highest 1% of scores were 3 times more likely to develop breast cancer
  • women with the lowest 1% of scores had a 70% lower risk of developing breast cancer

The researcher said the results suggest that the polygenic risk score is as important as other known risk factors, such as breast density or family history, in estimating risk.

In the second part of the study, the researchers looked to see if there were any overlap in risk accounting between the polygenic risk score and breast density scores. The researchers wanted to make sure that each risk factor was independent because if the polygenic risk score were repeating what was accounted for by another known risk factor, then it wouldn’t be worthwhile to add the polygenic score to a risk estimation model. The researchers confirmed that the two risk factors were independent.

The researchers then incorporated the polygenic risk score into the Breast Cancer Surveillance Consortium (BCSC) risk-prediction model, which uses breast density, family history of breast cancer, history of breast biopsy, age, and ethnicity to calculate breast cancer risk.

They compared the 5-year risk estimates calculated using the BCSC model with and without the polygenic risk score information. Adding the polygenic risk score made the model more accurate:

  • 11% of women who eventually were diagnosed with breast cancer were put into a higher risk category where they likely would have benefited from more aggressive screening with MRI or risk-reducing measures such as taking hormonal therapy preventively or even prophylactic mastectomy

"This genetic risk factor adds valuable information to what we already know can affect a woman's risk of developing breast cancer," said study co-author Celine Vachon, Ph.D., an epidemiologist at Mayo Clinic. "We are currently developing a test based on these results, and though it isn't ready for clinical use yet, I think that within the next few years we will be using this approach for better personalized screening and prevention strategies for our patients."

If you know that you have a higher-than-average risk of breast cancer, there are steps you can take to keep that risk as low as possible, as well as ways to detect any cancer that develops earlier, when it’s most treatable, including:

  • more aggressive screening plan, starting at an earlier age
  • hormonal therapy to block the effect of estrogen on breast tissue or reduce the amount of estrogen in the body
  • removing the healthy breasts (prophylactic mastectomy)

Having a more precise way to determine breast cancer risk, such as testing for the 77 SNPs identified in this study, could help women and their doctors make more informed decisions about risk reduction options.

Stay tuned to Research News to learn about the latest results that can lead to better ways to prevent, diagnose, and treat breast cancer.

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