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Study Estimates Relative Risk of Breast and Ovarian Cancer for 25 Genetic Mutations

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About 5% to 10% of breast cancers are thought to be hereditary, caused by mutated genes passed from parent to child.

Genes are particles in cells, contained in chromosomes, and made of DNA (deoxyribonucleic acid). DNA contains the instructions for building proteins. And proteins control the structure and function of all the cells that make up your body.

Think of your genes as an instruction manual for cell growth and function. Abnormalities in the DNA are like typographical errors. They may provide the wrong set of instructions, leading to faulty cell growth or function. In any one person, if there is an error in a gene, that same mistake will appear in all the cells that contain the same gene. This is like having an instruction manual in which all the copies have the same typographical error. A genetic error that causes harm is called a mutation.

Many inherited cases of breast cancer are associated with two gene mutations: BRCA1 (BReast CAncer gene one) and BRCA2 (BReast CAncer gene two).

The average woman in the United States has about a 1 in 8, or about 12%, risk of developing breast cancer in her lifetime. Women who have a BRCA1 or BRCA2 mutation (or both) can have up to a 72% risk of being diagnosed with breast cancer during their lifetimes. Breast cancers associated with BRCA1 or BRCA2 mutations tend to develop in younger women and occur more often in both breasts than cancers in women without these mutations.

Women with a BRCA1 or BRCA2 mutation also have an increased risk of developing ovarian, colon, and pancreatic cancers, as well as melanoma.

Men who have an abnormal BRCA2 gene have a higher risk of breast cancer than men who don't -- about 8% by the time they're 80 years old. This is about 80 times greater than average.

Men with an abnormal BRCA1 gene have a slightly higher risk of prostate cancer. Men with an abnormal BRCA2 gene are 7 times more likely than men without the abnormal gene to develop prostate cancer. Other cancer risks, such as cancer of the skin or digestive tract, also may be slightly higher in men with abnormal BRCA1 or BRCA2 genes.

We know that other gene mutations also are linked to breast cancer. For many years, genetic tests only looked for BRCA1 or BRCA2 mutations. Today, advances in genetic sequencing allow tests to look at panels of six to more than 100 genes in much less time and at a much lower cost. And while we now know that mutations in genes such as ATM and PALB2 also increase breast cancer risk, it’s been unclear by how much.

A study has taken the first step in helping to estimate the relative risk associated with 25 genetic mutations linked to breast and ovarian cancer.

The research was published online on June 27, 2017 by the journal JCO Precision Medicine. Read “Breast and Ovarian Cancer Penetrance Estimates Derived From Germline Multiple-Gene Sequencing Results in Women.”

"The results of this study will help to personalize our risk estimates and recommendations for preventive care," said Allison Kurian, M.D., associate professor of medicine and of health research and policy at Stanford University and lead author of the study. "A better understanding of cancer risks can help women and their clinicians make better-informed decisions about options to manage cancer risk."

To do the study, the researchers looked at the genetic test results of 95,561 women who chose to have genetic testing:

  • 26,384 women had been diagnosed with breast cancer (28%)
  • 5,020 women had been diagnosed with ovarian cancer (5%)
  • 64,649 had not been diagnosed with either type of cancer (68%)

All the women had the Myriad Genetics 25-gene panel test between September 2013 and September 2016. The test looked for mutations in the following genes:

  • APC
  • ATM
  • BARD1
  • BMPR1A
  • BRCA1
  • BRCA2
  • BRIP1
  • CDH1
  • CDK4
  • CHEK2
  • MLH2
  • MSH2
  • MSH6
  • NBN
  • P14ARF
  • P16
  • PALB2
  • PMS2
  • PTEN
  • RAD51C
  • RAD51D
  • SMAD4
  • STK11
  • TP53

Mutations in these genes have been linked to a higher risk of breast and ovarian cancer.

The researchers matched the women who had been diagnosed with cancer to women that hadn’t been diagnosed based on:

  • age
  • ethnicity
  • family history of cancer

The researchers then compared and analyzed the genetic test results between the matched pairs of women to estimate the risk of cancer associated with each mutation.

The researchers found that eight gene mutations were significantly associated with breast cancer:

  • ATM -- 1.7 times higher risk
  • BARD1 -- 2 times higher risk
  • BRCA1 -- about 6 times higher risk
  • BRCA2 -- 3 times higher risk
  • CHEK2 -- 2 times higher risk
  • PALB2 -- 3 times higher risk
  • PTEN -- about 6 times higher risk
  • TP53 -- 5 times higher risk

The highest increase in risk was associated with a BRCA1 mutation (5.91 times higher risk) and the lowest increase in risk was associated with an ATM mutation (1.74 times higher risk).

The researchers found that 11 gene mutations were significantly associated with ovarian cancer risk:

  • ATM -- 1.7 times higher risk
  • BRCA1 -- 12 times higher risk
  • BRCA2 -- 5 times higher risk
  • BRIP1 -- 2.6 times higher risk
  • MLH1 -- 3 times higher risk
  • MSH6 -- 2 times higher risk
  • MSH2 -- 2 times higher risk
  • NBN -- 2 times higher risk
  • RAD51C -- 5 times higher risk
  • RAD51D -- 5 times higher risk
  • STK11 -- 42 times higher risk

The highest increase in risk was associated with a STK11 mutation (41.9 times higher risk) and the lowest increase in risk was associated with an ATM mutation (1.69 times higher risk).

All these associations between the genetic mutations and higher breast or ovarian cancer risk were statistically significant, which means they were likely due to the genetic mutation and not just because of chance.

The researchers said they believe this study is the largest study of its kind, which gives it an advantage over other, smaller studies that have estimated cancer risk associated with genetic mutations. In many cases, the results of this study support what has been previously reported. Still, there were some surprises.

"One surprising finding was the association of an increased ovarian cancer risk with mutations in a gene called ATM," said Kurian. "Although this risk was relatively small numerically, it was statistically significant, and to our knowledge it had not previously been published. Additional studies will be important to determine the robustness and clinical relevance of this finding, and to expand the evidence base that we use to counsel our patients."

If you have a strong family history of breast or ovarian cancer, yet you and your family members had genetic testing years ago and tested negative for a BRCA1 or BRCA2 mutation, you may want to talk to your doctor about this study and ask if having a newer multigene panel test makes sense for you.

For more information on genetic and breast cancer risk, visit the Genetics page in the Lower Your Risk section.

Editor’s Note: This article was updated on Dec. 20, 2018, with updated information on cancer risks associated with BRCA mutations.

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