Why Are Women With BRCA1 and BRCA2 Mutations Being Diagnosed at Younger Age?

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Most inherited cases of breast cancer are associated with one of two abnormal genes: BRCA1 (BReast CAncer gene one) or BRCA2 (BReast CAncer gene two).

Everyone has BRCA1 and BRCA2 genes. The function of the BRCA genes is to repair cell damage and keep breast cells growing normally. But when these genes contain abnormalities or mutations that are passed from generation to generation, the genes don't function normally and breast cancer risk increases. Abnormal BRCA1 and BRCA2 genes may account for up to 10% of all breast cancers, or 1 out of every 10 cases.

Women with an abnormal BRCA1 or BRCA2 gene:

  • have between about a 40% and 85% lifetime risk of developing breast cancer
  • have a much higher-than-average lifetime risk of ovarian cancer; estimates range from 15% to 60%

Breast cancers associated with an abnormal BRCA1 or BRCA2 gene tend to develop in younger women and occur more often in both breasts than cancers in women without these gene mutations.

Some evidence suggests that hereditary breast and ovarian cancer is being diagnosed at a younger age in each successive generation of women with a BRCA1 or BRCA2 mutation. Researchers wanted to know if this younger and younger age at diagnosis was due to what’s called “genetic anticipation,” where a disease linked to a genetic mutation is passed on to the next generation and the symptoms appear at a younger age with each successive generation because of a change in the mutation. Or was this happening because of other reasons, including sampling bias when the information was collected or lifestyle/environmental factors?

A study suggests that environmental and lifestyle factors are causing women with a BRCA1 or BRCA2 mutation to be diagnosed with breast and/or ovarian cancer at younger ages.

The research was published online on March 15, 2016 in the journal Cancer. Read the abstract of “Genetic anticipation in BRCA1/BRCA2 families after controlling for ascertainment bias and cohort effect.”

To do the study, the researchers looked at 176 families from the Cancer Risk Clinic at the University of Chicago that had a known BRCA1 or BRCA2 mutation and had at least two family members diagnosed with the same cancer (breast or ovarian) in consecutive generations. The first person in the family found to have a BRCA1 or BRCA2 mutation (called a “proband” by researchers) did not have to be diagnosed with cancer.

Overall, 113 families had a BRCA1 mutation and 63 families had a BRCA2 mutation.

If at least two members of a family had been diagnosed with breast cancer in consecutive generations, the researchers classified the family as a breast cancer family. If at least two members of a family had been diagnosed with ovarian cancer in consecutive generations, the researchers classified the family as an ovarian cancer family.

The results showed that 155 families were considered breast cancer families, 38 families were considered ovarian cancer families, and 15 families were considered both breast and ovarian cancer families.

Of the 155 breast cancer families:

  • 94 families had a BRCA1 mutation
  • 61 families had a BRCA2 mutation
  • 579 family members had been diagnosed with breast cancer; of these, 469.1 were predicted to have a BRCA1 or BRCA2 mutation
  • 59 family members had been diagnosed with ovarian cancer; of these, 56.5 were predicted to have a BRCA1 or BRCA2 mutation
  • 96 probands were diagnosed with breast cancer
  • 10 probands were diagnosed with ovarian cancer
  • 7 probands were diagnosed with breast and ovarian cancer

Of the 36 ovarian cancer families

  • 29 families had a BRCA1 mutation
  • 7 families had a BRCA2 mutation
  • 74 family members had been diagnosed with breast cancer; of these, 60.5 were predicted to have a BRCA1 or BRCA2 mutation
  • 81 family members had been diagnosed with ovarian cancer; of these, 77.7 were predicted to have a BRCA1 or BRCA2 mutation
  • 12 probands were diagnosed with breast cancer
  • 8 probands were diagnosed with ovarian cancer
  • 3 probands were diagnosed with breast and ovarian cancer

The researchers used statistical models to analyze ages of cancer diagnosis in generations, as well as the probability that someone who hadn’t been tested would have a BRCA1 or BRCA2 mutation. Their initial calculations suggested that a younger age at diagnosis was due to genetic changes in the mutation -- genetic anticipation. Still, when the researchers corrected their calculations for selection bias, they found that a younger age at cancer diagnosis over time was likely because of environmental factors. In other words, daughters were diagnosed at younger ages than their mothers because their group was exposed to similar environmental/lifestyle factors. Researchers call this the “cohort effect.”

If you think about it, the results of this study make sense. At first, it seems possible that a BRCA1 or BRCA2 mutation could alter itself in each successive generation, causing disease earlier and earlier. But we know that some BRCA mutations probably first happened more than 1,000 years (50 generations) ago. If the BRCA mutations were changing and causing disease earlier and earlier, girls age 4 to 10 with a BRCA1 or BRCA2 mutation should have been routinely diagnosed with breast cancer after just a few generations. This hasn’t happened.

So it seems more likely that changes to our environment and lifestyle, including:

  • having children later in life or not at all
  • starting to menstruate at a younger age
  • using hormone replacement therapy
  • drinking alcohol
  • smoking cigarettes
  • not exercising
  • being overweight
  • exposure to chemicals in food, plastics, cosmetics, and other products

are a big part of the reason that breast cancer is being diagnosed at younger ages in women with a BRCA1 or BRCA2 mutation rather than changes in the genetic mutation itself.

If you know you have an abnormal breast cancer gene, you may be considering taking steps to keep your risk of breast and ovarian cancer as low as it can be. There are many lifestyle choices you can make, including:

  • maintaining a healthy weight
  • exercising regularly
  • limiting or avoiding alcohol
  • eating nutritious food
  • never smoking

There are also more aggressive steps you can take, including:

  • a 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 and/or ovaries (prophylactic mastectomy and/or prophylactic oophorectomy)

For more information on BRCA1 and BRCA2 genes, as well as all the risk-lowering steps you can take if you have an abnormal version of one or both of these genes, visit the Breast Cancer Risk Factors: Genetics page in the Breastcancer.org Lower Your Risk section.



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