BRCA Gene Mutations | Familial (Hereditary) Breast Cancer

BRCA gene mutations and familial breast cancer

BRCA gene mutations and breast cancer

Information about BRCA

Having a mutation in the BRCA1 or BRCA2 genes can increase a woman’s risk of developing breast cancer, by the age of 70, to between 65 and 85 per cent for BRCA1 mutations and between 40 and 85 per cent for BRCA2. This compares to the 12.5 per cent lifetime risk for the average woman in the UK.

Around 1 in 20 (5 per cent) of people diagnosed with breast cancer may have an inherited BRCA mutation, accounting for around 2,500 of the 50,000 cases diagnosed every year in the UK.

Having a BRCA mutation also increases the risk of developing ovarian cancer and a number of other cancers, which can develop earlier in life (‘early-onset’) such as pancreatic cancer, prostate cancer, sarcoma and adrenal carcinoma.

In the UK genetic testing can be carried out on the NHS if someone has a strong family history of breast cancer (and other related cancers).

Surveillance options for women with inherited BRCA mutations include annual MRI screening from 20 years of age, changing to mammography screening from age 40 or 50. Prevention options include an operation to remove both breasts (bilateral mastectomy) and/or ovaries (bilateral oophorectomy), or taking the chemopreventive drugs tamoxifen or raloxifene. (Read more about chemoprevention here).

Breast Cancer Campaign has invested over £9.6 million into research aiming to gain a greater understanding of the genetics of breast cancer, including the role of the BRCA1 and 2 genes.

A diagnosis of carrying BRCA can be a worrying and confusing time. We hope the below questions and answers are useful for anyone effected. You may also be interested in reading Charlotte's Blog, which details one woman's BRCA journey through diagnosis to her decision to have a risk-reducing double mastectomy. Read Charlotte's informative and moving account here.

BRCA Questions & Answers

Thanks to our Facebook community, we established which questions regarding BRCA you needed answers to. This is a work in progress and we will continue adding information in the future.

What is a BRCA mutation?

A BRCA mutation is a genetic alteration in either of the BRCA1 or BRCA2 genes. The genes called BReast CAncer (BRCA) 1 and 2 were discovered in the mid 1990s1,2,  through studies into families with a strong history of breast and ovarian cancer.

The BRCA genes are found in everyone and play an important role in repairing damage to the DNA in our cells. When a mutation occurs in BRCA1 or BRCA2 they can no longer repair DNA and so damage can accumulate, and this damage can lead to a cell becoming cancerous.

Around 1 in 20 (5 per cent) of people diagnosed with breast cancer may have an inherited BRCA mutation accounting for around 2,500 of the 50,000 cases diagnosed every year in the UK.

[1] Miki et al. (1994) A strong candidate for the breast and ovarian cancer susceptibility gene BRCA1. Science.

[2] Wooster et al. (1996) Identification of the breast cancer susceptibility gene BRCA2. Nature. 

What is your breast and ovarian cancer risk if you have a BRCA mutation?

Estimates of lifetime risk (by age 70) for female BRCA1 carriers have ranged from 65 to 85% for breast cancer and 40 to 50% for ovarian cancer3. For BRCA2 they have ranged from 40 to 85% for breast cancer and 10 to 25% for ovarian cancer. 

For men with a BRCA mutation there is some increase in breast cancer risk and the average risks by age 70 are:

BRCA1 mutation carriers: around 1%4
BRCA 2 mutation carriers: around 7%5  (this is still lower that the average risk for a woman with no BRCA mutation: 1 in 8 or 12.5%)

In the general UK population around one in 1,000 (0.1%) has inherited a BRCA1 mutation and a similar proportion has inherited a BRCA2 mutation6.  Therefore around one in 500 people (0.2%) will carry a BRCA mutation of some kind.

There is a 1 in 2 chance that the siblings or children of someone with a BRCA mutation will have inherited the same mutation. This is because a child will inherit either their mother or father’s copy of each BRCA gene, and this is down to chance.

More information on BRCA gene mutations and ovarian cancer is available from:
www.eveappeal.org.uk
www.ovacome.org.uk
www.ovarian.org.uk
www.targetovariancancer.org.uk

[3] http://www.nice.org.uk/nicemedia/live/13269/62338/62338.pdf

[4] http://www.nice.org.uk/nicemedia/live/13269/62338/62338.pdf

Another meta analysis with different ranges: Tai et al. (2007) Breast Cancer Risk Among Male BRCA1 and BRCA2 Mutation Carriers. J Natl Cancer Inst

[5] Evans et al. (2010) Risk of breast cancer in male BRCA2 carriers. J Med Genet

[6] Antoniou et al. (2002) A comprehensive model for familial breast cancer incorporating BRCA1, BRCA2 and other genes. Br J Cancer
And: http://www.royalmarsden.nhs.uk/SiteCollectionDocuments/gp-education/20110722/naz-rahman.pdf

Why have I seen different percentages reported for breast cancer risk? Is there a range in the risk if you have a BRCA mutation?

Different studies have reported different ranges and averages for breast and ovarian cancer risks caused by a BRCA mutation because they have all looked at different populations of women and some have used different methods of analysis.

There are many different types of BRCA mutation and each mutation can have a different affect on breast cancer risk. Also, information about a woman’s family history will be used in adition to gene analysis to calculate her individual risk, resulting in further variation. The frequency of each type of mutation will be different in every group studied, and this influences the overall risk calculation for that group and leads to different figures being reported.

The average ranges we have used above are from the NICE Clinical Guidelines for Familial Breast Cancer4.

Is it true there is a higher risks of BRCA mutations in people of Ashkenazi jewish descent?

In people of Ashkenazi jewish descent there are three known BRCA mutations that are more common than in the general population7. The frequency of these three mutations in the Askenazi jewish population is around 2%8, which is higher than the average frequency of BRCA mutations in the general UK population of 0.2%.

Because there are three known mutations in this population, people of Ashkenazi Jewish descent who have a family history of breast and ovarian cancer can be offered genetic testing that looks specifically for these mutations.

[7] Roa et al (1996) Ashkenazi Jewish population frequencies for common mutations in BRCA1 and BRCA2. Nature Genetics

[8] Struewing et al (1997) The Risk of Cancer Associated with Specific Mutations of BRCA1 and BRCA2 among Ashkenazi Jews. NEJM

Does having a BRCA mutations make a person more at risk of other cancers as well as breast cancer?

Having a BRCA mutation also increases the risk of developing ovarian cancer and a number of other cancers, which can develop earlier in life (‘early-onset’) such as pancreatic cancer, prostate cancer, sarcoma and adrenal carcinoma.

Any complex history of cancers other than breast or ovarian cancer, particularly at a young age, will be taken into consideration by health professionals in estimating breast cancer risk, and the likelihood that a person carries a BRCA mutation.

How do you find out whether you have a BRCA mutation?

In the UK, genetic testing can be carried out on the NHS if someone has a strong family history of breast cancer (and other related cancers), whether or not they have had breast cancer themselves. A GP will refer someone to genetic specialists if they have a strong family history of breast cancer and/or ovarian and related cancers.

Sadly breast cancer is so common that many people will have a history of the disease in their family without having a genetic fault. Because BRCA faults, and other genetic mutations linked to breast cancer, are very rare, and NHS resources are limited, only people who have a more extensive family history of breast and/or ovarian cancer are tested on the NHS.
After someone is referred by their GP, the genetic specialist will calculate the person’s likelihood of having a genetic mutation using information about their family history. Based on the outcome of this calculation the individual could be offered genetic counselling, to understand their risk levels, and then genetic testing.

What is the criteria for genetic testing on the NHS?

It’s important to note that the following are only a guide for the criteria that NHS healthcare professionals will use to determine whether a person should receive a genetic test – everyone’s situation is different and unique, and so it is the individual’s particular circumstances that are taken into account when making a decision.

However, the criteria below demonstrate the kinds of situations which might indicate someone has a strong family history of breast cancer and may be carrying a mutation in one of the BRCA genes or another genetic mutation linked to breast cancer. First-degree relatives include a mother, father, daughter, son, sister or brother. Second-degree relatives include a grandparent, grandchild, aunt, uncle, niece and nephew; half sister and half brother.

Female breast cancers only

  • One 1st degree relative and one 2nd degree relative diagnosed before average age 50.
  • Two 1st degree relatives diagnosed before average age 50.
  • Three or more 1st or 2nd degree relatives diagnosed at any age.

Male breast cancer

  • One 1st degree male relative diagnosed at any age.

Bilateral breast cancer

  • One 1st degree relative where 1st primary diagnosed before age 50. For bilateral breast cancer, each breast has the same count value as one relative.

Breast and ovarian cancer

  • One 1st or 2nd degree relative with ovarian cancer at any age and one 1st or 2nd degree relative with breast cancer at any age (one should be a 1st degree relative).

Genetic testing for BRCA mutations, and other genetic faults, is also available privately and private sector companies may use different criteria to assess whether genetic testing is appropriate, and offer different levels of counselling to individuals about their genetic risk.
 

Do I need a living relative with breast cancer in order to be tested for a BRCA mutation?

No, under updated guidelines from June 2013  from the National Institute for Health and Care Excellence ( NICE) people with a strong family history of breast cancer  will not always need a living relative with breast cancer available for testing to have genetic testing themselves on the NHS.

For people who have not had breast cancer, predictive tests for a known genetic mutation can be more sensitive than searching the whole gene for any type of mutation. This is because the genes are very long and contain complicated genetic material. So in some cases it is still preferable to carry out a diagnostic test on a relative who has had breast cancer first.

What types of genetic testing are available?

There are two types of genetic testing:

1. Diagnostic testing
This involves searching the DNA of a relative who has – or has had – breast cancer to see if there is a fault in one of their breast cancer genes.

If a relative who has or had breast cancer is not available for testing this type of test could be offered to people at high risk of having a genetic mutation.

If the result is positive this means that the genetic basis of breast cancer in the family is better understood and predictive testing can be done to see if other family members have that mutation.

2. Testing family members for a known mutation (predictive testing) 
If a gene fault is found in one person in a family, other family memebers can decide to have a predictive test, and will have genetic counselling first to help them understand their risks and the possible outcomes of genetic testing.

What are the outcomes of genetic testing?

The results of predictive genetic testing can either be positive, inconclusive or negative for a known genetic mutation.

A positive result means that a known genetic fault has been found that is linked to an increased risk of breast cancer. Other relatives can be tested for this fault and siblings or children of the tested person have a one in two chance of having inherited the fault.

An inconclusive result means that a known genetic mutation that increases risk has not been found.  There may still be an inherited mutation that is currently not known to geneticists, however other family members will not be able to be tested for a specific mutation.

If test results are inconclusive an individual’s estimated risk will not change and they will most probably have the same surveillance and risk-reduction options available.

A negative result means that an individual does not have the genetic fault linked to breast cancer that has been found in their family. This person can not pass the fault on to their children and will have the same risk of developing breast cancer as the general population.

Research into the genetics of breast cancer aims to get a better understanding of inherited mutations that increase breast cancer risk, meaning more people can get a more accurate picture of their risk of the developing the disease and whether this risk has been, or could be, inherited.

What surveillance and prevention options are available for women with a BRCA mutation or high chance of having a BRCA mutation? 

A summary of surveillance options can be found online in the NICE guidelines

Risk-reducing surgery

Risk-reducing mastectomy of both breasts (bilateral mastectomy) and oophorectomy is available on the NHS for women from ‘high-risk’ familes who either have a BRCA mutation or have a 20% or greater chance of a faulty BRCA1 or 2 gene in the family. Please refer to the Criteria for Genetic Testing information to see some of the guidelines used to help healthcare professionals decide whether an individual comes from a ‘high-risk’ family.

Mastectomy is thought to reduce breast cancer risk in BRCA carriers by 90%10 (to below the average risk for women without a mutation in the UK). Breast cancer can still occur in the chest wall so mastectomy cannot reduce risk by 100%. 

Women considering a bilateral mastectomy will have discussions about their individual risk factors, timing of surgery and conversations about breast reconstruction options with members of their healthcare team, as well as being offered counselling and access to supports groups and/or other women who have undergone the procedure.

Risk-reducing oophorectomy (removal of the ovaries) is thought to reduce breast cancer risk by around 25% for BRCA mutation carriers and ovarian cancer risk by around 85%11.

Women considering whether to have an oophorectomy procedure women will have similar discussions about risk and the timing of surgery, and will have counselling and access to information and support.

With both mastectomy and oophorectomy there is some chance that cancer will be discovered through the surgery and women will be informed of this risk before surgery.

[10] Hartmaan et al. (2001) Efficacy of Bilateral Prophylactic Mastectomy in BRCA1 and BRCA2 Gene Mutation Carriers. J Natl Cancer Inst

[11] Rebbeck et al. (2002) Prophylactic Oophorectomy in Carriers of BRCA1 or BRCA2 Mutations. NEJM

Chemoprevention

The chemoprevention drugs tamoxifen and raloxifene are given to reduce a woman’s risk of developing breast cancer.

Under new guidelines released by NICE in June 2013, five years of tamoxifen can be considered for pre-menopausal women at an increased risk of breast cancer unless they have a past history or may be at increased risk of thromboembolic disease or endometrial cancer. And post-menopausal women at an increased risk of breast cancer can consider tamoxifen or raloxifene for five years unless they have a past history or may be at increased risk of thromboembolic disease or endometrial cancer.

Read more about chemoprevention for breast cancer on this page.

What has Breast Cancer Campaign funded regarding BRCA research?

We have invested over £9.6 million of funds raised by our supporters into gaining a greater understanding of the genetics of breast cancer and learning more about breast cancer genes, such as BRCA1 and 2.
We have supported 31 projects, including 10 on-going projects, that have looked at better understanding and treating breast cancers related to a BRCA mutation, as well as how best to support those affected by BRCA related breast cancer.

Achievements from our previous projects have included:

  • We have discovered how faulty BRCA genes can alter the effectiveness of different chemotherapies. These findings will enable doctors to develop genetic tests to see exactly how they can personalise treatment options to ensure the best possible response for every patient.
  • We looked at how parents with a BRCA mutation communicate breast cancer risk to their children, with the aim of giving health professionals vital knowledge to develop appropriate and sensitive support for BRCA mutation carriers, their children and families. 
  • We have discovered numerous new proteins and genes which are associated with the growth and development of BRCA mutation related breast cancers, helping researchers to build up a picture of why and how these breast cancers form, and understand how we might better treat or even prevent them in the future.

Some of our current BRCA related research projects include:

Further information

Find out more about preventative risk-reducing mastectomies.

Find out more about chemoprevention.

Find out more about family history as a breast cancer risk factor.

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