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Your #AskBCRF Questions Have Been Answered

By BCRF | April 13, 2015

Renowned BCRF grantees who are genetics experts respond to questions surrounding gene mutations and breast cancer.

You asked, we listened and the answers are in.

Our #AskBCRF social media event was tailored for those who have been diagnosed with breast cancer – their siblings, children and relatives – who had questions surrounding inherited susceptibility to breast and ovarian cancer.

Actress and filmmaker Angelina Jolie Pitt brought the topic into the spotlight last month when she announced that she underwent two preventive surgeries because she carries a mutation in the BRCA1 gene.  On March 26 we opened our social channels to you, and many of you took the opportunity to pose your questions to our scientific community.

Now we have chosen some of your questions and shared them with our BCRF experts who are also our grantees. Contributing to this conversation were:


Dr. Mary-Claire King of the University of Washington

Known worldwide for her accomplishments in human genetics research, Dr. King was the first to show that breast cancer is inherited in some families, as the result of mutations in the gene that she named BRCA1. She is currently working on a study with several other BCRF researchers to identify all genes responsible for inherited predisposition to breast cancer among women of Ashkenazi Jewish ancestry and by extension among women of all ancestries.

Dr. Funmi Olopade of the University of Chicago

Dr. Olopade is a geneticist and medical oncologist whose work focuses on the genetic causes of breast cancer, with an emphasis on identifying women at risk and ensuring they have access to appropriate screening, prevention and treatment. She is considered an expert in cancer risk assessment and individualized treatment for the most aggressive forms of breast cancer including triple negative breast cancer.

Dr. Fergus Couch of Mayo Clinic

Dr. Couch studies the genetics of breast cancer. He has authored more than 300 publications relating to the discovery and clinical characterization of inherited genetic variants in cancer susceptibility genes.

Dr. Jeffrey Weitzel of the City of Hope

At the vanguard of personalized medicine, Dr. Weitzel’s multidisciplinary clinical research and training programs emphasize translational research in genomic cancer risk assessment, chemoprevention, targeted therapy, clinical and psychosocial outcomes, genetic epidemiology and health services research in underserved minorities, and hereditary cancer in Latin America. Recent studies by Dr. Weitzel and colleagues documented BRCA mutations in 25 percent of U.S. Hispanic women, highlighting a need for better access to genetic testing and counseling in this population.

Here are their responses:


Kathleen, Reina, Naniece, Roxie, Melissa, Rochelle and Marcia asked questions on other causes of hereditary breast cancer.

1. Are other genetic mutations besides BRCA1 and BRCA2 known to increase breast cancer risk? 

2. What is PALB2, how important is it in determining breast cancer risk and is it being included in genetic testing alongside BRCA1 and BRCA2?

Questions 1 and 2 answered below:

While BRCA1 and BRCA2 are the most frequently mutated genes in hereditary breast cancer, mutations in other genes including TP53, PTEN, CHK2, PALB2, ATM and BRIP2 are also known to confer some risk of breast cancer.  However, research has shown that together these genes account for only about 25% of inherited breast cancer, suggesting that other yet undiscovered genetic factors are at play.

Several BCRF investigators are working to help identify other risk variants and how best to use this information in clinical practice. A recent report in the New England Journal of Medicine, for instance, provided new evidence on the risk associated with mutations in the PALB2 gene.

“The PALB2 gene makes a protein that in healthy cells works with the BRCA1 and BRCA2 proteins,” Dr. King, a co-author on the study, said. “Inherited mutations that lead to loss of function of PALB2 increase risk of breast cancer nearly as severely as do mutations in BRCA2. This finding is based on a study published in the New England Journal of Medicine last August by a consortium including several of us.”

Dr. Couch, also an author of the PALB2 report, comments: “The lifetime risk of breast cancer due to mutations in PALB2 is 58% for women with a strong family history of breast cancer.”

Dr. King adds: “Against this bad news about PALB2, there are two pieces of good news. One is that mutations in PALB2 are very rare, affecting far fewer women than do mutations in BRCA1 or BRCA2. And second, genetic tests that screen for PALB2 mutations are already available.”

3. How can we learn more about PALB2 testing?

4. Why don’t we hear more about the other breast cancer associated genetic mutations?

Questions 3-4 answered below:

Dr. King comments:  “The field of cancer genetic testing is evolving very fast, and BCRF supporters – readers of this blog – are way ahead of the curve. Information about PALB2 and other breast cancer genes is likely to be widely dispersed over the next several months. Inherited mutations in BRCA1 and BRCA2 affect more women than do mutations in other breast cancer genes, so these “oldest sister” genes are the best known in the medical community.  Any physician or genetic counselor who can arrange genetic testing for BRCA1 and BRCA2 can also arrange testing for PALB2.”

5. What kinds of preventive measures are recommended for women who have tested positive for genetic mutations other than BRCA1 and BRCA?

Several preventive options are available for BRCA mutation carriers. Please refer to the National Cancer Institute Cancer Risk and Genetic Testing Fact Sheet (Item 12).

Brenda, Cynthia, Sylvia, Hazel, Dian, Candance, Helen and Cat asked questions related to genetic testing.

6. Should breast cancer patients from adoptive backgrounds be tested for BRCA mutations?

Dr. Weitzel comments: “Limited family history can lead to underestimates of risk of inherited breast cancer. For instance, if a woman's father did not have any sisters, there will be no information on paternal inheritance, and thus a whole generation of information is missing. In 2007, we reported that women with breast cancer whose fathers had no sisters were three times more likely to have a BRCA mutation than those with paternal aunts known to be cancer free.  Family structure should also be taken into account with the BRCA mutation prediction models, lest they underestimate familial risk. Clearly this is even more true for a person with an adoptive background.”

Dr. Olopade adds: “Most people who have been identified with a BRCA mutation do not have a strong family history of cancer. If we only use family history as the basis of genetic testing, we’re going to miss a lot of women with mutations.”

7. What is the probability of inheriting a breast cancer risk mutation from the paternal side of the family?

8. Should the children of women with breast cancer be tested for BRCA mutations if no other family history is evident? If so, at what age?

9. Should families with a history of breast cancer be tested for BRCA mutations, even if there is no prior history of BRCA mutation?

10. Who qualifies for the test? How and where is it performed?

Questions 7-10 answered below:

Dr. King comments: Inherited mutations in BRCA1 or BRCA2 or any of the other breast cancer genes are inherited from fathers as often as from mothers. We inherit half our genes from our fathers and half from our mothers, and these genes are no exceptions.  So it is as important to know the family history of breast cancer on the father’s side of the family as on the mother’s side of the family.  The challenge is that because fathers are very rarely affected with breast cancer, and our families are often small, the father’s family may not be informative.

These family history complexities are a major reason that I believe that all women, regardless of personal or family history of breast cancer, should be offered testing for mutations in BRCA1 and BRCA2 at about age 30, and that women with no mutations in either of these genes, but with a family history of breast or ovarian cancer – on either the mother or father’s side of the family – should be tested for mutations in the other breast cancer genes as well.

Testing is arranged through any physician, often via a referral to a genetic counselor. For many women, the cost of testing is covered by insurance. Costs of commercial testing are decreasing rapidly, so women with testing not covered by insurance can shop for the best price. The test itself involves simply drawing a small blood sample that is sent to the sequencing laboratory. 

Laurie and Arathi asked questions on BRCA and triple negative breast cancer.

11. Should a patient diagnosed with TNBC be tested for BCRA mutation? Should her family be tested?

12. Do TNBC patients with BRCA mutations have a better prognosis than those without BRCA mutation?

Questions 11-12 answered below:

Dr. Funmi Olopade comments: “BRCA1 mutations are the most common cause of TNBC, with BRCA2 not far behind. We can now test for BRCA1 and BRCA2 mutations in all populations to identify women at risk.”

“Now that we know that BRCA1 and BRCA2 mutations cause TNBC, we are developing better treatments and prevention strategies.  Normal DNA repair is lost in TNBC cells in patients with BRCA1 and BRCA2 mutations.  Several drugs targeting DNA repair pathways are being tested in clinical trials for women who have TNBC due to mutations in BRCA1 or BRCA2. We are trying to develop biomarkers to identify women who have the best response to these drugs so as to better treat women with TNBC in the future.”

Pamela posed a fundamental question.

13. Does the BRCA mutation cause cancer or just increase the risk? How are they linked?

Dr. King comments:  “No inherited mutation, in a BRCA gene or any other gene, by itself causes breast cancer. Each of us inherits two copies of every gene, one copy from our mother and one copy from our father.  For a woman with an inherited mutation on one copy of a BRCA gene, cancer develops when – but only when – the other copy of that BRCA gene also undergoes a mutation in a breast or ovarian epithelial cell.  These second mutations are somatic; that is, they happen during our lives rather than our being born with them.  Somatic mutations happen to everyone and are no more frequent in BRCA mutation carriers than in anyone else. The reason that breast or ovarian cancer develops so much more frequently in BRCA mutation carriers is that mutation carriers do not have a normal back-up copy of the BRCA gene to neutralize the effect of somatic mutations in breast and ovarian cells.”