Monday, October 5, 2009

Can Men Understand BRCA?

I was surprised when 23andMe added selected BRCA cancer mutations to the Carrier Status list in February of 2009, especially since everybody knows that Myriad Genetics holds a controversial patent to the BRCA1 and BRCA2 genes. Because Myriad is a Salt Lake City-based company, we watch them closely. And more importantly, I have a personal story with Myriad BRCA testing and a family member - which I will share at the end of this post.


Myriad originated in 1991 as a gene discovery company. Their researchers were able to access and link important genealogical and medical databases, which resulted in discovering the BRCA genes. The new database was named The Utah Population Database (UPDB). It originally contained information on 200,000 Mormon family groups and most of the1.6 million descendants of the initial 10,000 Utah settlers. This database was linked to the Utah Cancer Registry (which contains more than 100,000 entries), in which generated 40,000 cross-linked entries. Since then, the database has expanded with updated genealogical and public health records, and Intermountain Healthcare has linked its clinical data with the UPDB to offer an even more powerful research tool.

Anything Here for Me?

My 23andMe report cautions me to remember that the BRCA mutations covered by the report are only three of hundreds in the BRCA1 and BRCA2 genes that can cause cancer. The absence of these mutations does however not rule out the possibility that I may carry another cancer-causing variation in one of the other genes.

Click on image to enlarge

Population Risk

It seems like a small number when one reads that only 5 to 10 percent of breast cancers occur in women with a genetic predisposition for the disease. The incidence in men only accounts for 1% of all breast cancer. In addition, I learn that these mutations greatly increase not only the risk for breast cancer in women, but also the risk for ovarian cancer in women as well as prostate cancer among men. Additionally, 23andMe provides data for only three specific cancer-associated mutations that are found mainly in people with Ashkenazi Jewish ancestry.

Since I am not a woman, nor an Ashkenazi Jew (100% European according to my 23andme ancestry painting), is any of this information important to me? I think so. Because I am not a carrier, the children I may have will be at reduced risk of breast cancer. But my interest at this moment is not for me, but rather for affected family members, for whom I care deeply.

October is Breast Cancer Awareness Month

The National Breast Cancer Awareness Month (NBCAM) program is dedicated to promoting the importance of early screening and detection of breast cancer through a nationwide campaign held during the month of October. They are celebrating their 25th anniversary. Whenever I hear about a NBCAM activity, I think about what my sister-in-law (SIL) went through. She is a breast cancer survivor.

A Personal Story

Her story starts with her maternal Grandma, who was diagnosed with breast cancer at age 45. After several surgeries failed to “hack it out”, Grandma died at 49.

My SIL’s mother was first diagnosed with breast cancer at age 29. She had surgery to remove her breasts, followed by chemotherapy, but that didn’t stop the cancer from spreading to her spine, and finally her lungs. Even after complaining about respiratory difficulties, the lung cancer was not discovered until the autopsy. Mom also fought for 4 years before dying. My sister-in-law was seven years old.

Thinking It Was Inevitable

While growing up, my SIL always thought that at some point she would die of breast cancer herself. In 2001 when she was 25 years old, she heard about the Myriad BRCA test and wanted to take it. The test came back negative for any of the BRCA mutations, so she started to think she had dodged a bullet. She did have genetic counseling, which would have told her some risk still existed. She saw an oncologist, but did not have a mammogram since she was nursing a newborn at the time.

Three years after the negative Myriad test, my SIL was pregnant once again, and for the first time ever, found a lump in her breast. She had an ultrasound and was told that the lump was benign and would disappear after the pregnancy. Two weeks later she visited her Obstetrician and told the doctor she thought the lump was getting bigger. A needle biopsy by a breast surgeon revealed she had cancer.

A Prayer Is Answered

A small miracle followed. She began chemotherapy while pregnant with her fourth child. Her daughter was born as beautiful and healthy as her other children. After the birth she had a radical bi-lateral mastectomy, reconstruction, and radiation therapy.

I asked her if she felt modern medicine had let her down. She said no, because – she explained - she had always felt that it was her responsibility to follow through with the accurate diagnosis and treatment of her healthcare. However, she did feel that she should have asked an aunt to take the BRCA test to help interpret her results. Today, she is still interested in learning about new genetic testing for breast cancer that might help her three young daughters.

As their Uncle, these three beautiful little angels give me sweet hugs and a lot of love. As I thought about their future and possible inherited risk, I found myself feeling sad thinking about what they might face in the future. I can’t imagine how I would feel if I were their mother or father.

Perspective from a Certified Genetic Counselor

BRCA Mutations and Inherited Risk for Breast Cancer

Women who talk with me about inherited risk for breast cancer often ask about “the breast cancer gene”. I think it comes as a surprise to many of these women (and their husbands) that everyone, men and women, have BRCA genes. In fact, every person has two copies each of BRCA1 and BRCA2. One of each came via the egg cell from their mother, and one came in the sperm cell donated by their father that resulted in their personal conception; talk about personalized health! So although Grant does not carry one of the three common Ashkenazi (or Eastern European) Jewish BRCA mutations, he does carry BRCA genes in which hundreds of mutations are possible. Cheery thought!

Grant shared the story of his sister-in-law and her family’s experience with relentless breast cancer. Breast cancer at ages 45, 29, and 28 are the hallmark of hereditary breast cancer caused by a BRCA mutation. How could it be that Grant’s sister-in-law tested negative for BRCA mutations and then she was diagnosed with breast cancer? Her story helps to illustrate the promise and the pitfalls of genetic and genomic testing, and it is a good example of how genetic test results may be only part of the story of risk. I appreciate her willingness to have her brother-in-law share her story. (I hope he told her he was sharing the story!)

Mutation: A gene mutation is a permanent change in the DNA sequence that makes up a gene. Mutations range in size from a single DNA building block (DNA base) to a large segment of a chromosome.

The genomic test result that Grant received as part of 23andMe represents the mutations tested for during initial testing usually offered to individuals with Eastern European Jewish ancestry who have a family history of breast or ovarian cancer. I am not sure what led the designers of the 23andMe to select and report on BRCA mutations despite the fact that another company owns the patent for those genes. I suspect it may be because other labs have been licensed to conduct screening for the three mutations in certain specific populations.

Promise and Pitfall

I have the sense that Grant was not surprised to learn he is not a carrier of a BRCA mutation. I have not heard him mention or write about cancer in his biologic family. That is little consolation for the fact that his sister-in-law has developed breast cancer and his nieces (grandnieces, etc.) could develop breast cancer. The promise with genetic testing is the possibility that knowing if you are at risk, it may offer the opportunity to prevent cancer. The pitfall is the false hope that testing that is negative (no mutation detected) has ruled out risk for the disease.

As Grant’ s sister-in-law mentioned in her reflection, she wished that her aunt had been tested for BRCA mutations to help to interpret her results. If her aunt (her mother’s sister) had breast cancer and tested negative, then her negative result would have been meaningless. It would have indicated the fact that the cause of early breast cancer in the family had not yet been linked to a BRCA mutation. In the study of families with inherited breast and ovarian cancer, we know that BRCA is not the only reason for cancer in every family. There must be other hereditary factors besides BRCA that cause breast cancer. Researchers have not been able to identify another familial breast and ovarian cancer gene with the same dramatic impact of BRCA1 and BRCA2, but others or combinations of others must exist.

The Story Is Not Over

In the same way that 23andMe updates risk assessments as new SNPS are linked to diseases and reported back to Grant, new ways to evaluate BRCA genes have been added to the analysis in high risk families. The story of Grant’s sister-in-law and her genetic testing is not over. In 2001 - and again in 2007 - Myriad Genetics updated their analysis of BRCA genes to include evaluation for large gene rearrangements.

While rearrangements are also called mutations, the original testing for mutations involved sequence analysis of the genes and did not reveal that chunks of DNA could be missing (deleted) or copied more than once (duplicated). Several families, in whom a BRCA mutation was not originally detected, have since been found to have a duplication, or - more likely - a deletion. Grant’s sister-in-law could visit with a genetic counselor about this new testing option. The original result would inform the genetic counselor of the testing completed at the time of the test in 2001. There would not be a need to repeat the sequence test that was performed, but new analysis to look for a large rearrangement of BRCA1 or BRCA2 may provide the genetic key that would allow identification of at risk family members.

The promise of genetic testing is realized in the identification of those at increased risk. Individuals and their family members may use this information to attend carefully to the possibility of the development of cancer at younger than expected ages. It may also allow for early intervention in those at risk when preventive interventions are available.

Good resources for breast cancer information:

American Cancer Society:
Susan G. Komen:
Facing Our Risk of Cancer Empowered:
National Cancer Institute:


  1. These are all great points about the BRCA1 or BRCA2 gene mutations. I just wanted to point out in your UPDB summary that although Myriad's founders were the original folks who put the UPDB together, Myriad NEVER had access to the UPDB. All of the linkage work was done through the University of Utah. Myriad performed the sequencing because they were able to invest in the sequencers (very expensive at that time). It's an important point because the UPDB is not to be used directly by any for-profit. All research using the UPDB must be run by academics, but the research can be paid for by companies.

    Also, the mutations that the personal genomics companies tests for are not the critical ones - in fact, they are very minor mutations. I wouldn't put much faith in the results these companies give you as it relates to either BRCA1 or BRCA2.

    Keep up the good work. I have tried to post comments a couple of times but I had technical problems. Hopefully this time it works!


  2. Nice blog... BRCA1 gene provides instructions for making a protein that acts as a tumor suppressor and increased risk of developing the breast cancer disease. BRCA1 gene testing help to detect future health.