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Are mutations in BRIP1, BARD1, PALB2, and NBN associated with an increased risk for ovarian cancer?


This research is relevant for:

Checked Breast cancer survivors

Checked Women under 45

Checked Women over 45

Unhecked Men with breast cancer

Unhecked Metastatic breast cancer

Unhecked Triple negative breast cancer

Checked Previvors

Unhecked BRCA mutation carriers

Unhecked ER/PR +

Unhecked Her2+ breast cancer

Checked Other mutations: BRIP1, BARD1, PALB2, NBN

Checked Special populations: People who tested uninformative negative for mutations in BRCA

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Many women who meet national guidelines for genetic testing for BRCA mutations find that they do not carry a mutation in BRCA1 or BRCA2 despite their personal and family history of breast and/or ovarian cancer. Expanded panel tests now look for mutations in other genes associated with increased cancer risk. However, the extent of cancer risk for people with mutations in some of these other genes is not yet known. This study examines whether mutations in four genes found on many commercially available panels, BRIP1, BARD1, PALB2, and NBN, are associated with an increased risk for ovarian cancer. The researchers estimate that BRIP1 mutation carriers have about a 6% risk of developing ovarian cancer by age 80.


STUDY AT A GLANCE

This study is about:

Whether carriers of mutations in BRIP1, BARD1, PALB2, or NBN have an increased risk of ovarian cancer.

Why is this study important?

BRIP1, BARD1, PALB2, and NBN are genes found on many commonly used panels looking for gene mutations that increase risk of hereditary breast and ovarian cancer. However, the prevalence of these mutations (how common or rare these mutations are in the population) and the extent to which ovarian cancer risk is associated with mutations in these genes are not known.

Study findings:

  1. BRIP mutations were more common in women with ovarian cancer and women with a family history of ovarian cancer than in the general population. 
  2. Using computer models, the researchers calculate that mutations in BRIP1 are associated with about a 6% risk in ovarian cancer development by age 80.

What does this study mean for me?

This study demonstrates that mutations in BRIP1 (but not BARD1, PALB2, or NBN) moderately increase ovarian cancer risk. More work needs to be done to confirm this finding.  In fact, another recent study found that mutations in PALB2 also increased ovarian cancer risk.  It is important to note that while a 6% lifetime risk of ovarian cancer is significant and cause for concern, it is lower than the lifetime risk associated with BRCA mutations (which may be up to 50%).  

Questions to ask your health care provider:

  • I have a mutation in BRIP1, BARD1, PALB2, or NBN. How should I be cared for?
  • I have a mutation in BRIP1—what should factor into my decision about whether or not I should preventively remove my ovaries and fallopian tubes?
  • I tested negative for mutations in BRCA1/2 despite my personal and/or family cancer history.  Should I consider panel testing to see if I have a mutation in other genes that would increase my cancer risk?

IN DEPTH REVIEW OF RESEARCH

Study background:

A number of gene mutations that increase breast cancer risk also increase risk of ovarian cancer.  According to the study authors, “Epithelial ovarian cancer (EOC) is the most lethal gynecological malignancy, responsible for 13,000 deaths per year in the United States.” Identifying mutations that put women at increased risk for ovarian cancer would have a huge clinical impact. Currently, the known genetic risk factors barely account for half of the families that have a history of ovarian cancer, meaning there are other genetic risk factors to be found.

Previous studies have identified BRIP1, BARD1, PALB2, and NBN as genes in which mutation carriers potentially have an increased risk of developing ovarian cancer. Currently, mutations in PALB2 are associated with developing breast cancer (up to 58% for women) and it is believed that BRIP1, BARD1, and NBN also are associated with increased breast cancer risk. However, these studies were relatively small and did not include control patients, so further research is needed.

In August of 2015, Dr. Susan Ramus and colleagues from the University of Southern California Keck School of Medicine and other institutions published a study in the Journal of the National Cancer Institute (JNCI) that looked for mutations in the BRIP1, BARD1, PALB2, and NBN genes, comparing women with ovarian cancer who are at high risk of the disease due to family history or the presence of an inherited mutation against a control population at average risk for ovarian cancer.

Researchers of this study wanted to know:

Whether mutations in BRIP1, BARD1, PALB2, or NBN are associated with an increased risk of ovarian cancer.  

Population(s) looked at in the study:

This study looked at three groups of European women and compared them to each other in the results.

  • 3,236 women had invasive ovarian cancer.
  • 3,431 women had neither ovarian cancer nor a family history of ovarian cancer and were considered to be at average risk for the disease.
  • 2,000 women who did not have ovarian cancer but were at high-risk of developing ovarian cancer due to family history or an inherited mutation in BRCA1/2.

Study findings: 

  1. About 1% of women with ovarian cancer had a mutation in BRIP1. Additionally, 0.6% of women who were at high risk for ovarian cancer had a mutation in BRIP1. Only 0.09% of women at average risk for ovarian cancer had a mutation in BRIP1. This finding identifies mutations in BRIP1 as a risk factor for ovarian cancer.
  2. There were no differences in the percentages of mutations found in BARD1, NBN, or PALB2 in women who had ovarian cancer as compared to women who were at average risk of ovarian cancer, indicating that mutations in BARD1, NBN, and PALB2 are not believed to be risk factors for ovarian cancer in this population.
  3. The average age of ovarian cancer diagnosis in BRIP1 mutation carriers was about 64, which was higher than the average age of ovarian cancer diagnosis for women who did not carry BRIP1 mutations. Although this finding was close to achieving statistical significance, it did not, and so more research is needed to confirm the finding.
  4. Using computer models, the researchers claim that mutations in BRIP1 are associated with about a 6% risk of ovarian cancer by age 80.

Limitations:

The study authors acknowledge that they may have missed mutations in some women because they were only able to read about 92-99% of each gene, meaning that they missed some parts of participants’ DNA. The authors also were not able to identify women who had more complex changes in their DNA, including large genomic deletions (in which large pieces of a gene or multiple genes are missing) and rearrangements (which occur in DNA that has been inappropriately rearranged).

Conclusions:

This research identifies mutations in BRIP1 as a risk factor for ovarian cancer. According to the American Cancer Society, the average woman’s risk of ovarian cancer is less than 2%. The study estimates the risk for BRIP1 mutation carries to be about 6% by age 80, which is clinically significant but not as high as mutations in BRCA1 or BRCA2. As Drs. Judith Balmaña of the Vall d’Hebron Institute of Oncology and Susan Domchek of the Basser Center for BRCA say in the accompanying editorial, “As risks of developing BRIP1-associated ovarian cancer are moderate and developing breast cancer uncertain, the risk/benefit profile and timing of oophorectomy are different than for BRCA1/2 and we should not “default” to oophorectomy at age 40 years.”

It is important to keep in mind that BRIP1 and other genes that may increase ovarian cancer risk are still being studied to fully understand the risk that mutations in these genes may confer. This study did not identify PALB2 mutations as increasing ovarian cancer risk; however, a recent study published in JAMA Oncology on December 30, 2015 reached the opposite conclusion. The data from the JAMA Oncology paper indicates that PALB2 mutations (in addition to BRIP1 mutations) are associated with an increased risk of ovarian cancer, with an approximately 10% risk for PALB2 carriers. The JAMA Oncology  study results conclude that “if a lifetime risk of 10-15% is confirmed for these genes, it would be reasonable to consider a risk-reducing oophorectomy by age 45 years.” Management guidelines have not been created because more studies are needed to confirm or dispute these findings. 

References

http://www.cancer.org/cancer/ovariancancer/detailedguide/ovarian-cancer-risk-factors

Balmaña J and Domchek SM. “BRIP1 as an Ovarian Cancer Susceptibility Gene: Ready for the Clinic?” Journal of the National Cancer Institute, Published first on August 27, 2015. 

Ramus SJ, Song H, Dicks E, et al. “Germline Mutations in the BRIP1, BARD1, PALB2, and NBN Genes in Women With Ovarian Cancer.” Journal of the National Cancer Institute. Published first on August 27, 2015.  

Norquist B, Harrell M, Brady M, et al. “Inherited Mutations in Women With Ovarian Cancer.” JAMA Oncology, epublished ahead of print  December 30, 2015. 

Posted 2/9/16

 

 

Related Information and Resources

FORCE Information:  Should I get genetic testing

FORCE Information:  BRIP1 

FORCE Information: PALB2  

FORCE Information:  Risk management Guidelines 

Joining FORCEs Newsletter:  Voices of FORCE- Beyond BRCA 

Be Empowered Webinar:  The Promise and Peril of Panel of Panel Genetic Testing for Inherited Cancer Susceptibility 

 

 

 

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