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


This article is most relevant for:
People with an inherited mutation in BRIP1, BARD1, PALB2, NBN

This article is also relevant for:

Checked Breast cancer survivors

Checked People with a genetic mutation linked to cancer risk

Checked Previvors

Checked Women under 45

Checked Women over 45

Checked Other mutations: BRIP1, BARD1, PALB2, NBN

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


Be a part of XRAY

Relevance: Medium-High

Relevance

Strength of Science: Medium-High

Strength of Science

Research Timeline: Human Research

Research Timeline

Rating Details

Read the article

Printer Friendly Page

Many women who have genetic testing for an inherited mutation find that they do not carry a mutation in BRCA1 or BRCA2 despite their personal and family history of breast and/or ovarian cancer. Panel tests look for mutations in other genes associated with increased cancer risk. However, the cancer risk for people with mutations in some of these other genes is not yet known. This study looks at whether mutations in four genes, BRIP1, BARD1, PALB2, and NBN, are associated with an increased risk for ovarian cancer. The researchers found that BRIP1 mutation carriers have about a 6% risk of developing ovarian cancer by age 80. (02/09/16)

Contents

At a glance Questions for your doctor
Findings     In-depth                 
Clinical trials Limitations
Guidelines Resources and references


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 these findings. Other studies have suggested that mutations in PALB2 also increased ovarian cancer risk. For women with BRIP1 mutations, it is important to note that while a 6% lifetime risk of ovarian cancer is significant, it is lower than the lifetime risk associated with BRCA mutations (which may be up to 50%).  

Posted 2/9/16

(back to top)

Expert Guidelines

The National Comprehensive Cancer Network (NCCN) brings together a panel of experts to  create guidelines for genetic testing for inherited mutations that increase cancer risk. NCCN Guidelines for women with mutations in PALB2, NBN, BRIP1 and other genes include the following:

Ovarian Cancer Risk Management

  • Women with mutations in following genes should consider risk-reducing removal of ovaries and fallopian tubes at age 45-50:
    • BRIP1
    • RAD51C
    • RAD51D

Breast Cancer Screening: 

  • Annual screening mammogram (consider 3D mammography) and annual MRI with contrast beginning at age 30, or earlier based on family breast cancer history for women with mutations in following genes:
    • PALB2
    • CDH1
    • NF1
  • Annual screening mammogram (consider 3D mammography) and annual MRI with contrast beginning at age 40, or earlier based on family breast cancer history for women with mutations in following genes:
    • ATM
    • CHEK2
    • NBN

Breast Cancer Risk Management

  • Discussing the option of risk-reducing mastectomy based of family history of breast cancer for women with mutations in:
    • ATM
    • CHEK2
    • NBN
    • NF1
    • PALB2

At the moment, NCCN does not have guidelines for risk management for people with BARD1 mutations.

It is important for people with mutations in these genes to consult with a genetics expert to determine the best risk management plan based on their personal and family medical history and other circumstances. 

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, should I have surgery to remove my ovaries and fallopian tubes? 
  • What is the ideal age for risk-reducing removal of the 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?
  • Can you refer me to a genetic counselor? 

Open Clinical Trials

  • NCT02665195: Prospective Registry of Multiplex Testing (PROMPT). This study is being done to learn more about how changes in certain genes may be linked to cancer. The want to better understand the risks that are linked to genetic changes in these less well-studied genes in order to give better advice to families with mutations in these genes. 
  • NCT02760849: The Women Choosing Surgical Prevention (WISP) Trial. The goal of the WISP Study is to compare whether removal of fallopian tubes only, delaying removal of the ovaries can safely improve sexual functioning and menopausal symptoms compared to standard risk-reducing removal of the ovaries and fallopian tubes (also known as risk-reducing salpingo-oophorectomy or RRSO). The study is open to women with mutations in any of the following genes:  BRCA1, BRCA2, BRIP1, PALB2, RAD51C, RAD51D, BARD1, MSH2, MSH6, MLH1, PMS2, or EPCAM.

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. 

(back to top)

1 like

Back to XRAY Home

Search XRAY studies and articles

Back to XRAY Home

FORCE:Facing Our Risk of Cancer Empowered