STUDY AT A GLANCE

This study is about:

Whether increasing the number of genes examined for mutations beyond those that increase breast/ovarian cancer risk is useful for healthcare providers and their ovarian/breast cancer patients.    

Why is this study important?

As more and more genes are being added onto cancer risk-increasing test panels, more changes in patients’ genes are being found. But because a lot of this is new, little information is known about how these changes in patients’ DNA affects their cancer risk.  

Study findings: 

1. 253 families who did not carry a BRCA mutation were tested for 25 candidate genes known to be associated with breast/ovarian cancer. 26 families were found to have a mutation in one of 12 genes that increase breast cancer risk.

2. 2 of the 253 families who did not carry a mutation in BRCA or another breast cancer risk-increasing gene had a mutation in a gene associated with another cancer susceptibility syndrome. These gene mutations increase the risk of cancers other than breast and/or ovarian.

3. 95% of individuals tested had a variant of unknown significance (VUS) in at least one gene.

What does this mean for me?

If you are interested in genetic testing to learn if there is an inherited genetic mutation causing the breast/ovarian cancer in your family, this study indicates that panel testing provides useful information. However, looking beyond the 20-30 known breast/ovarian cancer genes brings more confusion than clinical utility.

Questions to ask your health care provider:

• I tested negative for a BRCA mutation despite a strong personal and/or family history of breast cancer. Should I consider expanded panel testing?
• I am considering genetic testing after being diagnosed with breast cancer before age 50. Which genes should I have tested?
• I have a variant of unknown significance in the ________ gene. What care should I receive?\
• My report says that my variant is benign and not disease causing. But a variant is still a change in my gene. How do researchers know that this change is not dangerous?

IN DEPTH REVIEW OF RESEARCH

Study background:

A lot of information is known about how to care for BRCA mutation carriers. This wasn’t the case a little over a decade ago when BRCA was first discovered to play a role in cancer risk. However, BRCA is only responsible for up to half of hereditary breast cancers; researchers and health care providers are working to find and learn more about other genes that are involved. Because of so many advances in genetic testing, healthcare providers can now easily look for mutations in genes other than BRCA1 and BRCA2.

Up to 110 genes associated with cancer risk can now be tested for a mutation! Some health care providers are beginning to use a technique called “exome sequencing” in the clinic, which looks at all of a patient’s genes, not only those that are known to increase cancer risk. We know how to interpret changes in BRCA genes, but additional sequencing increases the chance that changes in genes that are not yet understood will be found. Instead of getting a clear “disease causing” or “not disease causing” result, patients can learn that they have a change in one or more genes that is classified as a “variant of unknown significance (VUS).” A gene change is classified as a VUS when it is unknown whether that change is disease causing or not. Since there is uncertainty around VUSs, receiving this type of result can be extremely confusing for patients and their health care providers.

Kara N. Maxwell and her colleagues from the Perelman School of Medicine at the University of Pennsylvania and other institutions published research in the May 2016 issue of American Journal of Human Genetics. Their study evaluates the efficiency of the American College of Medical Genetics (ACMG) variant classification system, and looks at how helpful it is to test for mutations in genes beyond known breast/ovarian cancer risk-increasing genes in individuals with a personal or family history of breast/ovarian cancer. Maxwell’s paper explores the issue of "classification"—variants need to be classified and agreed upon, so that all clinical laboratories consistently categorize individual variants in the same way when identifying those that do or do not cause disease (variants that do not cause disease are often called “benign” variants). Unfortunately, this is not always the case, and inconsistent classification of variants now exist between different clinical laboratories. This inconsistency was motivation for the ACMG to publish guidelines for variant classification, in an effort to provide a standard framework for variant classification. Because these guidelines are relatively new (published in 2015), researchers and healthcare providers do not know if they are efficient.

Researchers of this study wanted to know:

• if increasing the number of genes sequenced for mutations beyond breast/ovarian cancer risk increasing genes is useful for healthcare providers and their ovarian/breast cancer patients. 
• if the American College of Medical Genetics (ACMG) variant classification system is a valid method of variant classification.

Population(s) looked at in the study:

This study population included 404 individuals (from 253 families) who

• had breast or ovarian cancer and were from a family with at least three first- to third-degree relatives who also had breast or ovarian cancer, and were under 60, or
• had a primary breast and primary ovarian cancer diagnosis, or
• had an early breast cancer (under 45 years old).

The exomes of these individuals (where the researchers specifically looked at 180 genes and not only those genes associated with increased risk of disease or cancer) were sequenced. Variants were classified as “pathogenic” (disease causing), “benign” (not disease causing), or VUS (variant of unknown significance), and then compared to classifications found in other databases, such as Clinvar. This type of validation is critical for assuring that patients get the best information on whether or not their mutation is associated with increased risk of cancer.

Study findings: 

1. 253 families who did not carry a BRCA mutation were tested for 25 candidate genes known to be associated with breast/ovarian cancer. 26 families were found to have a mutation in one of 12 genes that increase breast cancer risk.
2. 2 of the 253 families who did not carry a BRCA mutation or a mutation in another breast cancer risk-increasing gene had a mutation in a gene associated with another cancer susceptibility syndrome. These are gene mutations that increase risk of cancers other than breast and/or ovarian.
3. 95% of individuals tested had a variant of unknown significance (VUS) in at least one gene.

Limitations:

This is a relatively small study population. Study authors say that research using more people that will find more variants and include more than 180 genes is needed to confirm their results. Additionally, the researchers classified variants in genes where the majority are well characterized. The American College of Medical Genetics (ACMG) system of classification may not work as well in other situations, such as when less is known about the genes and variants associated with the disease. 

Conclusions:

This study suggests that looking for genes beyond those that are known to increase breast/ovarian cancer risk does not provide a lot of useful information for breast/ovarian cancer patients. Rather, it creates more confusion due to the high amount of VUSs found (95%). Breast/ovarian cancer patients should feel confortable getting breast/ovarian cancer panels done when looking for mutations.

Posted June 13, 2016

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References

Maxwell KN, Hart SN, Vijal J, et al. “Evaluation of ACMG-Guideline-Based Variant Classification of Cancer Susceptibility and Non-Cancer-Associated Genes in Families Affected by Breast Cancer.” The American Journal of Human Genetics. 2016 May 5; 98(5): 801-810.