Expanding Panel Testing Beyond Known Breast/Ovarian Cancer Genes Produces More Questions Than Answers

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Three of the most well-known genes that can mutate and raise the risk of breast and/or ovarian cancer are BRCA1, BRCA2, and PALB2. Women who inherit a mutation, or abnormal change, in any of these genes -- from their mothers or their fathers -- have a much higher-than-average risk of developing breast cancer and/or ovarian cancer. (Abnormal PALB2 genes are suspected to raise the risk of ovarian cancer, but larger studies need to confirm that risk.) Men with these mutations have an increased risk of breast cancer, especially if the BRCA2 gene is affected, and possibly of prostate cancer. Many inherited cases of breast cancer have been associated with mutations in these three genes.

The function of the BRCA and PALB2 genes is to keep breast cells growing normally and prevent any cancer cell growth. But when these genes contain the mutations that are passed from generation to generation, they do not function normally and breast cancer risk increases. Abnormal BRCA1, BRCA2, and PALB2 genes may account for up to 10% of all breast cancers, or 1 out of every 10 cases.

Most people who develop breast cancer have no family history of the disease. However, when a strong family history of breast and/or ovarian cancer is present, there may be reason to believe that a person has inherited an abnormal gene linked to higher breast cancer risk. Some people choose to undergo genetic testing to find out. A genetic test involves giving a blood or saliva sample that can be analyzed to pick up any abnormalities in these genes.

In the United States, several laboratories perform commercial BRCA1, BRCA2, and PALB2 testing, including Myriad Genetic Laboratories, Ambry Genetics, and GeneDx. They report results within 2 to 4 weeks.

Abnormalities in other genes have also been associated with breast cancer risk. BRCA1 and BRCA2 mutations are the most common cause of hereditary breast cancer. Right now, PALB2 and other breast cancer gene abnormalities appear to be a less common cause of breast cancer, although testing for many of these genes is now also available. People who decide to have genetic testing may choose to be tested for only the BRCA1 and BRCA2 genes or to have multiple breast cancer-related genes tested together through a panel test.

A study has found that expanding the panel test beyond genes known to be linked to a higher risk of breast and/or ovarian cancer for people diagnosed with breast or ovarian cancer doesn’t add much benefit and raises more questions than answers.

The research was published in the May 5, 2016 issue of the American Journal of Human Genetics. Read the abstract of “Evaluation of ACMG-Guideline-Based Variant Classification of Cancer Susceptibility and Non-Cancer-Associated Genes in Families Affected by Breast Cancer.”

In some cases, a family may have many women who have been diagnosed with breast cancer younger than age 50 and/or ovarian cancer at any age, yet their genetic testing results are negative. So the cancer could be due to an inherited genetic abnormality that hasn’t been identified yet.

Researchers wanted to know if it would benefit breast/ovarian cancer patients to expand the panel of genes tested to include genes not associated with breast or ovarian cancer, as well as genes not linked to cancer at all.

To do the study, the researchers did whole exome sequencing on 404 people in 253 families with a history of breast and/or ovarian cancer. Whole exome sequencing is a laboratory process that figures out the precise order of all the DNA building blocks in all the expressed genes in a living thing’s genome. A genome is an organism’s complete set of DNA, including all its genes. In humans the genome contains more than 3 million DNA base pairs.

The researchers then analyzed a 180-gene panel that included:

  • 25 genes associated with higher breast/ovarian cancer risk
  • 123 genes associated with a higher risk of other cancers
  • 32 genes associated with a higher risk of cardiovascular disease

Using guidelines from the American College of Medical Genetics and Genomics (ACMG), the researchers identified 1,605 genetic changes (also called variants):

  • 11% of people with no BRCA1 or BRCA2 mutations had known mutations in other genes associated with a higher risk of cancer; most of these mutations moderately increase the risk of breast or ovarian cancer
  • 12% of people had variants of uncertain significance in genes linked to breast/ovarian cancer; a variant of uncertain significance is an unusual change in a gene, but the change has NOT been clearly linked to a higher risk of cancer
  • when genes not linked to breast or ovarian cancer also were included in the analysis, 78% of the families had variants of uncertain significance
  • overall, 95% of people had at least one variant of uncertain significance

"Adding on the additional cancer susceptibility genes to the 'breast cancer susceptibility' genes opened up more questions than it answered," said Katherine Nathanson, M.D., professor of translational medicine and human genetics at the University of Pennsylvania and lead author of the study. "This study therefore adds to prior findings of ours and demonstrates little incremental utility to testing non-breast cancer susceptibility genes in breast cancer families."

The researchers said their analysis highlights the complexities of genetic testing and counseling, which continues to increase as genetic sequencing becomes more commonplace and less expensive.

"These findings add layers of complexity in counseling for cancer risk," said the study's first author Kara Maxwell, M.D., hematology/oncology instructor at the University of Pennsylvania. "A patient would now be expected to understand not only that a genetic finding could be found that may or may not be related to the cancer in their family, but that genetic variants could be found that may or may not put themselves and their family members at risk for a disease they weren't even thinking about at the time."

If you and/or some of your family members have been diagnosed with breast, ovarian, or prostate cancer, you may be interested in the possibility of genetic testing. Meeting with a professional genetic counselor first can help you figure out the connection between your family’s genes and your risk of disease and whether genetic testing is right for your unique situation.

A professional genetic counselor also can help you make sense of genetic testing results, especially if you have one or more variants of uncertain significance.

To find a professional genetic counselor who specializes in family-related cancer risk, talk to your doctor or check with the hospitals and cancer centers in your area. The National Society of Genetic Counselors also has an online tool to help you find a genetic counselor in your area.

For more information on genetic testing and counseling, visit the Breastcancer.org Genetic Testing pages.



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