Findings allow for better risk assessment and personalized treatment for BRCA2 carriers
Key takeaways:
- Researchers assigned clinical classifications to thousands of BRCA2 variants of uncertain significance.
- Research about how the pathogenic variants affect response to drug treatments is ongoing.
Researchers determined the clinical classification of more than 90% of potential BRCA2 variants of uncertain significance in the part of the gene that is central to BRCA2 function, according to study results.
The findings from the multi-institutional international study will help clinicians give thousands of women a proper risk evaluation for developing breast or ovarian cancers, as well as other malignancies.
“The variants of uncertain significance problem for BRCA2 may not exist 3 years from now,” Fergus J. Couch, PhD, Zbigniew and Anna M. Scheller professor of medical research, as well as chair of the division of experimental pathology and laboratory medicine at Mayo Clinic, told Healio. “That’s great news for all the women who have these variants. They’ll at least know what they have. That stress and the uncertainty is all gone. We’ll know how to treat these people.”
Background
Approximately one in 400 people, and one in 100 diagnosed with breast cancer, have a BRCA2 mutation, Couch said.
People who have a BRCA2 loss-of-function pathogenic mutation have a 69% lifetime risk for developing breast cancer and a 15% risk for ovarian cancer, according to study background.
BRCA2 also has been associated with pancreatic and prostate cancers.
However, about 20% of individuals who have a BRCA2 mutation have a variant of uncertain significance (VUS), of which there are about 5,000, according to Couch.
“We don’t actually know if the VUS do anything to the biology or the function of the gene,” Couch said. “Do they cause risk or not? We don’t know. For the patient, it’s a real problem. If they were known to have a pathogenic mutation, they could benefit from improved screening. They could benefit potentially from prophylactic surgeries to reduce their risk. They can get treated with [poly(ADP)-ribose polymerase (PARP)] inhibitors. If you have a VUS, you don’t qualify for any of that.”
Methods and results
Couch and colleagues evaluated every possible variant in an area of the gene considered “the hotspot” for pathogenic variants, they wrote.
The area accounts for about 20% of the gene.
Researchers used CRISPR-Cas9 to conduct a functional analysis of 6,960 potential variants.
“We wanted to make sure that we covered every DNA base across this region of BRCA2,” Couch said. “You go one nucleotide at a time, putting all possible mutations into each one to completely blanket the whole region. Only about 30% of those variants have ever actually been seen in humans to date, but they will be in time. The idea here is that we'll have a complete catalog of everything.”
Researchers obtained functional analysis scores for all but one variant investigated.
They found approximately 91% of variants could be classified as pathogenic (6.6%), likely pathogenic (4.7%), benign (1.3%) or likely benign (78.7%).
Researchers acknowledged study limitations, including the “small level of error in functional evaluation,” which could lead to misclassified variants.
“They’re all very rare,” Couch said. “There’s some that occur a little bit more than the others, but they’re still very rare individually — maybe one to three families in the world that we’ve seen. But when you have 5,000 of them, it adds up. On a national level in the United States, you could probably say 20,000 to 30,000 individuals [have these], and that’s probably conservative.”
‘Understand all variants’
If a patient gets diagnosed with a VUS, there is not much a clinician can do.
However, about once a year, companies that conduct BRCA genetic testing update variant classifications.
“They send a new letter to that physician who ordered the test saying, ‘Here’s an upgrade. Your patient actually has a benign or a pathogenic mutation. Please pass this on to your patient,’” Couch said.
Couch and colleagues would like to see all testing companies use their data and send comprehensive updates on BRCA2 mutations.
Additionally, an expert panel can review the data and make their own recommendations.
“The goal is the data will run through the companies,” Couch said. “They’ll reclassify and send out updates. But also it’ll run through the NIH/ClinGen expert panel, and they’ll post it as an expert panel-approved variant on the ClinVar website, and the information will be available for everybody that way, too.”
More research must be conducted, he added.
Couch and colleagues are evaluating drugs, such as PARP inhibitors, against these pathogenic variants to see if they can influence the response to the drugs.
“Will they respond to the same drugs that the classical BRCA2 mutations do?” he asked.
They also plan to investigate hypomorphs, which create a partial loss of function.
“Right now, if you have a BRCA1 or BRCA2 mutation, we basically tell the patient they have a 70% lifetime risk for breast cancer and about a 15% to 30% lifetime risk for ovarian cancer,” Couch said. “That’s a known pathogenic variant. With these hypomorphs — and we think there’s quite a large number of them out there — they might only be 20% to 30% risk for breast cancer. We have to sort all of that out. Why are they lower risk? Are they really lower risk? What kind of drugs will work for these people?”
Another research group in the United Kingdom plans to evaluate all mutations in the entire BRCA2 gene, Couch said.
“We think most of the pathogenic variants are in this little region that we went after,” Couch said. “We don’t know what ]else] will be found in the rest of the gene. I don’t think it’s going to be a lot of pathogenic mutations per se, but the work still should be done just to check.”
Similar studies can be conducted on other predisposition genes, as well.
“The goal is to understand all variants in all predisposition genes,” Couch said.
For more information:
Fergus J. Couch, PhD, can be reached at couch.fergus@mayo.edu.
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