Weixing Zhao, PhD, assistant professor of Biochemistry and Structural Biology, at The University of Texas Health Science Center at San Antonio, talks about the BRCA1 gene.
Interview conducted by Ivanhoe Broadcast News in 2024.
What would you want the audience to know about this discovery?
Zhao: This question has puzzled the field for almost three decades. Specifically, we wanted to understand how and why BRCA1 has a unique function known as E3 ligase activity, which attaches a small molecule called ubiquitin to target proteins. This activity is unique to BRCA1 and not found in BRCA2, another important tumor suppressor gene. A first task for us is to establish whether this activity is important for tumor suppression and genome stability. Through our research, we discovered an E3 ligase dead mutant of BRCA1, which helps us demonstrate the critical role of this E3 activity in maintaining genomic stability.
Is it correct to say that you’re recreating the environment where it begins to go bad within the lab? How do you test it under these circumstances?
Zhao: Yes, we created both defective and active versions of BRCA1 and compared their outcomes in cells. This allows us to understand the function of the wild-type protein. For instance, a defective mutant cannot repair DNA breaks efficiently, highlighting the importance of BRCA1 in maintaining genomic stability.
How does what happens in the lab translate to real-life applications, particularly for women who may undergo mastectomies due to BRCA1 mutations?
Zhao: Nowadays, people can sequence their genes, including BRCA1, to detect mutations. If a mutation’s impact is unknown, our research can help determine if it affects BRCA1’s function. If a mutation is harmful, it may indicate a higher risk for cancer. Conversely, if a mutation does not affect BRCA1 function, preventive surgeries like mastectomies might not be necessary. Our findings can guide clinical decisions and treatments.
How will the gene be identified in a woman to prevent unnecessary mastectomies?
Zhao: Genetic sequencing can be done at any stage of life. By analyzing the sequence, we can identify mutations and test their impact in the lab. This information can help determine if a mutation is harmful or benign, guiding decisions about preventive measures.
What is the timeline for this research to impact clinical practices?
Zhao: Not sure, however, the information from our study can be used for clinical research. Depending on the speed of clinical research, it might take a few year for our research to impact clinical practices.
What FDA approvals are needed for this research to be used in clinical settings?
Zhao: Our research provides pre-clinical data that needs to be validated in clinical trials. If clinical trials support our findings, the data can be incorporated into treatment protocols and approved by the FDA for use in clinical settings.
How does AI intersect with your research?
Zhao: AI can learn from our data and predict the impact of new BRCA1 mutations. This predictive model can help evaluate the risk associated with specific mutations, aiding in treatment and prevention strategies.
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Zhao: Based on the data we produced and data from other groups, in combination with AI, we can provide more precise information for patient consultations. For instance, when people have their genomes sequenced, powerful AI tools, combined with this data, can help determine a patient’s health status within a few weeks or months. This can reassure patients who are mostly healthy and potentially avoid unnecessary preventive surgeries. For those who do have health issues, the AI can provide more accurate assessments, guiding better treatment decisions.
And you said there’s different degrees even if you have the BRCA gene mutation, and it doesn’t necessarily mean that you’re going to develop cancer, right?
Zhao: Yeah. Not all BRCA1/2 gene mutations will cause high risk of cancer development. The whole specturem of understanding BRCA1/2 and its mutation variants can help in making informed decisions about preventive measures and treatments.
So what you’re saying is, rather than just having a blanket percentage odds, that’s going to cause somebody to have a mastectomy. Eventually, the AI and your pre-clinical data and clinical data, is going to combine as a predictive model.
Zhao: Yes.
Can you describe that?
Zhao: Certainly. The data produced from basic research labs like ours, clinical labs, and family history of patients will all be combined. When enough patient mutants are studied, this information, combined with AI predictions, will form a powerful database. This database can evaluate new mutations discovered in new patients, determining if they pose a high, low, or intermediate risk. Based on this information, we can better guide patient treatment and prevention strategies. This will be a very powerful tool.
How did you get involved in this? What led you to this research?
Zhao: My interest in cancer research began after my father was diagnosed with cancer. I shifted my focus from photosynthesis to DNA repair, a crucial area in cancer etiology and treatment. During my postdoctoral work at Yale University, I began studying BRCA1 and BRCA2, key proteins in DNA repair.
So the mutation that you’re going to impact is a mutant protein. Is that what you would call it, not a mutant allele, but a mutant protein?
Zhao: The protein is produced by DNA. The mutation happens at the DNA level, which then translates to the protein. When this mutation occurs, the protein can no longer function properly. Normally, this BRCA1 protein acts as a tumor suppressor, preventing tumor formation. However, when it becomes defective, it can no longer suppress tumors, leading to the development of cancer.
And the end result of this is going to be a predictive test, gathering of data. It’s not going to be popping a pill, it’s going to be testing data from the patient, right?
Zhao: Yes, the primary focus will be on testing data from the patient. This information will be powerful for evaluation and classification of mutations. Additionally, this activity will help determine whether we can use this system to develop new drugs. Tumor suppression involves preventing tumor formation, but when cancer cells gain some abnormal functions for robust cell growth, it can lead to drug resistance. If we can find a way to inhibit the critical functions that lead to this resistance, it would be fantastic. However, this is a long-term goal, and we are still in the early stages. It may take 10 years to develop these new tools and drugs. Our current information is for evaluation and classification, helping physicians and patients make informed decisions about treatment and prevention.
What is the end goal of your research?
Zhao: Our goal is to produce data that can be used to evaluate and classify BRCA1 mutations, helping physicians and patients make informed decisions about treatment and prevention. In the long term, we also hope to develop new drugs to counteract drug resistance in cancer treatment.
END OF INTERVIEW
This information is intended for additional research purposes only. It is not to be used as a prescription or advice from Ivanhoe Broadcast News, Inc. or any medical professional interviewed. Ivanhoe Broadcast News, Inc. assumes no responsibility for the depth or accuracy of physician statements. Procedures or medicines apply to different people and medical factors; always consult your physician on medical matters.
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