Understanding Mesothelioma Genetics and the Potential for Early Diagnosis

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• Genetic Landscape of Mesothelioma
• Common Genetic Mutations in Mesothelioma
• BAP1 Cancer Syndrome and Risk
• Importance of Mutation Order
• Challenges in Early Detection
• Future Preventive Strategies
• Full Transcript

Genetic Landscape of Mesothelioma

Dr. Dean Fennell, MD, provides a comprehensive overview of the genetic landscape of mesothelioma. He explains that recent years have brought a better understanding of this cancer's unique molecular signature. Mesothelioma is characterized by a relatively small number of mutations that are very commonly altered. This genetic profile distinguishes it from many other cancer types. Dr. Dean Fennell, MD, emphasizes that this knowledge forms the foundation for all current and future research into targeted therapies and early detection methods.

Common Genetic Mutations in Mesothelioma

Dr. Dean Fennell, MD, identifies three primary genetic alterations found in the vast majority of mesothelioma patients. The first involves the gene BAP-1 (BRCA-associated protein). The second common alteration is a copy number change involving the deletion of CDKN2A and MTAP genes. The third major alteration affects NF2, a member of the Hippo pathway. These three genetic changes represent the core molecular signature of mesothelioma. Understanding these mutations is crucial for developing targeted treatment approaches.

BAP1 Cancer Syndrome and Risk

Dr. Dean Fennell, MD, discusses the important work of Dr. Michele Carbone in identifying BAP1 cancer syndrome. A germline mutation of BAP-1, first shown in 2011, increases mesothelioma risk. This syndrome is associated not only with mesothelioma but also with uveal melanomas and renal cancer. Dr. Fennell clarifies that this affects a very rare patient population. Most mesotheliomas occur sporadically through asbestos exposure. However, having a germline BAP-1 mutation significantly increases the chance of developing mesothelioma if exposed to asbestos.

Importance of Mutation Order

Dr. Dean Fennell, MD, highlights a critical area of ongoing research: the order of mutations in mesothelioma development. Understanding the sequence of genetic changes is essential for designing effective treatments. Researchers are working to identify the very first mutations that occur in mesothelioma formation. This knowledge would help capture the cancer's vulnerabilities that emerge early during development. Dr. Fennell's work focuses on determining these initial mutations to create more targeted therapeutic approaches.

Challenges in Early Detection

Dr. Dean Fennell, MD, addresses the significant challenges in early mesothelioma detection. In a small study, circulating free DNA was not widely detectable in mesothelioma patients. This makes the prospect of a blood test based on genetic markers more challenging for this cancer. Dr. Fennell mentions research on HMGB1 as a potential early marker from Dr. Michele Carbone's group. However, he concludes that currently, no reliable method exists for early mesothelioma tumor detection. This limitation prevents effective preventive intervention at present.

Future Preventive Strategies

Dr. Dean Fennell, MD, emphasizes that early detection and prevention are key to dealing with mesothelioma. He believes the field is reaching a point where searching for mesothelioma might become possible. The improved understanding of genomic underpinnings provides a foundation for future screening methods. Dr. Fennell acknowledges that while circulating DNA tests show promise for other cancers, mesothelioma presents unique challenges. The interview with Dr. Anton Titov, MD, concludes that despite current limitations, research continues toward developing effective preventive strategies for high-risk populations.

Full Transcript

Dr. Anton Titov, MD: Let's talk about the genetics of mesothelioma. What is the unique molecular signature of mesothelioma? We know that mesothelioma has a long pre-malignant state. Is that an opportunity for perhaps some form of molecular or imaging screening for people at risk for mesothelioma? Or is it not practically feasible?

Dr. Dean Fennell, MD: So again, excellent question. The last few years have allowed us to get a better understanding of the genetic landscape of this cancer. There are a number of things about mesothelioma that make it quite unique, actually, amongst some cancers. In that, we see a relatively small number of mutations which are very commonly altered.

These include things like the gene BAP-1 or BRCA-associated protein. We see a common mutation or copy number alteration involving the deletion of a gene called CDKN2A and MTAP. And we see NF2, a member of another group of genes, and a common pathway called the Hippo pathway had been altered. So these three alterations are seen in the vast majority of patients with mesothelioma.

Now, in terms of predisposition to mesothelioma, back in 2011, it was shown that the mutation of BAP-1 in the germline increases risk. This is work from Dr. Michele Carbone, who has made a huge contribution to this area of understanding the transmission of mutations in the germline for BAP-1. This can indeed be associated with what we call BAP-1 cancer syndrome, associated not only with mesothelioma but uveal melanomas in the eye, for example.

Another cancer, renal cancer, can be more common with BAP-1 mutations. But this affects a very rare group of patients. This is not universal in mesothelioma. Most mesotheliomas occur sporadically through exposure to asbestos.

But we believe now, based on good evidence, that having a germline mutation increases the chance of getting mesothelioma if exposed to asbestos. So I think the main challenge really around our understanding of genetics is not just the genes present in mature mesothelioma.

But it is important what the order of mutation was that led to the mesothelioma forming. And this is something that we've been working on trying to understand whether there is such a thing as a mutation order. We are really trying to work out what those very first mutations in mesothelioma might be, in order for us to be able to design treatments that are most likely to capture these cancer's vulnerabilities that emerge early during the development of cancer.

Dr. Anton Titov, MD: So mesothelioma is deadly cancer diagnosed at late stages. What was applied to other cancers are screening programs, vaccinations, of course, for cancers like HPV. Do you see a more preventive or early diagnosis strategies applied to mesothelioma in any foreseeable future?

Dr. Dean Fennell, MD: Well, absolutely. I think with all cancers, early detection, and, if possible, early prevention is the key to dealing with this cancer. I think we are just at the point now where certainly the idea of searching for mesothelioma might become possible because now we have a good understanding of what the genomic underpinnings of this cancer are.

In a small study, which we have done, we have not been able to see circulating free DNA occurring widely within this population of mesothelioma patients. And therefore, the idea of a wonderful blood test that could pick up genetics of mesothelioma on circulating free DNA may be more challenging for this particular cancer.

We have heard about certain factors, HMGB1, for example. It was from again a work from Dr. Michele Carbone group in Hawaii. That may suggest that HMGB1 is a very early marker of mesothelioma. HMGB1 could be detected early in this population of patients.

But as we are at present, we simply don't have any way of being able to detect mesothelioma tumors early on. We cannot, therefore, intervene with a preventative strategy.