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Rare Cancers, Rarer Discoveries
MESOTHELIOMA TURKEY
Research in two small villages in the Cappadocia region of Turkey led to one of the most important discoveries in the fight against the rare cancer mesothelioma. Now, one of the lead researchers shares his story.

Sometimes, the most interesting medical discoveries happen by chance. Consider the case of Dr. Michele Carbone, who, in 1996, was asked to give a talk in Turkey and later stumbled upon what would lead to a major medical breakthrough in the understanding of the genetic components leading to mesothelioma.

Carbone’s discoveries, which took him from the Iraqi border to the streets of Louisiana and Wisconsin and everywhere in between, demonstrate the profound importance of faith and financial support in studies catered toward rare cancers. But the path to discovery was not a simple one.

During his visit to Turkey, Carbone heard stories about villages in a remote part of Cappadocia where there was an epidemic of mesothelioma deaths. According to rumors, 50 percent of people died from the debilitating cancer. This intrigued Carbone. “There is no epidemic of cancer in which 50 percent of people died. That never happened,“ Carbone recalls today. “I mean, even with heavy smokers, 10 percent get cancer. Maybe 15 percent. But 50 percent? Never heard of it.”

Upon investigation, Carbone was struck by “the tragedy of the place.” “They were very simple, poor people,” says Carbone. “I mean today, nobody had clothes or things like that. You’re talking about homes where there is no bathroom in the house.” But what was most surprising to Carbone was the discrepancies in who was dying and who was not in the small villages.

“I was told in this house, everybody died of mesothelioma, and in this other one, no one did.”

Researchers and people in the villages believed it was due to excessive amounts of erionite, one of the six fibers typically ascribed to asbestos, its commercial name. Villagers were exposed to asbestos because the terrain naturally contained it. But that still did not explain the high rates of diagnosis and death from mesothelioma. “About 4.65 percent of people working continuously in asbestos mines for 10 years get mesothelioma,” says Carbone. “But there was 50 percent here, and it was only in certain homes. The thing didn’t make sense. That’s a small village. Everybody’s exposed to the same stuff. Everything is asbestos.”

About 4.65 percent of people working continuously in asbestos mines for 10 years get mesothelioma. [...] But there was 50 percent here, and it was only in certain homes. The thing didn’t make sense. That’s a small village. Everybody’s exposed to the same stuff. Everything is asbestos.

Dr. Michele Carbone

Upon returning to America, Carbone decided to dedicate his research to figuring out what was going on, even as his colleagues discouraged him from wasting his time. “They told me you’re going to ruin your career. Who do you think is going to ever care about two villages in the middle of nowhere and give you funds to do that?” Carbone recalls.

But he forged on, spending his vacation time doing research in these villages. And despite the disbelief of those around him, grant money began to pour in, including a $10 million grant in 2006 from the National Cancer Institute to continue his research on finding what he believed to be the genetic marker causing mesothelioma.

Once he began working and publishing about the mesothelioma epidemic in Cappadocia, a number of American families began calling him. Most said what Carbone described was also occurring in their families. Carbone began to visit the families, and when family members had surgeries, he took samples (with their permission) back to his lab to study them. Two families in particular, one in Wisconsin and one in Louisiana, stood out to him. In one family, five cases of mesothelioma occurred within two generations, and in the other, there were seven. Carbone also noticed other cancers in these families—eye melanoma, in particular.

Four years and six months into his research, Carbone still had nothing due to a number of factors, including an insufficient amount of specimens to pin-point exactly where the gene was located. And with only six months remaining in his funding, there was too much genome left that needed to be sequenced.

However, one patient provided a breakthrough. That patient first developed eye melanoma and later developed mesothelioma. “And that was very weird, because there are 2,000 mesotheliomas in the country and 2,000 eye melanomas in the country, which means it is a very rare cancer,” says Carbone. “I went to my biostatician and asked, ‘What’s the chance this happened by chance?’ And he called me back and said it’s a one-in-100-million chance. This was not a coincidence.”

It’s very important to be able to tell someone, ‘Look, you have the bad luck of mesothelioma, but you have the good luck that your mesothelioma is occurring on a background of germline mutation.' [...] There is a good chance that you will be around for much, much longer, and hopefully 20 years from now.

-Dr. Michele Carbone

Refocusing his research on eye melanoma, Carbone found that most people with the disease had deletions in a gene on chromosome 3B. On his list of unfinished genomes to sequence was chromosome 3. Carbone went back to his lab and put his team at the University of Hawai’i at Mānoa to work on 3B. “Either it’s on 3B, or it’s not,” says Carbone. Luckily, Carbone’s theory proved to be true, and they found the gene. A paper on their findings, what is now called the BAP1 cancer syndrome, was published in 2011. Since then, around 677 additional published papers have since referenced his team’s findings.

Eight years later, Carbone’s team continues to make important discoveries in the study of mesothelioma. In 2017, the team pub-lished in the journal Nature about how the BAP1 gene causes cancer. The BAP1 gene regulates the IP3R3 channel inside cells which moves calcium. A mutated or damaged gene causes calcium levels in the cells to decrease, making them “more likely to become malignant when exposed to environmental carcinogens.” According to their research, people who carry mutations on the BAP1 gene are more susceptible to asbestos, sunlight, and other environmental carcinogens. The team also discovered that cancer cells with a BAP1 gene mutation (about 20 percent) are resistant to chemotherapy. Around 70 percent of mesotheliomas, 90 percent of eye melanomas, and 90 percent of renal cell carcinomas contain BAP1 mutations on their tumor cells. “We found that cancer cells become much more responsive to chemotherapy when BAP1 levels are restored and calcium channels are fixed and stabilized,” Carbone told the University of Hawai’i at Mānoa in 2017. “The fixed channel should be able to prevent cancer in people who have inherited BAP1 mutations and to help treat cancers whose tumor cells have developed BAP1 mutations.”

According to research Carbone’s team published in 2018 in the journal Clinical Oncology, despite the increased likelihood for obtaining mesothelioma, people with a germline mutation above one typically have a less aggressive form of the disease. They live, on average, about six years, compared to the typical one-year rate for most mesothelioma cases. About 20 percent can live an additional 15 to 20 years. “It’s very important to be able to tell someone, ‘Look, you have the bad luck of mesothelioma, but you have the good luck that your mesothelioma is occurring on a background of germline mutation,’” says Carbone. “There is a good chance that you will be around for much, much longer, and hopefully 20 years from now.”

These new discoveries have brought a sea change for how we treat cancer, including mesothelioma. While traditional treatments like chemotherapy and new treatments like immunotherapy have not proven to be successful in treating the disease, discoveries like Carbone’s have given other researchers a much better understanding of how mesotheliomas, and other cancers, occur. “Some people get cancer, some people don’t, and that is a combination [of] the type of exposures that you have in the environment. This mix of your own gene background with the environment determines your outcome,” says Carbone. “The BAP1 cancer syndrome is the poster model to study the gene environment interaction.”

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