New Discovery: How and Why BAP1 Mutation Increases Susceptibility to Environmental Carcinogens

Michele Carbone and Haining Yang

Michele Carbone, MD, PhD, Director of Thoracic Oncology at the University of Hawaii (UH) Cancer Center, along with his team, have discovered why people carrying mutations of the BAP1 gene are more susceptible to environmental carcinogens, including asbestos, radiation, and ultraviolet light.

BAP1 mutations are seen in approximately 20 percent of all cancers, and Dr. Carbone and his team found that in such cases, cancer cells are resistant to chemotherapy.

They discovered that the BAP1 gene regulates a channel (called IP3R3) inside the cell that moves calcium. When a BAP1 mutation is present, calcium levels inside the cells decrease, making it more likely that the cells will become malignant when exposed to environmental carcinogens.

BAP1 mutations make up tumor cells of 70 percent of mesotheliomas. There are two types of BAP1 mutations: germline and somatic. A germline BAP1 mutation is inherited, meaning a person is born with it, and thought to be extremely rare. A somatic BAP1 mutation can occur spontaneously, such as when BAP1 is damaged as the cell becomes cancerous. Somatic BAP1 mutations are the type that are resistant to chemotherapy, and it is this type of mutation to which these new findings apply.

The team found that fixing and stabilizing the calcium channels and restoring BAP1 levels will make the cancer cells more responsive to chemotherapy. “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,” said Dr. Carbone.

The findings by Dr. Carbone and his team at UH Cancer Center have been published in Nature, a premier scientific journal.

“I came to Hawaii all the way from Italy and I achieved my dreams. I very much hope that our discovery will help save many lives,” said Angela Bononi, co-author and post-doctoral fellow in Dr. Carbone’s lab.

On the significance of the findings, Dr. Carbone stated, “We want to prevent and treat cancer in as many people as possible. We hope to start a clinical trial, within five years or less, to test the susceptibility to chemotherapy in patients with BAP1 mutated tumors.”

Dr. Michele Carbone is a past recipient of the Meso Foundation’s Pioneer Award for his achievements in mesothelioma research, including his role in the discovery of the BAP1 gene mutation in mesothelioma.

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