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New Genetic Variant Discovered to Cause Peritoneal Mesothelioma

NEW YORK (GenomeWeb) – Investigators at Brigham and Women's Hospital (BWH) have discovered a new cause of mesothelioma linked to a rearrangement in the anaplastic lymphoma kinase (ALK) gene. Unlike previously known causes, this discovery signals potential therapeutic procedures for patients whose tumors harbor the genetic mutation.

The team's findings, published today in JAMA Oncology, examined 88 consecutive patients with malignant peritoneal mesothelioma who had been diagnosed at a single institution between 2005 and 2015. They also explored ALK rearrangement in a separate series of 205 patients with pleural mesothelioma.

The ALK gene is crucial during embryonic development of the nervous system, but the gene normally shuts down as a patient gets older. Previous studies of genetic rearrangements in lymphoma and lung cancer have found that certain genetic mutations can inadvertently switch on ALK, causing cancer cells to grow and divide.

Mesothelioma occurs in 3,000 new cases every year in the US. Only about 300 of those are peritoneal mesothelioma, which develop in the lining of the patient's abdomen. In rare cases, young patients who have never been exposed to either radiation therapy or asbestos develop the disease. Principal investigator Lucian Chirieac and his colleagues initially stumbled upon the predicament while attempting to treat a patient at BWH.

"We had a young patient with peritoneal mesothelioma that was difficult to diagnose," first author Yin Hung said in a statement. "We extended our molecular diagnostics to test for a genetic rearrangement that had been reported in lymphoma and lung cancer, but never in mesothelioma. When it came back positive, we were intrigued."

Identifying ALK-positive mesothelioma by immunohistochemistry, the team confirmed the tumor with FISH testing. They performed targeted next-generation sequencing of DNA and RNA to identify ALK fusion partners, allowing the researchers to map out the exact genetic rearrangement underlying the disease.

The team identified ALK rearrangements in 3 percent of cases. In contrast, all patients with pleural mesotheliomas were ALK-negative. The three positive cases involved young women that lacked asbestos fibers, had no history of therapeutic radiation, and lacked the typical cytogenetic and molecular abnormalities usually present in peritoneal mesothelioma.

The FDA has approved several ALK inhibitors for treating non-small cell lung cancer. Targeting ALK with therapeutic drugs can turn the gene off, temporarily inhibiting cancer progression without damaging healthy cells. And while the costs of targeted therapy remain high, the costs of diagnostic testing for the genetic rearrangements are relatively inexpensive, the researchers noted.

Chirieac and his colleagues aim to extend their study of ALK-positive mesotheliomas in a global patient population.

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