Genetic Cause of Peritoneal Mesothelioma Discovered

Mesothelioma is a rare and aggressive tumor that, in many cases, results from exposure to asbestos, but other causes of the disease have emerged, including treatment with high-intensity therapeutic radiation and, more recently, an inherited genetic mutation.

There are about 3,000 new cases of mesothelioma each year in the USA, and only about 300 of those are peritoneal mesothelioma, which forms in the lining of the abdomen. Most cases of mesothelioma result decades after exposure to asbestos or radiation therapy. In rare cases, young patients who have never been exposed to either risk factor are diagnosed with the disease.


Scientists at Brigham and Women's Hospital (Boston, MA, USA) and their collaborators studied 88 consecutive patients (39 men, 49 women; median age 61, range 17-84 years) with peritoneal mesotheliomas diagnosed at a single institution between 2005 and 2015. They identified anaplastic lymphoma kinase (ALK)-positive mesotheliomas by immunohistochemistry; confirmed with fluorescence in situ hybridization; and performed targeted next-generation sequencing of tumor DNA and RNA to get a full picture of the exact genetic rearrangement underpinning the disease.

The investigators reported that anaplastic lymphoma kinase was positive by immunohistochemistry in 11 (13%) peritoneal mesotheliomas (focal weak in 8, diffuse strong in 3). In focal weak ALK-positive cases, no ALK rearrangement was detected by FISH or next-generation sequencing. In strong diffuse ALK-positive cases, FISH confirmed ALK rearrangements, and next-generation sequencing identified novel fusion partners ATG16L1, STRN, and TPM1. Patients with ALK-rearranged peritoneal mesotheliomas were women and younger than patients without ALK rearrangement (median age 36 versus 62), but all other clinicopathologic characteristics such as size of tumor nodules, histology, treatment, and survival were not different. No asbestos fibers were detected in ALK-rearranged cases.

The authors concluded that they have identified unique ALK rearrangements in a subset of patients with peritoneal mesothelioma, each lacking asbestos fibers, therapeutic radiation, and cytogenetic and molecular alterations typically found in these tumors. Identification of clinically actionable ALK rearrangements may represent a novel pathogenetic mechanism of malignant peritoneal mesothelioma with promise for targeted therapy.

Lucian R. Chirieac, MD, a thoracic oncology pathologist and senior author of the study, said, “Mesothelioma is highly lethal and has no cure. Often, it is not diagnosed until at a late stage, when many tumors have already formed. Although this mutation only exists in a small percentage of cases, this discovery points to a potential therapeutic avenue for these patients." The study was published on September 14, 2017, in the journal JAMA Oncology.

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