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Brief Report
September 14, 2017

Identification of ALK Rearrangements in Malignant Peritoneal Mesothelioma

Author Affiliations
  • 1Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston
  • 2Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston
  • 3Department of Surgery, Brigham and Women's Hospital and Harvard Medical School, Boston
JAMA Oncol. Published online September 14, 2017. doi:10.1001/jamaoncol.2017.2918
Key Points

Question  Is malignant peritoneal mesothelioma associated with anaplastic lymphoma kinase (ALK) rearrangements?

Findings  In a large series of 88 consecutive patients with peritoneal mesothelioma, we identified ALK rearrangements in 3% of cases that (1) present in young women (25% of women younger than 40 years), (2) lack asbestos fibers, (3) have no history of therapeutic radiation, and (4) lack the typical cytogenetic and molecular abnormalities usually present in peritoneal mesothelioma.

Meaning  Identification of clinically actionable ALK rearrangements reveals a novel pathogenetic mechanism of malignant peritoneal mesothelioma with promise for targeted therapy.

Abstract

Importance  Malignant peritoneal mesothelioma is a rare, aggressive tumor arising from the peritoneal lining, induced by asbestos, therapeutic radiation, or germline mutations. Nevertheless, the molecular features remain largely unknown.

Objective  To investigate anaplastic lymphoma kinase (ALK) rearrangements in a large series of peritoneal mesothelioma and characterize the mutational landscape of these tumors.

Design, Setting, and Participants  We 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. We identified ALK-positive mesotheliomas by immunohistochemistry and confirmed ALK rearrangement by fluorescence in situ hybridization (FISH). In ALK-rearranged cases, we characterized the fusion partners using targeted next-generation sequencing of both tumor DNA and RNA. In select cases, we quantified asbestos fibers by combined scanning electron microscopy and x-ray spectroscopy. We also explored ALK rearrangement in a separate series of 205 patients with pleural mesothelioma.

Main Outcomes and Measures  Identification and characterization of novel ALK rearrangements and correlations with clinicopathologic characteristics.

Results  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 vs 62; Mann-Whitney test, P = .02), but all other clinicopathologic characteristics (size of tumor nodules, histology, treatment, and survival) were not different. No asbestos fibers were detected in ALK-rearranged cases. Furthermore, loss of chromosomal region 9p or 22q or genetic alterations in BAP1, SETD2, or NF2 typically present in peritoneal mesothelioma were absent in the ALK-rearranged cases. All pleural mesotheliomas were ALK-negative by immunohistochemistry.

Conclusions and Relevance  We 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.

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