Identification of ALK Rearrangements in Malignant Peritoneal Mesothelioma

Our plain-English summary of Identification of ALK Rearrangements in Malignant Peritoneal Mesothelioma, by Y.P. Hung, F. Dong, J.C. Watkins, et al (JAMA Oncology, 2018).

The study

• Authors: Y.P. Hung, F. Dong, J.C. Watkins, V. Nardi, R. Bueno, P. Dal Cin, J.J. Godleski, C.P. Crum, L.R. Chirieac
• Journal: JAMA Oncology
• Published: 2018;4(2):235-238
• Cited by: 105 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

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.

In plain English

This brief report from Brigham and Women's Hospital in Boston looked for rearrangements of a gene called ALK in 88 consecutive patients with malignant peritoneal mesothelioma diagnosed between 2005 and 2015. The authors stained tumor tissue for the ALK protein, confirmed rearrangements with a genetic test, and sequenced tumor DNA and RNA. In select cases they measured asbestos fibers by electron microscopy and x-ray spectroscopy. Eleven tumors (13%) stained positive for ALK. Three of 88 patients (3%) had an ALK rearrangement, including 2 of 8 women under 40. All three were women, and they were younger than patients without the rearrangement (median age 36 vs 62). No asbestos fibers were detected in these three cases, and they lacked the genetic changes typically seen in peritoneal mesothelioma. Overall survival did not differ significantly between patients with and without the rearrangement, though only three had it. All 205 pleural mesotheliomas tested were ALK-negative. The authors concluded that ALK rearrangements may represent a new mechanism behind some peritoneal mesotheliomas, with promise for targeted therapy. They noted that the small number of cases limited comparisons and that larger studies are needed.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Single-institution study of consecutive archived cases (molecular pathology case series), published as a brief report
• Who was studied: 88 consecutive patients with peritoneal mesothelioma (39 men, 49 women; median age 61, range 17 to 84) diagnosed at Brigham and Women's Hospital, Boston, 2005 to 2015; plus a separate series of 205 patients with pleural mesothelioma
• Exposure: Not an exposure study. Asbestos fibers were measured in select cases by combined scanning electron microscopy and x-ray spectroscopy. The text does not give fiber types or the number of cases tested.
• Main results:
  • ALK protein staining was positive in 11 (13%) of the 88 peritoneal mesotheliomas: focal weak in 8 and diffuse strong in 3.
  • No ALK rearrangement was found in the focal weak ALK-positive peritoneal cases.
  • ALK rearrangements were found in 3 of 88 (3%) peritoneal mesothelioma patients, including 2 of 8 (25%) women under 40.
  • Sequencing identified the ALK fusion partners ATG16L1, STRN and TPM1, one in each rearranged case.
  • Patients with ALK-rearranged peritoneal mesothelioma were women and younger than patients without ALK rearrangement (median age 36 vs 62; P = .02).
  • No asbestos fibers were detected in the ALK-rearranged peritoneal cases.
  • The ALK-rearranged cases lacked the loss of chromosomal region 9p or 22q and the BAP1, SETD2 and NF2 alterations typically present in peritoneal mesothelioma.
  • Overall survival did not differ significantly between peritoneal mesothelioma patients with and without ALK rearrangement (present vs absent: HR 0.5; 95% CI 0.1 to 1.8; P = .29). Only 3 patients had the rearrangement.
  • Patients with weak focal ALK expression had shorter overall survival than those with absent or diffuse strong expression (median survival 4.8, 38.4 and 79.2 months respectively; 3-way analysis, P = .03).
  • All 205 pleural mesotheliomas were ALK-negative on staining.
• The authors' conclusion: The authors concluded that clinically actionable ALK rearrangements may represent a new pathogenetic mechanism of malignant peritoneal mesothelioma, with promise for targeted therapy.
• Limitations the authors state:
  • The small number of ALK-rearranged cases prevented definitive comparison of clinical and pathologic characteristics.
  • Larger multi-institutional prospective studies are needed to confirm the correlative findings and to test ALK-targeted therapy.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Lung cancer, Mesothelioma, Peritoneal mesothelioma.

Medical terms in this study, explained in our Lexicon: Peritoneal Mesothelioma, Germline Mutation, Mesothelioma, Immunohistochemistry, Fluorescence In Situ Hybridization (FISH), Next-Generation Sequencing (NGS), Scanning Electron Microscopy (SEM), Pleural Mesothelioma.

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