Anaplastic Lymphoma Kinase Gene Rearrangement in Children and Young Adults With Mesothelioma

Abstract

Introduction: Children and young adults diagnosed with malignant mesothelioma may have unique genetic characteristics. In this study, we evaluated for the presence of the anaplastic lymphoma kinase (ALK) translocations in these patients.

Methods: In a prospective study of mesothelioma natural history (ClinicalTrials.gov number NCT01950572), we assessed for the presence of the ALK translocation in patients younger than 40 years, irrespective of the site of disease. The presence of this translocation was assessed by means of fluorescence in situ hybridization (FISH). If the patients tested positive for the ALK translocation, both immunohistochemistry and RNA sequencing were performed on the tumor specimen.

Results: Between September 2013 and December 2018, 373 patients were enrolled in the mesothelioma natural history study, of which 32 patients were 40 years old or younger at the time of their mesothelioma diagnosis. There were 25 patients with peritoneal mesothelioma, five with pleural mesothelioma, one with pericardial mesothelioma, and one with bicompartmental mesothelioma. Presence of an ALK translocation by FISH was seen in two of the 32 patients (6%) with mesothelioma. Both patients, a 14-year-old female and a 27-year-old male, had peritoneal mesothelioma and had no history of asbestos exposure, prior radiation therapy, or predisposing germline mutations. Neither had detectable ALK expression by immunohistochemistry. RNA sequencing revealed the presence of an STRN fusion partner in the female patient but failed to identify any fusion protein in the male patient.

Conclusions: Young patients with peritoneal mesothelioma should be evaluated for the presence of ALK translocations. Presence of this translocation should be assessed by FISH and these patients could potentially benefit from tyrosine kinase inhibitors targeting ALK.

Keywords: ALK mutation; FISH testing; Mesothelioma; Peritoneal mesothelioma; Targeted therapy; Young patients.

Published by Elsevier Inc.

Figures

Figure 1.

Pathological Analysis of Patient Tumor Samples. A and B) H&E (Haemotoxylin and Eosin) of the FFPE samples for our patients. 1A) Histologic exam at 10x revealing Epithelioid mesothelioma with features of well differentiated papillary mesothelioma in our 14 year old peritoneal mesothelioma patient. 1B) Histologic exam at 20x revealing Epithelioid mesothelioma with a solid pattern in our 27 year old peritoneal mesothelioma patient. C and D) FISH Analysis of the FFPE samples using signal patterns of ALK split-apart probes. The commonly used ALK split-apart FISH test uses dual color labelled probes covering the ALK gene (green) and 3’ flanking region of ALK (red). When translocation occurs, the normal closely signal pattern, which appears yellow, separates into distinct green and red signals. 1C) FISH staining showing positivity of the ALK translocation in 100% of nuclei in our 14 year old peritoneal mesothelioma patient. 1D) FISH staining showing positivity of the ALK translocation in 33% of nuclei in our 27 year old peritoneal mesothelioma patient.

Figure 2.

Peritoneal Mesothelioma with ALK-STRN Fusion mapping breakpoint to exon 3 of STRN and Intron 19 of ALK. The resulting fusion protein contains domains for the Striatin protein and the kinase domain for ALK.