PMID- 28910456 OWN - NLM STAT- MEDLINE DCOM- 20190905 LR - 20220311 IS - 2374-2445 (Electronic) IS - 2374-2437 (Print) IS - 2374-2437 (Linking) VI - 4 IP - 2 DP - 2018 Feb 1 TI - Identification of ALK Rearrangements in Malignant Peritoneal Mesothelioma. PG - 235-238 LID - 10.1001/jamaoncol.2017.2918 [doi] AB - 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. FAU - Hung, Yin P AU - Hung YP AD - Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston. FAU - Dong, Fei AU - Dong F AD - Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston. FAU - Watkins, Jaclyn C AU - Watkins JC AD - Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston. FAU - Nardi, Valentina AU - Nardi V AD - Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston. FAU - Bueno, Raphael AU - Bueno R AD - Department of Surgery, Brigham and Women's Hospital and Harvard Medical School, Boston. FAU - Dal Cin, Paola AU - Dal Cin P AD - Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston. FAU - Godleski, John J AU - Godleski JJ AD - Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston. FAU - Crum, Christopher P AU - Crum CP AD - Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston. FAU - Chirieac, Lucian R AU - Chirieac LR AD - Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston. LA - eng PT - Journal Article PL - United States TA - JAMA Oncol JT - JAMA oncology JID - 101652861 RN - 0 (Oncogene Proteins, Fusion) RN - EC 2.7.10.1 (ALK protein, human) RN - EC 2.7.10.1 (Anaplastic Lymphoma Kinase) SB - IM CIN - JAMA Oncol. 2018 Jul 1;4(7):1011-1012. PMID: 29710106 CIN - JAMA Oncol. 2018 Jul 1;4(7):1011. PMID: 29710343 MH - Adolescent MH - Adult MH - Aged MH - Aged, 80 and over MH - Anaplastic Lymphoma Kinase/*genetics/metabolism MH - DNA Mutational Analysis/methods MH - Female MH - High-Throughput Nucleotide Sequencing MH - Humans MH - Immunohistochemistry MH - In Situ Hybridization, Fluorescence MH - Lung Neoplasms/*genetics/metabolism MH - Male MH - Mesothelioma/*genetics/metabolism MH - Mesothelioma, Malignant MH - Middle Aged MH - *Mutation MH - Oncogene Proteins, Fusion/genetics MH - Peritoneal Neoplasms/*genetics/metabolism MH - *Translocation, Genetic/genetics MH - Young Adult PMC - PMC5838580 COIS- Conflict of Interest Disclosures: Dr Chirieac, served on the Advisory board for Merck Sharp & Dohme and undertakes medicolegal work related to mesothelioma and lung cancer. Dr Bueno receives support from the National Cancer Institute, Verastem, Genentech-Roche, and Castle Biosciences via research grants to Brigham and Women's Hospital. The financial disclosures do not apply to the current study, which is not associated with a specific source of funding. EDAT- 2017/09/15 06:00 MHDA- 2019/09/07 06:00 PMCR- 2018/09/14 CRDT- 2017/09/15 06:00 PHST- 2017/09/15 06:00 [pubmed] PHST- 2019/09/07 06:00 [medline] PHST- 2017/09/15 06:00 [entrez] PHST- 2018/09/14 00:00 [pmc-release] AID - 2653897 [pii] AID - cbr170019 [pii] AID - 10.1001/jamaoncol.2017.2918 [doi] PST - ppublish SO - JAMA Oncol. 2018 Feb 1;4(2):235-238. doi: 10.1001/jamaoncol.2017.2918.