title: Hippo pathway gene mutations in malignant mesothelioma: revealed by RNA and targeted exon sequencing.
abstract: BACKGROUND
  Malignant mesothelioma (MM) is an aggressive neoplasm causatively associated with exposure to asbestos. MM is rarely responsive to conventional cytotoxic drugs, and the outcome remains dismal. It is, therefore, necessary to identify the signaling pathways that drive MM and to develop new therapeutics specifically targeting the molecules involved.
  
  
  METHODS
  We performed comprehensive RNA sequencing of 12 MM cell lines and four clinical samples using so-called next-generation sequencers.
  
  
  RESULTS
  We found 15 novel fusion transcripts including one derived from chromosomal translocation between the large tumor suppressor 1 (LATS1) and presenilin-1 (PSEN1) genes. LATS1 is one of the central players of the emerging Hippo signaling pathway. The LATS1-PSEN1 fusion gene product lacked the ability to phosphorylate yes-associated protein and to suppress the growth of a MM cell line. The wild-type LATS1 allele was undetectable in this cell line, indicating two-hit genetic inactivation of its tumor suppressor function. Using pathway-targeted exon sequencing, we further identified a total of 11 somatic mutations in four Hippo pathway genes (neurofibromatosis type 2 [NF2], LATS2, RASSF1, and SAV1) in 35% (8 of 23) of clinical samples. Nuclear staining of yes-associated protein was detected in 55% (24 of 44) of the clinical samples. Expression and/or phosphorylation of the Hippo signaling proteins, RASSF1, Merlin (NF2), LATS1, and LATS2, was frequently absent.
  
  
  CONCLUSIONS
  The frequent alterations of Hippo pathway molecules found in this study indicate the therapeutic feasibility of targeting this pathway in patients with MM.
authors.affiliation: Division of Chemotherapy and Clinical Research, National Cancer Center Research Institute, Tokyo, Japan; Department of Pulmonary Medicine and Oncology, Graduate School of Medicine, Nippon Medical School, Tokyo, Japan.
authors.forename: Akihiko
authors.initials: A
authors.lastname: Miyanaga
authors.affiliation: Division of Chemotherapy and Clinical Research, National Cancer Center Research Institute, Tokyo, Japan.
authors.forename: Mari
authors.initials: M
authors.lastname: Masuda
authors.affiliation: Division of Pathology and Clinical Laboratories, National Cancer Center Hospital, Tokyo, Japan.
authors.forename: Koji
authors.initials: K
authors.lastname: Tsuta
authors.affiliation: BioBusiness Group, Mitsui Knowledge Industry, Tokyo, Japan.
authors.forename: Kumiko
authors.initials: K
authors.lastname: Kawasaki
authors.affiliation: Division of Chemotherapy and Clinical Research, National Cancer Center Research Institute, Tokyo, Japan.
authors.forename: Yuka
authors.initials: Y
authors.lastname: Nakamura
authors.affiliation: BioBusiness Group, Mitsui Knowledge Industry, Tokyo, Japan.
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Sakuma
authors.affiliation: Division of Thoracic Surgery, National Cancer Center Hospital, Tokyo, Japan.
authors.forename: Hisao
authors.initials: H
authors.lastname: Asamura
authors.affiliation: Department of Pulmonary Medicine and Oncology, Graduate School of Medicine, Nippon Medical School, Tokyo, Japan.
authors.forename: Akihiko
authors.initials: A
authors.lastname: Gemma
authors.affiliation: Division of Chemotherapy and Clinical Research, National Cancer Center Research Institute, Tokyo, Japan. Electronic address: tyamada@ncc.go.jp.
authors.forename: Tesshi
authors.initials: T
authors.lastname: Yamada
mesh_terms: D000217:Acyltransferases; D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D051017:Apoptosis Regulatory Proteins; D015820:Cadherins / Q000235:genetics; D018797:Cell Cycle Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D059472:Exome; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D008654:Mesothelioma / Q000235:genetics* / Q000378:metabolism; D020559:Monomeric GTP-Binding Proteins / Q000235:genetics; D009154:Mutation; D025581:Neurofibromin 2 / Q000235:genetics / Q000378:metabolism; D015514:Oncogene Proteins, Fusion / Q000235:genetics*; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism; D053764:Presenilin-1 / Q000235:genetics*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000235:genetics; D017422:Sequence Analysis, DNA; D017423:Sequence Analysis, RNA; D015398:Signal Transduction / Q000235:genetics*; D014157:Transcription Factors / Q000378:metabolism; D059467:Transcriptome; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism; D000091102:YAP-Signaling Proteins
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D051017:Apoptosis Regulatory Proteins; D015820:Cadherins; D018797:Cell Cycle Proteins; C502403:FAT1 protein, human; C502404:FAT2 protein, human; D047908:Intracellular Signaling Peptides and Proteins; C000605934:LATS1-PSEN1 fusion protein, human; D025581:Neurofibromin 2; D015514:Oncogene Proteins, Fusion; C508853:PSEN1 protein, human; D010750:Phosphoproteins; D053764:Presenilin-1; C411762:RASSF1 protein, human; C425300:RASSF2 protein, human; C519911:RASSF6 protein, human; D011993:Recombinant Fusion Proteins; C415864:SAV1 protein, human; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; C513637:WWC1 protein, human; D000091102:YAP-Signaling Proteins; C088374:YAP1 protein, human; D000217:Acyltransferases; C108675:TAFAZZIN protein, human; C092745:LATS1 protein, human; C406449:LATS2 protein, human; D017346:Protein Serine-Threonine Kinases; D020559:Monomeric GTP-Binding Proteins