title: Immunohistochemical detection of MTAP and BAP1 protein loss for mesothelioma diagnosis: Comparison with 9p21 FISH and BAP1 immunohistochemistry.
abstract: Differentiating malignant pleural mesothelioma (MPM) from reactive mesothelial hyperplasia (RMH) is still challenging. Detection of homozygous deletion (HD) of 9p21 region including p16INK4A(p16) by fluorescence in situ hybridization (FISH) and immunohistochemical detection of loss of BRCA1 associated protein 1 (BAP1), are reliable markers for MPM diagnosis. However, not all laboratories are equipped to perform 9p21 FISH; immunohistochemistry (IHC) is a more common and feasible technique. Thus, we sought to develop a IHC-based method that could predict the deletion of p16 in MPM in concordance with 9p21 FISH.
  
  
  
  We examined the expression of the 9p21.3-related proteins (p14, p15, p16, and methylthioadenosine phosphorylase (MTAP)) and BAP1 using IHC in 51 MPM and 25 RMH cases, and assessed their correlation with HD of p16 detected by FISH. The diagnostic usefulness of IHC of the 9p21.3-related proteins and BAP1 and their combinations was assessed using the cut-off values set by receiver operating characteristic (ROC) analysis.
  
  
  
  Among the 9p21.3-related proteins, MTAP IHC findings showed best concordance with 9p21 FISH results (kappa coefficient of 0.69) and a specificity of 100%. We also examined the combinations of MTAP IHC with the other products. The loss of p16 and MTAP had better concordance (kappa coefficient of 0.71), although lower specificity (85%). For differentiating MPM from RMH, only MTAP showed 100% specificity among the 9p21.3-related proteins, as did BAP1 IHC and 9p21 FISH. Among BAP1 combinations, only that of BAP1 with MTAP showed 100% specificity. Its sensitivity was 76.5%, which was lower than BAP1 IHC and 9p21 FISH combination (84.3%), but higher than BAP1 IHC alone (60.8%) or 9p21 FISH alone (60.8%).
  
  
  
  A combination of MTAP or BAP1 loss detected by IHC can likely detect MPM with good sensitivity and 100% specificity, and serve as useful ancillary IHC for discriminating MPM from RMH.
authors.affiliation: Department of Pathology, Fukuoka University Hospital and School of Medicine, 7-45-1 Nanakuma, Jonan-ku, Fukuoka 814-0180, Japan; Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan; Department of Clinical Radiology, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Hida
authors.affiliation: Department of Pathology, Fukuoka University Hospital and School of Medicine, 7-45-1 Nanakuma, Jonan-ku, Fukuoka 814-0180, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Hamasaki
authors.affiliation: Department of Pathology, Fukuoka University Hospital and School of Medicine, 7-45-1 Nanakuma, Jonan-ku, Fukuoka 814-0180, Japan.
authors.forename: Shinji
authors.initials: S
authors.lastname: Matsumoto
authors.affiliation: Department of Pathology, Hyogo College of Medicine, 1-1 Mukogawa-cho, Nishinomiya, Hyogo 663-8131, Japan.
authors.forename: Ayuko
authors.initials: A
authors.lastname: Sato
authors.affiliation: Department of Pathology, Hyogo College of Medicine, 1-1 Mukogawa-cho, Nishinomiya, Hyogo 663-8131, Japan.
authors.forename: Tohru
authors.initials: T
authors.lastname: Tsujimura
authors.affiliation: Department of Pathology, Osaka Prefectural Medical Center for Respiratory and Allergic Disease, 3-7-1 Habikino, Habikino-shi, Osaka 583-8588, Japan.
authors.forename: Kunimitsu
authors.initials: K
authors.lastname: Kawahara
authors.affiliation: Department of Thoracic Surgery, Fukuoka University Hospital and School of Medicine, 7-45-1 Nanakuma, Jonan-ku, Fukuoka 814-0180, Japan.
authors.forename: Akinori
authors.initials: A
authors.lastname: Iwasaki
authors.affiliation: Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.
authors.forename: Tatsuro
authors.initials: T
authors.lastname: Okamoto
authors.affiliation: Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.
authors.forename: Yoshinao
authors.initials: Y
authors.lastname: Oda
authors.affiliation: Department of Clinical Radiology, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Honda
authors.affiliation: Department of Pathology, Fukuoka University Hospital and School of Medicine, 7-45-1 Nanakuma, Jonan-ku, Fukuoka 814-0180, Japan. Electronic address: kaznabes@fukuoka-u.ac.jp.
authors.forename: Kazuki
authors.initials: K
authors.lastname: Nabeshima
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D019313:BRCA1 Protein / Q000378:metabolism*; D045744:Cell Line, Tumor / Q000378:metabolism / Q000473:pathology; D003937:Diagnosis, Differential; D005260:Female; D019942:Genes, p16; D006801:Humans; D006965:Hyperplasia / Q000473:pathology; D007150:Immunohistochemistry; D017404:In Situ Hybridization, Fluorescence; D008175:Lung Neoplasms / Q000175:diagnosis / Q000378:metabolism; D008297:Male; D008654:Mesothelioma / Q000175:diagnosis* / Q000378:metabolism; D000086002:Mesothelioma, Malignant; D008875:Middle Aged; D010997:Pleural Neoplasms / Q000175:diagnosis* / Q000378:metabolism; D011683:Purine-Nucleoside Phosphorylase / Q000378:metabolism*
chemical_list: D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D011683:Purine-Nucleoside Phosphorylase; C021784:5'-methylthioadenosine phosphorylase
keywords: 9p21 FISH; BAP1; Diagnosis; Immunohistochemistry; MTAP; Malignant pleural mesothelioma