title: Low homozygous/high heterozygous deletion status by p16 FISH correlates with a better prognostic group than high homozygous deletion status in malignant pleural mesothelioma.
abstract: Homozygous deletion (homo-d) of the p16 (CDKN2A) gene, as determined by fluorescence in situ hybridization (FISH), helps differentiate malignant pleural mesothelioma (MPM) from reactive mesothelial hyperplasia (RMH). Heterozygous deletion (hetero-d) has also been identified variably in p16 FISH. This study aimed to investigate the significance of homo-d and hetero-d of p16 in the diagnosis and prognosis of MPM.
  
  
  
  p16 FISH was performed in 93 MPMs and 47 RMHs. Real-time polymerase chain reaction (PCR) and methylation specific PCR (MSP) were also performed for cases in which DNA was available. Overall survival (OS) was assessed via the Kaplan-Meier method and logrank test.
  
  
  
  Cutoff values for homo-d and hetero-d were set at 10% and 47%, respectively, based on p16 FISH results in RMH. In MPM, 80/93 (86.0%) were homo-d positive, and 15/93 (16.1%) were hetero-d positive. No RMH was homo/hetero-d positive. In nine cases of MPM with the low homo-d (<30%)/high hetero-d (>47%) pattern, FISH with a shorter probe caused a slight increase (from 20.1% to 26.5%) in the mean percentage of homo-d and a decrease in that of hetero-d (from 59.6% to 55.6%). Four cases in which the low homo-d/high hetero-d pattern was maintained with the shorter probe were further analyzed by real-time PCR, which separated them into a two (n=2) or one allele deletion group (n=2). MSP revealed no promoter methylation in the two cases with one allele deletion. The OS was significantly shorter in homo-d positive cases (n=24) than homo-d negative cases (n=5, p=0.0002) in the 29 MPM cases with follow-up data. Also, low homo-d/high hetero-d cases (n=5) had a significantly better prognosis than high homo-d (≥30%) cases (n=17, p=0.011).
  
  
  
  Within p16 homo-d positive MPMs with poorer prognosis, the low homo-d/high hetero-d pattern may belong to a better prognostic subgroup in homo-d positive MPMs.
authors: Departments of Pathology, Fukuoka University Hospital and School of Medicine, Fukuoka, Japan.
authors: Makoto
authors: M
authors: Hamasaki
authors: Departments of Pathology, Fukuoka University Hospital and School of Medicine, Fukuoka, Japan.
authors: Shinji
authors: S
authors: Matsumoto
authors: Departments of Thoracic Surgery, Fukuoka University Hospital and School of Medicine, Fukuoka, Japan.
authors: Sousei
authors: S
authors: Abe
authors: Departments of Thoracic Surgery, Fukuoka University Hospital and School of Medicine, Fukuoka, Japan.
authors: Daisuke
authors: D
authors: Hamatake
authors: Pathology and Cytology Center of the PCL Fukuoka, Fukuoka, Japan.
authors: Toshiaki
authors: T
authors: Kamei
authors: Department of Pathology, Tokyo Women's Medical University Yachiyo Medical Center, Yachiyo, Japan.
authors: Kenzo
authors: K
authors: Hiroshima
authors: Department of Pathology, Osaka Prefectural Hospital Organization, Osaka Prefectural Medical Center for Respiratory and Allergic Disease, Habikino, Japan.
authors: Kunimitsu
authors: K
authors: Kawahara
authors: Department of Pathology, Hyogo College of Medicine, Hyogo, Japan.
authors: Ayuko
authors: A
authors: Sato
authors: Department of Pathology, Hyogo College of Medicine, Hyogo, Japan.
authors: Tohru
authors: T
authors: Tsujimura
authors: Department of Diagnostic Pathology, Graduate School of Medicine, Chiba University, Chiba, Japan.
authors: Yukio
authors: Y
authors: Nakatani
authors: Departments of Thoracic Surgery, Fukuoka University Hospital and School of Medicine, Fukuoka, Japan.
authors: Yasuhiro
authors: Y
authors: Yoshida
authors: Departments of Thoracic Surgery, Fukuoka University Hospital and School of Medicine, Fukuoka, Japan.
authors: Akinori
authors: A
authors: Iwasaki
authors: Departments of Pathology, Fukuoka University Hospital and School of Medicine, Fukuoka, Japan. Electronic address: kaznabes@fukuoka-u.ac.jp.
authors: Kazuki
authors: K
authors: Nabeshima
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D005260:Female; D017353:Gene Deletion; D018628:Gene Dosage; D019942:Genes, p16; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D008175:Lung Neoplasms / Q000235:genetics* / Q000401:mortality*; D008297:Male; D008654:Mesothelioma / Q000235:genetics* / Q000401:mortality*; D000086002:Mesothelioma, Malignant; D008875:Middle Aged; D010997:Pleural Neoplasms / Q000235:genetics* / Q000401:mortality*; D011379:Prognosis; D016019:Survival Analysis; D055815:Young Adult
keywords: 9p21 FISH; Heterozygous deletion; Homozygous deletion; Malignant pleural mesothelioma; Prognosis; p16