title: Hypermethylation of CpG islands in p16 as a prognostic factor for diffuse large B-cell lymphoma in a high-risk group.
abstract: OBJECTIVE
  The aim of the study was to analyze the methylation status of the promoter regions of p15 and p16 and to assess the prognostic significance of promoter hypermethylation in diffuse large B-cell lymphoma (DLBCL).
  
  
  METHODS
  DLBCL was diagnosed by morphology and immunohistochemical analysis according to the World Health Organization (WHO) classification. The methylation status of CpG islands in the p15 and p16 promoters was analyzed by methylation-specific polymerase chain reaction in 49 DLBCLs.
  
  
  RESULTS
  Hypermethylation of the p15 and p16 promoters was detected in 20 (41%) and 22 (45%) of the 49 DLBCLs, respectively. Among all patients with DLBCL, there was no significant difference in the overall survival between those with hypermethylated and unmethylated p15 (P=0.442) or between those with hypermethylated and unmethylated p16 (P=0.468). Therefore, methylation was analyzed in combination with evaluation of clinical features using the international prognostic index (IPI). In the high-intermediate-risk and high-risk groups, patients with hypermethylated p16 had significantly lower survival rates than those of patients in the same risk group with unmethylated p16 (P=0.010).
  
  
  CONCLUSIONS
  Our results suggest that hypermethylation of the p16 promoter indicates a poor prognosis in high-intermediate-risk and high-risk DLBCL patients, and may be a useful marker for selection of appropriate treatment when used in conjunction with the IPI.
authors.affiliation: Second Department of Pathology, Showa University School of Medicine, 1-5-8 Hatanodai, Shinagawa-Ku, Tokyo 142-8555, Japan. eshiozawa@aol.com
authors.forename: Eisuke
authors.initials: E
authors.lastname: Shiozawa
authors.forename: Masafumi
authors.initials: M
authors.lastname: Takimoto
authors.forename: Reiko
authors.initials: R
authors.lastname: Makino
authors.forename: Daisuke
authors.initials: D
authors.lastname: Adachi
authors.forename: Bungo
authors.initials: B
authors.lastname: Saito
authors.forename: Toshiko
authors.initials: T
authors.lastname: Yamochi-Onizuka
authors.forename: Tadanori
authors.initials: T
authors.lastname: Yamochi
authors.forename: Junko
authors.initials: J
authors.lastname: Shimozuma
authors.forename: Takashi
authors.initials: T
authors.lastname: Maeda
authors.forename: Yohko
authors.initials: Y
authors.lastname: Kohno
authors.forename: Keiichiro
authors.initials: K
authors.lastname: Kawakami
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Nakamaki
authors.forename: Shigeru
authors.initials: S
authors.lastname: Tomoyasu
authors.forename: Akira
authors.initials: A
authors.lastname: Shiokawa
authors.forename: Hidekazu
authors.initials: H
authors.lastname: Ota
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000235:genetics*; D018899:CpG Islands; D050762:Cyclin-Dependent Kinase Inhibitor p15 / Q000235:genetics; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics*; D019175:DNA Methylation; D005260:Female; D006801:Humans; D016393:Lymphoma, B-Cell / Q000175:diagnosis / Q000235:genetics*; D016403:Lymphoma, Large B-Cell, Diffuse / Q000175:diagnosis / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D009367:Neoplasm Staging; D011237:Predictive Value of Tests; D011379:Prognosis; D012307:Risk Factors; D015996:Survival Rate; D013997:Time Factors
chemical_list: D014408:Biomarkers, Tumor; D050762:Cyclin-Dependent Kinase Inhibitor p15; D019941:Cyclin-Dependent Kinase Inhibitor p16