title: P53, N- and K-Ras, and beta-catenin gene mutations and prognostic factors in nasal NK/T-cell lymphoma from Hokkaido, Japan.
abstract: We have shown previously that nasal natural killer (NK)/T-cell lymphoma was associated with Epstein-Barr virus (EBV) and had peculiar clinical features. However, little is known about its biological and genetic changes. The aim of this study is to determine the p53, N- and K-ras, and beta-catenin status in this lymphoma in relation to EBV status and clinical features. The study group consisted of 32 Japanese patients with nasal NK/T-cell lymphoma. The p53 and beta-catenin expression, phenotype, and EBV-oncogenic protein latent membrane protein type 1 (LMP-1) were determined by immunoperoxidase staining. The presence of EBV-encoded small nuclear early region (EBER) RNA was determined by in situ hybridization. The p53 mutations (exons 5 to 9), N- and K-ras mutations (exons 1 and 2), and beta-catenin mutations (exon 3) were analyzed by direct sequencing of the PCR-amplified products that were obtained from laser-microdissected tissues. CD56, CD43, and CD3 were expressed in 32 (100%), in 31 (96%), and in 18 (56%) tumors, respectively. EBER RNA was detected in 31 (96%) tumors. LMP-1 was expressed in 15 (48%) tumors, and p53 and beta-catenin protein were overexpressed in 18 (56%) and 4 (13%) tumors, respectively. Six mutations of the p53 gene, 1 mutation of each N- and K-ras gene, and 8 mutations of beta-catenin gene were detected in 6 (19%), 1 (3%), and 5 (16%) tumors, respectively. The p53 missense mutation was associated with LMP-1 expression (P = 0.038), but not with p53 overexpression. Kaplan-Meier analysis as well as univariate analysis using Cox proportional hazards model showed that high lactate dehydrogenase (LDH) level (P = 0.009, P = 0.0100, respectively), large cell, immunoblastoid polymorphous histology (P = 0.005, P = 0.0162, respectively), and p53 missense mutations (P = 0.021, P = 0.0342, respectively) were significantly related to worse cause-specific survival. Multivariate analysis showed that p53 missense mutation was the most independent among these 3 factors. Although the incidence of thep53, N- and K-ras, and beta-catenin gene mutations is not high, p53 missense mutation has a prognostic value for aggressive course in nasal NK/T-cell lymphoma.
authors.affiliation: Department of Otolaryngology--Head and Neck Surgery, Asahikawa Medical College, Hokkaido, Japan.
authors.forename: Miki
authors.initials: M
authors.lastname: Takahara
authors.forename: Kan
authors.initials: K
authors.lastname: Kishibe
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Bandoh
authors.forename: Satoshi
authors.initials: S
authors.lastname: Nonaka
authors.forename: Yasuaki
authors.initials: Y
authors.lastname: Harabuchi
mesh_terms: D000328:Adult; D000368:Aged; D003598:Cytoskeletal Proteins / Q000235:genetics* / Q000378:metabolism; D004273:DNA, Neoplasm / Q000032:analysis; D018572:Disease-Free Survival; D020031:Epstein-Barr Virus Infections / Q000150:complications / Q000235:genetics / Q000473:pathology; D005260:Female; D016158:Genes, p53; D011905:Genes, ras; D006103:Granuloma, Lethal Midline / Q000235:genetics* / Q000473:pathology / Q000821:virology; D004854:Herpesvirus 4, Human / Q000235:genetics / Q000302:isolation & purification; D006801:Humans; D007564:Japan; D007694:Killer Cells, Natural / Q000473:pathology; D016399:Lymphoma, T-Cell / Q000235:genetics* / Q000473:pathology / Q000821:virology; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense; D009669:Nose Neoplasms / Q000235:genetics* / Q000473:pathology / Q000821:virology; D015689:Oncogene Protein p21(ras) / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000032:analysis; D012269:Ribosomal Proteins / Q000032:analysis; D015534:Trans-Activators / Q000235:genetics* / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D051176:beta Catenin
chemical_list: C495270:CTNNB1 protein, human; D003598:Cytoskeletal Proteins; D004273:DNA, Neoplasm; D016601:RNA-Binding Proteins; D012269:Ribosomal Proteins; D015534:Trans-Activators; D016159:Tumor Suppressor Protein p53; D051176:beta Catenin; C067169:RPL22 protein, human; D015689:Oncogene Protein p21(ras)