title: Characterization and Prognostic Significance of Methylthioadenosine Phosphorylase Deficiency in Nasopharyngeal Carcinoma.
abstract: Identification of cancer-associated genes by genomic profiling contributes to the elucidation of tumor development and progression. The methylthioadenosine phosphorylase (MTAP) gene, located at chromosome 9p21, plays a critical role in tumorigenicity and disease progression in a wide variety of cancers. However, the prognostic impact of MTAP in patients with nasopharyngeal carcinoma (NPC) remains obscured. Through data mining from published transcriptomic database, MTAP was first identified as a differentially downregulated gene in NPC. In this study, our aim was to evaluate the expression of MTAP in NPC and to clarify its prognostic significance.MTAP immunohistochemistry was retrospectively performed and analyzed in biopsy specimens from 124 NPC patients who received standard treatment without distant metastasis at initial diagnosis. The immunoexpression status was correlated with the clinicopathological variables, disease-specific survival (DSS), distant metastasis-free survival (DMFS), and local recurrence-free survival (LRFS). Real-time quantitative polymerase chain reaction (PCR) was used to measure MTAP gene dosage. In some cases, we also performed methylation-specific PCR and pyrosequencing to assess the status of promoter methylation.MTAP deficiency was significantly associated with advanced tumor stages (P = 0.023) and univariately predictive of adverse outcomes for DSS, DMFS, and LRFS. In the multivariate comparison, MTAP deficiency still remained prognostically independent to portend worse DSS (P = 0.021, hazard ratio = 1.870) and DMFS (P = 0.009, hazard ratio = 2.154), together with advanced AJCC stages III to IV. Homozygous deletion or promoter methylation of MTAP gene were identified to be significantly associated with MTAP protein deficiency (P < 0.001).MTAP deficiency was correlated with an aggressive phenotype and independently predictive of worse DSS and DMFS, suggesting its role in disease progression and as an independent prognostic biomarker of NPC, which potentially offers new strategy of targeted treatment for patients lacking MTAP expression.
authors.affiliation: From the Department of Pathology, E-DA Hospital, I-Shou University, Kaohsiung, Taiwan (H-LH); Institute of Biomedical Science, National Sun Yat-Sen University, Kaohsiung, Taiwan (H-LH, Y-LS); Department of Anesthesiology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan (Y-EL); Department of Radiation Oncology, Chi-Mei Medical Center, Liouying, Tainan, Taiwan (S-WL); Department of Pathology, Chi-Mei Medical Center, Tainan, Taiwan (T-JC, C-FL); National Institute of Cancer Research, National Health Research Institutes, Tainan, Taiwan (C-FL); Department of Biotechnology, Southern Taiwan University of Science and Technology, Tainan, Taiwan (C-FL); and Institute of Clinical Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan (C-FL).
authors.forename: Hong-Lin
authors.initials: HL
authors.lastname: He
authors.forename: Ying-En
authors.initials: YE
authors.lastname: Lee
authors.forename: Yow-Ling
authors.initials: YL
authors.lastname: Shiue
authors.forename: Sung-Wei
authors.initials: SW
authors.lastname: Lee
authors.forename: Tzu-Ju
authors.initials: TJ
authors.lastname: Chen
authors.forename: Chien-Feng
authors.initials: CF
authors.lastname: Li
mesh_terms: D002277:Carcinoma; D015536:Down-Regulation; D005260:Female; D015870:Gene Expression; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D000077274:Nasopharyngeal Carcinoma; D009303:Nasopharyngeal Neoplasms / Q000175:diagnosis* / Q000235:genetics* / Q000473:pathology; D060787:Neoplasm Grading; D009367:Neoplasm Staging; D011379:Prognosis; D016016:Proportional Hazards Models; D011683:Purine-Nucleoside Phosphorylase / Q000172:deficiency* / Q000235:genetics*; D060888:Real-Time Polymerase Chain Reaction; D012189:Retrospective Studies
chemical_list: D011683:Purine-Nucleoside Phosphorylase; C021784:5'-methylthioadenosine phosphorylase