He Hong-Lin, Lee Ying-En, Shiue Yow-Ling, Lee Sung-Wei, Chen Tzu-Ju, Li Chien-Feng
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).
Medicine (Baltimore). 2015 Dec;94(49):e2271. doi: 10.1097/MD.0000000000002271.
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.
通过基因组分析鉴定癌症相关基因有助于阐明肿瘤的发生和发展。位于9号染色体p21的甲硫腺苷磷酸化酶（MTAP）基因在多种癌症的致瘤性和疾病进展中起关键作用。然而，MTAP在鼻咽癌（NPC）患者中的预后影响仍不明确。通过对已发表的转录组数据库进行数据挖掘，MTAP首次被确定为NPC中差异下调的基因。在本研究中，我们的目的是评估MTAP在NPC中的表达，并阐明其预后意义。对124例初诊时接受标准治疗且无远处转移的NPC患者的活检标本进行回顾性MTAP免疫组化检测和分析。免疫表达状态与临床病理变量、疾病特异性生存（DSS）、无远处转移生存（DMFS）和无局部复发生存（LRFS）相关。采用实时定量聚合酶链反应（PCR）检测MTAP基因剂量。在某些情况下，我们还进行了甲基化特异性PCR和焦磷酸测序以评估启动子甲基化状态。MTAP缺陷与晚期肿瘤分期显著相关（P = 0.023），单因素分析可预测DSS、DMFS和LRFS的不良预后。在多因素比较中，MTAP缺陷在预后方面仍然独立，预示着更差的DSS（P = 0.021，风险比 = 1.870）和DMFS（P = 0.009，风险比 = 2.154），同时与美国癌症联合委员会（AJCC）III至IV期晚期相关。MTAP基因的纯合缺失或启动子甲基化与MTAP蛋白缺陷显著相关（P < 0.001）。MTAP缺陷与侵袭性表型相关，独立预测更差的DSS和DMFS, 表明其在疾病进展中的作用以及作为NPC的独立预后生物标志物，这可能为缺乏MTAP表达的患者提供新的靶向治疗策略。
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