Immunohistochemically Detected Expression of 3 Major Genes (CDKN2A/p16, TP53, and SMAD4/DPC4) Strongly Predicts Survival in Patients With Resectable Pancreatic Cancer
Immunohistochemically Detected Expression of 3 Major Genes (CDKN2A/p16, TP53, and SMAD4/DPC4) Strongly Predicts Survival in Patients With Resectable Pancreatic Cancer
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DOI：
10.1097/sla.0b013e3182827a65
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发表时间：
2013-08-01
影响因子：
9
通讯作者：
Yachida, Shinichi
中科院分区：
文献类型：
--
作者：
Oshima, Minoru;Okano, Keiichi;Yachida, Shinichi
目的：本回顾性研究的目的是阐明3个主要基因（CDKN2A/p16、TP53和SMAD4/DPC4）状态的临床意义。背景：最近的全外显子组测序显示，胰腺导管腺癌（PDAC）基因组的4个常见突变基因（KRAS, TP53， CDKN2A/p16和SMAD4/DPC4）的结构值得注意。方法：由于KRAS基因在几乎所有PDAC患者中都发生突变，我们通过免疫组织化学方法测定了4个基因中TP53、CDKN2A/p16和SMAD4/DPC4的状态，并分析了106例接受根治性手术的PDAC患者与临床病理结果（包括生存和疾病进展模式）的关系。结果：81.1%的pdac中检测到p53免疫标记异常，p53与肿瘤去分化（P = 0.022）和局部复发（P = 0.020）相关。p16和Smad4/Dpc4免疫标记的缺失分别占67.0%和60.4%。p16免疫标记的缺失与淋巴浸润（P = 0.012）和术后广泛转移（P < 0.001）相关。Smad4/Dpc4免疫标记与肿瘤大小（P = 0.006）、淋巴浸润（P = 0.033）、淋巴结转移（P = 0.006）有显著相关性。有趣的是，所有6例5年生存率的患者都有完整的SMAD4/DPC4。Kaplan-Meier生存分析显示，淋巴结转移（P = 0.001）、淋巴侵袭（P = 0.008）、肿瘤(T)因子（T3 vs. T1/T2, P = 0.004）、p16免疫标记的缺失（P = 0.029）和Smad4/Dpc4免疫标记的缺失（P < 0.001）与总生存期缩短显著相关。多因素分析显示，Smad4/Dpc4免疫标记的缺失是影响总生存和无病生存的一个独立且显著的不良预后因素。在分析这3个基因的组合状态时，变异数量的增加反映了较差的生存率。结论：这3个基因的遗传改变及其积累与PDAC的恶性行为密切相关。他们在诊断时的免疫组织化学评估可能提供一种新的预后工具，帮助决定患者的最佳治疗策略。
Objective: The goal of this retrospective study was to clarify the clinical implications of the status of the 3 major genes (CDKN2A/p16, TP53, and SMAD4/DPC4).Background: Recent whole-exome sequencing had shown that the landscape of the pancreatic ductal adenocarcinoma (PDAC) genome is notable for 4 frequently mutated genes (KRAS, TP53, CDKN2A/p16, and SMAD4/DPC4).Methods: We determined immunohistochemically the status of TP53, CDKN2A/p16, and SMAD4/DPC4 among the 4 genes because the KRAS gene is mutated in virtually all PDAC patients, and analyzed relationships with clinicopathological findings, including survival and patterns of disease progression, in 106 patients with PDAC undergoing radical surgery.Results: Abnormal immunolabeling of p53 was detected in 81.1% of PDACs and was significantly associated with tumor dedifferentiation (P = 0.022) and the presence of locoregional recurrence (P = 0.020). Loss of p16 and Smad4/Dpc4 immunolabeling was identified in 67.0% and 60.4%, respectively. Loss of p16 immunolabeling was associated with lymphatic invasion (P = 0.012) and postoperative widespread metastases (P < 0.001). A significant correlation was found between Smad4/Dpc4 immunolabeling and tumor size (P = 0.006), lymphatic invasion (P = 0.033), and lymph node metastasis (P = 0.006). Interestingly, all of the 6 patients demonstrating 5-year survival had intact SMAD4/DPC4. Kaplan-Meier survival analysis showed that lymph node metastasis (P = 0.001), lymphatic invasion (P = 0.008), the tumor (T) factor (T3 vs. T1/T2, P = 0.004), loss of p16 immunolabeling (P = 0.029), and loss of Smad4/Dpc4 immunolabeling (P < 0.001) were significantly associated with shorter overall survival. Multivariate analysis revealed that loss of Smad4/Dpc4 immunolabeling was an independent and significant poor prognostic factor for overall and disease-free survival. On analysis of combinations of the status of these 3 genes, increasing number of alterations reflected poorer survival.Conclusions: Genetic alterations of these 3 genes and their accumulation are strongly associated with malignant behavior of PDAC. Their immunohistochemical assessment at the time of diagnosis may provide a new prognostic tool, assisting in deciding optimal therapeutic strategies for patients.