Department of Gastroenterological Surgery, Faculty of Medicine, Kagawa University, Kagawa, Japan.
Ann Surg. 2013 Aug;258(2):336-46. doi: 10.1097/SLA.0b013e3182827a65.
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).
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).
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.
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.
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.
本回顾性研究旨在阐明 3 个主要基因（CDKN2A/p16、TP53 和 SMAD4/DPC4）状态的临床意义。
最近的全外显子组测序表明，胰腺导管腺癌（PDAC）基因组的特征是 4 个经常发生突变的基因（KRAS、TP53、CDKN2A/p16 和 SMAD4/DPC4）。
我们确定了这 4 个基因中 TP53、CDKN2A/p16 和 SMAD4/DPC4 的免疫组化状态，因为 KRAS 基因几乎存在于所有 PDAC 患者中，并且分析了它们与临床病理发现之间的关系，包括 106 例接受根治性手术的 PDAC 患者的生存和疾病进展模式。
在 81.1%的 PDAC 中检测到 p53 的异常免疫标记，并且与肿瘤去分化（P=0.022）和局部复发的存在（P=0.020）显著相关。p16 和 Smad4/Dpc4 的免疫标记丢失分别为 67.0%和 60.4%。p16 免疫标记丢失与淋巴管浸润（P=0.012）和术后广泛转移（P<0.001）有关。Smad4/Dpc4 免疫标记与肿瘤大小（P=0.006）、淋巴管浸润（P=0.033）和淋巴结转移（P=0.006）之间存在显著相关性。有趣的是，所有 6 例 5 年生存的患者均有完整的 SMAD4/DPC4。Kaplan-Meier 生存分析显示，淋巴结转移（P=0.001）、淋巴管浸润（P=0.008）、肿瘤（T）因素（T3 与 T1/T2，P=0.004）、p16 免疫标记丢失（P=0.029）和 Smad4/Dpc4 免疫标记丢失（P<0.001）与总生存时间显著相关。多变量分析显示，Smad4/Dpc4 免疫标记丢失是总生存和无病生存的独立预后不良因素。对这 3 个基因状态的组合分析表明，改变的数量增加反映了较差的生存。
这些 3 个基因的遗传改变及其累积与 PDAC 的恶性行为密切相关。在诊断时对其进行免疫组化评估可能提供一种新的预后工具，有助于为患者制定最佳治疗策略。
