Frequent loss of heterozygosity of SMAD4 locus and prognostic impacts of SMAD4 immunohistochemistry in gastric adenocarcinoma with enteroblastic differentiation.
Frequent loss of heterozygosity of SMAD4 locus and prognostic impacts of SMAD4 immunohistochemistry in gastric adenocarcinoma with enteroblastic differentiation.
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SMAD4 位点杂合性的频繁丢失以及 SMAD4 免疫组织化学对伴肠母细胞分化的胃腺癌的预后影响。
DOI：
10.1016/j.humpath.2019.03.005
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发表时间：
2019
期刊：
影响因子：
3.3
通讯作者：
Yao T.
中科院分区：
文献类型：
--
作者：
Yatagai N;Saito T;Akazawa Y;Hayashi T;Yanai Y;Tsuyama S;Murakami T;Ueyama H;Watanabe S;Nagahara A;Yao T.
胃腺癌伴肠母细胞分化是胃腺癌的一种罕见变异型。临床病理上，GAED具有侵袭性，即使在早期也以血管侵犯、淋巴管侵犯和肝转移为特征。在我们先前的下一代测序研究中，通过拷贝数变异分析发现Smad4基因是一种常见的缺失基因；因此，我们在51例GAEDs(早期：17例，晚期：34例)中检测了Smad4的临床病理影响。我们对Smad4突变进行了Sanger测序，并对Smad4基因进行了杂合性缺失(LOH)分析，同时对Smad4进行了免疫组织化学分析，以确定其临床病理相关性和对生存的影响。Smad4基因的杂合性缺失频率为45.1%，在胃腺癌中的杂合率明显高于常规胃腺癌。在任何情况下都没有发现Smad4突变。Smad4低表达的病例占60.8%，其表达与临床分期和淋巴结转移显著相关，并有增大肿瘤大小和淋巴转移的趋势。36例患者中有21例转移淋巴结中Smad4表达降低。生存分析显示，Smad4表达降低显著影响患者的总生存期(OS)和无复发生存期(RFS)，但多因素分析显示只有肝转移和淋巴浸润性(Ly+)是OS和RFS的独立预后因素。Smad4基因是该病的易感基因之一。
Gastric adenocarcinoma with enteroblastic differentiation (GAED) is a rare variant of gastric adenocarcinoma. Clinicopathologically, GAED is known to be aggressive and is characterized by frequent vascular invasion, lymphatic invasion, and liver metastasis even in early stages. SMAD4 was identified as a frequently deleted gene in GAED by copy number variation analysis in our previous next-generation sequencing study; therefore, we examined the clinicopathological impacts of SMAD4 in 51 cases of GAEDs (early: 17, advanced: 34). We performed Sanger sequencing for SMAD4 mutations and loss of heterozygosity (LOH) analysis of the SMAD4 locus, in addition to immunohistochemistry for SMAD4, to determine its clinicopathological correlations and impacts on survival. The frequency of LOH at the SMAD4 locus was 45.1%, and it was significantly higher in GAED compared to in conventional gastric adenocarcinoma. SMAD4 mutations were not found in any case. Reduced SMAD4 expression was found in 60.8% of cases; it was significantly correlated with advanced stages and lymph node metastasis and showed trends of larger tumor size and lymphatic invasion. Reduced SMAD4 expression in metastatic lymph nodes was found in 21 of 36 cases. Survival analysis revealed that reduced SMAD4 expression significantly affected the patient’s overall survival (OS) and recurrence-free survival (RFS), although multivariate analysis showed that only liver metastasis and lymphatic infiltration (Ly+) were independent prognostic factors for OS and RFS. The SMAD4 locus is one of the susceptibility genes in this