Department of Gastroenterological Surgery, Osaka Metropolitan University Graduate School of Medicine, 1-4-3 Asahimachi, Abeno-ku, Osaka, 545-8585, Japan.
Molecular Oncology and Therapeutics, Osaka Metropolitan University Graduate School of Medicine, 1-4-3 Asahimachi, Abeno-ku, Osaka, 545-8585, Japan.
BMC Cancer. 2022 Jun 1;22(1):598. doi: 10.1186/s12885-022-09681-3.
Tumor heterogeneity has frequently been observed in gastric cancer (GC), but the correlation between patients' clinico-pathologic features and the tumoral heterogeneity of GC-associated molecules is unclear. We investigated the correlation between lymph node metastasis and the intra-tumoral heterogeneity of driver molecules in GC.
We retrospectively analyzed the cases of 504 patients who underwent a gastrectomy at the Department of Gastroenterological Surgery, Osaka Metropolitan University and 389 cases drawn from The Cancer Genome Atlas (TCGA) data. We performed a clustering analysis based on eight cancer-associated molecules including HER2, c-Met, and p-Smad2 using the protein expression revealed by our immunohistochemical study of the patients' and TCGA cases. We determined the correlations between HER2 expression and the other molecules based on the degree of lymph node metastasis.
Immunohistochemical staining data showed that a 43 of the 504 patients with GC (8.5%) were HER2-positive. In the HER2-positive cases, the expressions of c-Met and p-Smad2 were increased in accord with the lymph-node metastatic level. The overall survival of the HER2-positive GC patients with both p-Smad2 and c-Met expression was significantly (p = 0.030) poorer than that of the patients with p-Smad2-negative and/or c-Met-negative expression. The results of the TCGA data analysis revealed that 58 of the 389 GC cases (14.9%) were ERBB2-positive. MET expression was more frequent in the N1 metastasis group than the N0 group. In the high lymph-node metastasis (N2 and N3) group, SMAD2 expression was more frequent, as was ERBB2 and MET expression.
p-Smad2 and c-Met signaling might play important roles in lymph node metastasis in HER2-positive GC.
胃癌（GC）中经常观察到肿瘤异质性，但患者临床病理特征与 GC 相关分子的肿瘤异质性之间的相关性尚不清楚。我们研究了 GC 中驱动分子的淋巴结转移与肿瘤内异质性之间的相关性。
我们回顾性分析了在大阪市立大学胃肠外科接受胃切除术的 504 例患者和来自癌症基因组图谱（TCGA）数据的 389 例患者的病例。我们使用我们对患者和 TCGA 病例的免疫组织化学研究揭示的蛋白质表达，对包括 HER2、c-Met 和 p-Smad2 在内的 8 种癌症相关分子进行聚类分析。我们根据淋巴结转移程度确定了 HER2 表达与其他分子之间的相关性。
免疫组织化学染色数据显示，504 例 GC 患者中有 43 例（8.5%）为 HER2 阳性。在 HER2 阳性病例中，c-Met 和 p-Smad2 的表达随着淋巴结转移水平的增加而增加。具有 p-Smad2 和 c-Met 表达的 HER2 阳性 GC 患者的总生存期明显（p=0.030）差于 p-Smad2 阴性和/或 c-Met 阴性表达的患者。TCGA 数据分析的结果显示，389 例 GC 病例中有 58 例（14.9%）为 ERBB2 阳性。MET 表达在 N1 转移组比 N0 组更频繁。在高淋巴结转移（N2 和 N3）组中，SMAD2 表达更频繁，而 ERBB2 和 MET 表达也更频繁。
p-Smad2 和 c-Met 信号可能在 HER2 阳性 GC 的淋巴结转移中发挥重要作用。
