Department of Thoracic Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Shandong Province, P. R. China.
Cancer Med. 2021 Aug;10(15):5088-5100. doi: 10.1002/cam4.4065. Epub 2021 Jun 21.
Despite recent improvements in treatment technologies, such as surgical resection and chemoradiotherapy, the prognosis of patients with esophagogastric junction adenocarcinoma (EJA) remains poor due to early lymph node metastasis. Since few studies have investigated genes associated with lymph node metastasis in EJA, we aimed to screen lymph node metastasis-associated genes and clarify their expression status and prognostic significance in EJA.
The differential frequency of mutations between carcinoma and para-carcinoma tissues from 199 cases with EJA was detected using targeted next-generation sequencing (tNGS). Following a stratified analysis to determine that gender has no effect on the frequency of gene mutations, lymph node metastasis-related genes, including CDK6, MET, NOTCH1, and LRP1B, were screened, and CDK6 and LRP1B were selected for further study as they displayed significant differences in mutation rates. Differences in their expression status were verified using immunohistochemical (IHC) staining in 18 CDK6- and 17 LRP1B-mutated samples and a randomly matched control group.
tNGS revealed that CDK6 and LRP1B mutation frequencies were significantly different between EJA cases with (N ≥ 1) or without (N = 0) lymph node metastasis. In particular, CDK6 mutation frequency was expected less, whereas that of LRP1B was remarkably higher in cases with stage N0 than in those with stage N ≥ 1. IHC staining confirmed significant differences in CDK6 and LRP1B expression status between the study and control cohorts. Chi-square tests revealed that a high CDK6 expression status correlated significantly with smoking history (p = 0.044), T stage (p = 0.035), N stage (p = 0.000), and advanced TNM stage (p = 0.001) in EJA, whereas a high LRP1B expression status only correlated with BMI (p = 0.013) and N stage (p = 0.000). Furthermore, as confirmed by survival status investigation, a high LRP1B expression status predicted good prognosis, and a high CDK6 expression status was an independent predictor of poor prognosis in patients with EJA.
Taken together, the findings of this study demonstrate that a high CDK6 and LRP1B expression status promotes and inhibits lymph node metastasis in patients with EJA, respectively, suggesting that both CDK6 and LRP1B are significantly potential predictors of lymph node metastasis and prognosis in EJA.
尽管手术切除和放化疗等治疗技术最近有所改进，但由于早期淋巴结转移，食管胃结合部腺癌（EJA）患者的预后仍然较差。由于很少有研究探讨与 EJA 淋巴结转移相关的基因，我们旨在筛选与淋巴结转移相关的基因，并阐明其在 EJA 中的表达状态和预后意义。
使用靶向下一代测序（tNGS）检测 199 例 EJA 癌旁组织与癌组织之间的突变差异频率。在分层分析确定性别对基因突变频率无影响后，筛选出与淋巴结转移相关的基因，包括 CDK6、MET、NOTCH1 和 LRP1B，并进一步研究 CDK6 和 LRP1B，因为它们的突变率差异显著。在 18 例 CDK6 突变和 17 例 LRP1B 突变样本以及随机匹配的对照组中，使用免疫组织化学（IHC）染色验证其表达状态的差异。
tNGS 显示，EJA 病例中（N≥1）或无（N=0）淋巴结转移时，CDK6 和 LRP1B 突变频率有显著差异。特别是，在 N0 期病例中，CDK6 突变频率预期较低，而 LRP1B 突变频率显著较高。免疫组化染色证实了研究队列和对照组之间 CDK6 和 LRP1B 表达状态的显著差异。卡方检验显示，在 EJA 中，CDK6 高表达状态与吸烟史（p=0.044）、T 分期（p=0.035）、N 分期（p=0.000）和晚期 TNM 分期（p=0.001）显著相关，而 LRP1B 高表达状态仅与 BMI（p=0.013）和 N 分期（p=0.000）相关。此外，通过生存状况调查证实，LRP1B 高表达状态预测预后良好，而 CDK6 高表达状态是 EJA 患者预后不良的独立预测因素。
综上所述，本研究结果表明，CDK6 和 LRP1B 高表达状态分别促进和抑制 EJA 患者的淋巴结转移，提示 CDK6 和 LRP1B 均为 EJA 淋巴结转移和预后的显著潜在预测因子。
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