原发性肝癌发生KRAS基因突变患者的超声特征及KRAS基因突变与淋巴结转移的相关性

摘要/Abstract

摘要： 目的探讨原发性肝癌发生KRAS基因突变患者的超声特征及KRAS基因突变与淋巴结转移的相关性。方法纳入2018年3月至2021年3月联勤保障部队第九〇九医院收治的原发性肝癌患者168例,根据淋巴结转移情况将其分为肝癌伴肝外转移患者组(n=63)和肝癌无转移对照组(n=105)。采集患者的外周血及癌组织和癌旁组织,KRAS基因突变采用KRAS/NRAS基因突变联合检测试剂盒,癌和癌旁组织中KRAS蛋白表达水平采用免疫组织化学方法进行检测。分析发生KRAS基因突变的原发性肝癌患者的超声特征及其KRAS基因突变与淋巴结转移的相关性。结果 168例肝癌患者中共检出36例患者KRAS基因突变,均为伴肝外转移组患者,KRAS基因突变率为57.14%(36/63),无肝外转移组患者KRAS基因突变率为0,差异有统计学意义(χ²=76.364,P<0.05)。KRAS高表达组与KRAS低表达组对比,除肿瘤大小差异无统计学意义(P>0.05)外;KRAS蛋白在肿瘤结节数≥2个、肿瘤包膜(-)、血流分级Ⅲ级及血管侵袭情况(+)的患者中表达水平较肿瘤结节个数1个、肿瘤包膜(+)、血管侵袭情况(-)及血流分级Ⅰ、Ⅱ级的患者明显偏高,差异均有统计学意义(χ²=8.333、3.955、10.823、4.730,均P<0.05)。KRAS蛋白高表达组RI明显高于KRAS蛋白低表达组,肿瘤结节数≥2个的患者RI较肿瘤结节数为1个的患者显著偏高,差异有统计学意义(t=18.725、21.897,P<0.05)。logstic二元回归分析结果显示,肝癌组织中KRAS蛋白的表达水平与肿瘤结节个数、肿瘤包膜、血流分级、血管侵袭情况及RI等超声参数均显著相关。KRAS蛋白的表达水平越高,肿瘤的包膜形成减少,肿瘤结节个数越多,血管侵袭情况越严重,血流分级和RI值越高。结论肝癌伴肝外转移患者存在明显的KRAS基因突变,且KRAS基因突变与肝癌的进展密切相关,检测肝癌组织中的KRAS基因表达水平并结合彩超影像学表现可为临床诊断提供理论依据。

关键词: 原发性肝癌, KRAS基因突变, 超声特征, 淋巴结转移, 相关性分析

Abstract: Objective To investigate the ultrasonographic features of primary liver cancer (PLC) patients with KRAS gene mutation, and investigate the correlation between KRAS gene mutation and lymph node metastasis.Methods A total of 168 patients with primary liver cancer admitted to our hospital from March 2018 to March 2021 were prospectively included as the research subjects. According to the occurrence of lymph node metastasis, they were divided into metastasis group (n=63) and non-metastasis group (n=105). Peripheral blood, cancer and para-cancer tissues were collected from the 2 groups, respectively. The KRAS gene mutation was detected by the KRAS/NRAS gene mutation combined detection kit. The KRAS protein expression levels in cancer and para-cancer tissues were detected by immunohistochemistry. Color Dopplar ultrasound was used to detect the imaging manifestations of liver tumors in 2 groups. To analyze the ultrasonic characteristics of primary liver cancer patients with KRAS gene mutation and the correlation between KRAS gene mutation and lymph node metastasis.Results (1) Among 168 patients with liver cancer, 36 patients with KRAS gene mutation. The KRAS gene mutation rate in patients with extrahepatic metastasis group was 57.14%(36/63), which was significantly higher than that in patients without extrahepatic metastasis group 0% (0/105). The difference was statistically significant (χ²=76.364, P<0.05). (2) Thirty-six patients with KRAS gene mutation were divided into KRAS low expression group and KRAS high expression group according to the expression level of KRAS protein. There was no significant difference of tumor size between the 2 groups (P>0.05). The expression level of KRAS protein in the patients with the number of tumor nodules ≥2, tumor capsule (-), blood flow grade III and vascular invasion (+) was significantly higher than that in the patients with the number of single tumor nodule, tumor capsule (+), blood vessel invasion (-), and blood flow grades I and II. The differences were statistically significant (χ²=8.333, 3.955, 10.823, 4.730, P<0.05). (3) The RI of the KRAS protein high expression group was significantly higher than that of the KRAS protein low expression group. The RI of the patient with the number of tumor nodules ≥2 was significantly higher than that with single tumor nodule, (t=18.725,21.897, P<0.05). (4) The results of Log stic binary regression analysis showed that the expression level of KRAS protein in liver cancer tissues was positively correlated with the number of tumor nodules, blood flow grade, vascular invasion, RI and other ultrasonic parameters. The higher the expression level of KRAS protein is, and negatively correlated with the capsule formation of the tumor.Conclusion KRAS gene mutation is more frequent in patients with primary liver cancer, especially in those combined with extrahepatic metastasis. KRAS gene mutation is closely related to the progression of liver cancer. KRAS gene expression level in liver cancer tissues combined with color Dopplar ultrasound imaging analysis can provide a reference value for clinical diagnosis and treatment for liver cancer.

Key words: Primary liver cancer, KRAS gene mutation, Ultrasonic characteristics, Lymph node metastasis, Correlation analysis

黄诗雯, 曾美惠. 原发性肝癌发生KRAS基因突变患者的超声特征及KRAS基因突变与淋巴结转移的相关性[J]. 肝脏, 2022, 27(12): 1280-1283.

HUANG Shi-wen, ZENG Mei-hui. Ultrasonographic characteristics of primary liver cancer patients with KRAS gene mutation and the correlation between KRAS gene mutation and lymph node metastasis[J]. Chinese Hepatolgy, 2022, 27(12): 1280-1283.

参考文献

[1] Sim HW, Knox J. Hepatocellular carcinoma in the era of immunotherapy. Curr Probl Cancer, 2018,42(1):40-48.
[2] 原发性肝癌和肝转移瘤的治疗:第一部分——核医学技术.中华核医学与分子影像杂志,2021,41(10):635-640.
[3] Hartke J, Johnson M, Ghabril M. The diagnosis and treatment of hepatocellular carcinoma. Semin Diagn Pathol, 2017,34(2):153-159.
[4] 张容容,邵明义,符宇,等基于文献计量学阐述中成药治疗原发性肝癌的研究进展.中成药:1-6.
[5] 毕新宇,蔡建强.应重视肝细胞癌的规范化治疗.中华外科杂志,2021,59(10):812-815.
[6] 毕晓峰,郭蕾,李文斌,德国.结直肠癌KRAS和BRAF基因突变分子病理流行病学研究.中华肿瘤防治杂志,2021,28(11):805-810.
[7] 吴婧婧,黄琦,孙妩弋,等.原发性肝细胞癌免疫治疗药物的临床药理研究进展.安徽医科大学学报,2021,56(11):1842-1846.
[8] 丁惠国,屠红,曲春枫,等.原发性肝癌的分层筛查与监测指南(2020版).中华肿瘤防治杂志,2021,28(02):83-99.
[9] 张明佺,潘俊辰,黄蓬.RAS基因与脂代谢在恶性肿瘤中的相互调控.浙江大学学报(医学版),2021,50(01):17-22.
[10] Simanshu DK, Nissley DV, McCormick F. RAS proteins and their regulators in human disease. Cell, 2017,170(1):17-33.
[11] Delire B, Stärkel P. The Ras/MAPK pathway and hepatocarcinoma: pathogenesis and therapeutic implications. Eur J Clin Invest, 2015,45(6):609-23.
[12] Zinatizadeh MR, Momeni SA, Zarandi PK, et al. The role and function of ras-association domain family in cancer: a review. Genes Dis, 2019,6(4):378-384.
[13] O'Dell MR, Huang JL, Whitney-Miller CL, et al. Kras(G12D) and p53 mutation cause primary intrahepatic cholangiocarcinoma.Cancer Res, 2012,72(6):1557-67.
[14] Ye H, Zhang C, Wang BJ, et al. Synergistic function of Kras mutation and HBx in initiation and progression of hepatocellular carcinoma in mice. Oncogene, 2014,33(43):5133-8.
[15] 尹小兰,许青. 原发性肝癌中KRAS及BRAF基因突变及其临床意义. 现代肿瘤医学(15期):2419-2422.
[16] 郭艳, 王茜, 杨志杰. 肝细胞癌FMNL3基因表达与彩超影像表现的相关性. 实用医学杂志, 2015, 31(4):606-609.