KRAS基因突变对经肝动脉化疗栓塞术治疗的中晚期原发性肝癌患者预后的预测价值

刘旭初; 覃世运; 陈丽君; 陈娟; 尤晓光

doi:10.3969/j.issn.1001-5256.2022.11.015

KRAS基因突变对经肝动脉化疗栓塞术治疗的中晚期原发性肝癌患者预后的预测价值

DOI: 10.3969/j.issn.1001-5256.2022.11.015

刘旭初^1a, , ,,
覃世运^1a,
陈丽君^1a,
陈娟^1b,
尤晓光²

1a.
海南省第三人民医院(三亚中心医院) 肿瘤治疗中心，海南三亚 572000
1b.
海南省第三人民医院(三亚中心医院) 药学部，海南三亚 572000
2.
海南医学院第一附属医院放射科，海口 570102

基金项目:

海南省重点研发科技发展项目 (SQ2019KJHZ0073)

伦理学声明：本研究方案于2017年1月8日经海南省第三人民医院伦理委员会审批，批号：伦(审)2017-09，所纳入患者均签署知情同意书。

利益冲突声明：本研究不存在研究者、伦理委员会成员、受试者监护人以及与公开研究成果有关的利益冲突。

作者贡献声明：刘旭初、覃世运、陈丽君、陈娟、尤晓光负责课题设计，资料分析，撰写论文；刘旭初负责拟定写作思路，指导撰写文章并最后定稿。

详细信息

通信作者:
刘旭初，273286268@qq.com

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出版历程
- 收稿日期: 2022-04-12
- 录用日期: 2022-06-25
- 出版日期: 2022-11-20

Prognostic value of KRAS mutations in patients with advanced primary liver cancer treated with transcatheter arterial chemoembolization

Xuchu LIU^{1a
, ,
,},
Shiyun QIN^1a,
Lijun CHEN^1a,
Juan CHEN^1b,
Xiaoguang YOU²

1a.
Tumor Treatment Center, Sanya Central Hospital, The Third People's Hospital of Hainan Province, Sanya, Hainan 572000, China
1b.
Department of Pharmacy, Sanya Central Hospital, The Third People's Hospital of Hainan Province, Sanya, Hainan 572000, China
2.
Department of Radiology, the First Affiliated Hospital of Hainan Medical College, Haikou 570102, China

Research funding:

Key R&D Technology Development Projects in Hainan Province (SQ2019KJHZ0073)

More Information

Corresponding author: LIU Xuchu, 273286268@qq.com(ORCID: 0000-0002-2868-3574)

摘要

摘要: 目的探讨KRAS基因状态对经肝动脉化疗栓塞(TACE)治疗中晚期肝癌患者预后的预测价值。方法选择2017年4月—2020年5月在海南省第三人民医院接受TACE治疗的中晚期肝癌患者97例为研究对象。检测患者KRAS基因突变状态，并分析KRAS基因突变状态与患者TACE治疗预后的关系。计量资料两组间比较采用t检验，计数资料两组间比较采用χ²检验，生存分析绘制Kaplan-Meier生存曲线，生存曲线比较采用Log-rank检验，对可能影响患者预后的各因素进行Cox回归分析。结果 97例患者中共检出KRAS基因突变患者34例(35.05%)，其中检出12号密码子突变患者21例(61.76%)，13号密码子突变患者13例(38.24%)。KRAS基因突变与患者肝硬化、肝内转移、肿瘤数目均显著相关(χ²值分别为0.035、3.965、6.593，P值均＜0.05)。Kaplan-Meier生存分析结果显示，KRAS基因野生型患者无进展生存期及总体生存时间均显著优于KRAS突变型(χ²值分别为4.465、4.280，P值均＜0.05)。Cox分析结果显示，KRAS基因状态、肝内转移、肿瘤数目、BCLC分期进入回归模型为影响患者总体生存预后的重要因素(P值均＜0.05)。结论 KRAS基因突变在肝癌患者中较为常见，KRAS基因突变与患者TACE术后不良预后密切相关，可成为患者临床预后监测的潜在指标。
- 肝肿瘤 /
- 基因 /
- 化学栓塞, 治疗性 /
- 预后
Abstract: Objective To assess the prognostic value of KRAS mutation in patients with advanced primary liver cancer treated with transcatheter arterial chemoembolization (TACE). Methods Ninety-seven patients with advanced primary liver cancer who received TACE treatment in The Third People's hospital from April 2017 to May 2020 were included. The mutation status of KRAS was detected, and its relationship with the prognosis of TACE was investigated. The t-test was used for comparison of continuous data between two groups, and the chi-square test was used for comparison of categorical data between two groups. Survival analysis was performed using Kaplan-Meier survival curve and compared using Log-rank test. Cox regression analysis was performed to identify the prognostic factors. Results Among 97 patients with advanced liver cancer, KRAS mutations were detected in 34 patients (35.05%), including 21 patients with codon 12 mutation (61.76%) and 13 patients with codon 13 mutation (38.24%). KRAS mutation was associated with liver cirrhosis, intrahepatic metastasis and the number of tumors (χ²=0.035, 3.965, and 6.593, all P < 0.05). Survival analysis showed that the progression free survival and overall survival were significantly longer in KRAS wild-type patients than in KRAS mutant patients (χ²=4.465 and 4.280, all P < 0.05). Multivariate Cox analysis revealed that KRAS mutation, intrahepatic metastasis, number of tumors and BCLC stage were important factors affecting the overall survival and prognosis of patients (all P < 0.05). Conclusion KRAS mutation is common in patients with advanced primary liver cancer and is closely associated with a poor prognosis after TACE. It may become a potential indicator of clinical prognosis.
- Liver Neoplasms /
- Genes /
- Chemoembolization, Therapeutic /
- Prognosis

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图 1 KRAS基因12、13密码子序列突变图谱

注：a, KRAS基因12、13密码子野生型基因序列；b, KRAS基因12密码子GGT→GAT突变；c, KRAS基因12密码子GGT→GTT突变；d, KRAS基因13密码子GGC→GAC突变。

Figure 1. Mutation map of KRAS gene codons 12 and 13

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图 2 KRAS基因状态与患者PFS的关系

Figure 2. Relationship between KRAS gene status and progression-free survival analysis of patients

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图 3 KRAS基因状态与患者OS的关系

Figure 3. Relationship between KRAS gene status and overall survival analysis of patients

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表 1 KRAS基因突变状态与患者临床特征的关系

Table 1. The relationship between KRAS gene mutation status and clinical characteristics of patients

临床资料	KRAS突变型 (n=34)	KRAS野生型 (n=63)	统计值	P值
性别(例)			χ²=0.370	0.543
男	20	41
女	14	22
年龄(岁)	55.12±14.21	56.93±10.04	t=0.730	0.468
乙型肝炎病史(例)			χ²=0.057	0.811
阴性	30	56
阳性	4	7
ALT(U/L)	49.85±14.20	51.24±15.22	t=0.439	0.662
凝血酶原时间(s)	12.83±1.84	13.02±2.10	t=0.443	0.659
总胆红素(mmol/L)	17.94±3.73	18.05±3.16	t=0.153	0.878
白蛋白(g/L)	40.27±6.49	40.53±5.98	t=0.198	0.843
AFP(ng/L)	438.95±109.32	409.64±97.58	t=1.353	0.179
肿瘤大小(cm)	7.39±2.30	7.02±2.15	t=0.789	0.432
肝硬化(例)			χ²=0.035	0.852
有	27	49
无	7	14
肝内转移(例)			χ²=3.965	0.047
有	16	17
无	18	46
肿瘤数目(例)			χ²=6.593	0.010
单个	23	56
多个	11	7
腹水(例)			χ²=0.057	0.811
无	31	55
有	3	8
Child-Pugh分级(例)			χ²=0.056	0.812
A	24	43
B	10	20
BCLC分期(例)			χ²=0.074	0.785
B	22	39
C	12	24

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表 2 影响患者预后的Cox分析

Table 2. Cox analysis affecting patient outcomes

自变量	RR	95%CI	P值
性别(男性=0，女性=1)	2.734	0.983~7.935	0.283
年龄(≥60岁=0，＜60岁=1)	3.038	0.627~10.293	0.276
KRAS基因状态(突变型=0，野生型=1)	18.273	5.584~98.305	0.001
乙型肝炎病史(有=0，无=1)	5.484	0.719~9.380	0.193
ALT(≥40 U/L=0，＜40 U/L=1)	2.079	0.417~12.953	0.389
凝血酶原时间(≥12 s=0，＜12 s=1)	1.092	0.271~9.182	0.849
总胆红素(≥18 nmol/L=0，＜18 nmol/L=1)	1.684	0.495~7.293	0.711
白蛋白(≥40 g/L=0，＜40 g/L=1)	2.087	0.408~11.235	0.419
AFP(≥400 ng/L=0，＜400 ng/L=1)	2.193	0.602~11.293	0.619
肿瘤大小(≥7 cm=0，＜7 cm=1)	2.183	0.485~7.304	0.280
肝硬化(有=0，无=1)	1.804	0.198~10.237	0.695
肝内转移(有=0，无=1)	11.475	3.029~56.490	0.018
肿瘤数目(单发=0，多发=1)	10.038	2.973~19.328	0.021
腹水(有=0，无=1)	2.013	0.421~8.106	0.174
Child-Pugh分级(A=0，B=1)	2.189	0.569~7.491	0.209
BCLC分期(B=0，C=1)	12.384	2.385~29.305	0.011

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