结节性硬化基因1/2突变与肝细胞癌进展及预后的关系

张勇; 毛正发

doi:10.3969/j.issn.1001-5256.2021.01.017

结节性硬化基因1/2突变与肝细胞癌进展及预后的关系

DOI: 10.3969/j.issn.1001-5256.2021.01.017

张勇,
毛正发^,

江苏大学附属医院普外科，江苏镇江 225500

基金项目:

国家自然科学基金 (81502372)

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，特此声明。

作者贡献声明：张勇负责课题设计，资料分析，撰写论文；毛正发负责收集数据，修改论文；张勇、毛正发负责拟定写作思路，指导撰写文章并最后定稿。

详细信息

作者简介:
张勇(1978—)，男，副主任医师，主要从事肝胆病方面的研究

通信作者:
毛正发，2630698662@qq.com

中图分类号: R735.7
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- 被引次数: 0
出版历程
- 收稿日期: 2020-07-02
- 录用日期: 2020-08-03
- 出版日期: 2021-01-20

Association of tuberous sclerosis gene 1/2 mutations with the progression of hepatocellular carcinoma and prognosis

Yong ZHANG,
Zhengfa MAO^,

Department of General Surgery, The Affiliated Hospital of Jiangsu University, Zhenjiang, Jiangsu 225500, China

摘要

摘要: 目的探讨肝细胞癌(HCC)患者结节性硬化基因1/2(TSC1/2)突变与HCC严重程度及预后的关系，为HCC的诊断及治疗提供可行性依据。方法选取2012年1月—2020年1月江苏大学附属医院收治的HCC患者492例，其中59例患者出现TSC1/2基因突变(TSC1突变20例，TSC2突变41例，共同突变2例)，分析TSC1/2突变组患者的临床特征，及TSC1/2突变与HCC临床分期相关性。对35例突变组和35例未突变组患者进行3年随访，观察TSC1/2突变对HCC预后的影响。计数资料两组间比较采用χ²检验；等级资料两组间比较采用Kruskal-Wallis H秩和检验；采用多元logistic回归分析相关性，随访资料采用Kaplan-Meier生存分析。结果 492例HCC患者中，TSC1/2基因总体突变率为11.99%。TSC1、TSC2基因突变组患者性别、年龄、Child-Pugh评分及肿瘤大小与未突变组相较差异均无统计学意义(P值均＞0.05)，两组肿瘤个数、肝外转移情况及PS评分比较差异均有统计学意义(P值均＜0.05)。logistic回归分析结果显示，TSC1/TSC2基因突变与HCC临床分期严重程度呈正相关(OR=1.706，P＜0.05)。随访结果显示，TSC1/2突变组患者的生存率明显低于未突变组，前者3年病死率高达60.3%，与未突变组(38.6%)比较差异有统计学意义(χ²=3.923, P＜0.05)。结论 TSC1/2基因突变可能早期预测HCC的恶性进展，TSC1/2突变的患者预后更差，应用基因突变靶向药物治疗对于延缓HCC发展可能具有一定疗效。
- 癌, 肝细胞 /
- 结节性硬化症 /
- 基因 /
- 突变
Abstract: Objective To investigate the association of tuberous sclerosis gene 1/2 (TSC1/2) mutation with disease severity and prognosis in patients with hepatocellular carcinoma (HCC), and to provide a feasible basis for the diagnosis and treatment of HCC. Methods A total of 492 patients with HCC who were admitted to The Affiliated Hospital of Jiangsu University from January 2012 to January 2020 were enrolled, among whom 59 had TSC1/2 mutations (20 with TSC1 mutations, 41 with TSC2 mutations, and 2 had both TSC1 and TSC2 mutations). The clinical features of patients with TSC1/2 mutations were analyzed, and the association of TSC1/2 mutations with the clinical stage of HCC was analyzed. The 35 patients in the mutation group and 35 in the non-mutation group were followed up for 3 years to observe the effect of TSC1/2 mutations on the prognosis of HCC. The chi-square test was used for comparison of categorical data between groups; the Kruskal-Wallis H test was used for comparison of ranked data between groups; a multivariate logistic regression analysis was used to investigate association; the Kaplan-Meier survival analysis was used to analyze follow-up data. Results For the 492 patients with HCC, the overall TSC1/2 mutation rate was 11.99%. There were no significant differences in sex, age, Child score, and tumor size between the TSC1/TSC2 mutation group and the non-mutation group (all P > 0.05), while there were significant differences in tumor number, extrahepatic metastasis, and PS score between the two groups (all P < 0.05). The logistic regression analysis showed that TSC1/TSC2 gene mutation was positively correlated with the severity of HCC (odds ratio=1.706, P < 0.05). The follow-up results showed that the TSC1/2 mutation group had a significantly lower survival rate than the non-mutation group, and there was a significant difference in 3-year mortality rate between the TSC1/2 mutation group and the non-mutation group (60.3% vs 38.6%, χ²=3.923, P < 0.05). Conclusion TSC1/TSC2 gene mutation may predict the malignant progression of HCC in the early stage, and patients with TSC1/2 mutation tend to have poor prognosis. Targeted drug therapy for gene mutations may have a certain effect in delaying the progression of HCC.
- Carcinoma, Hepatocellular /
- Tuberous Sclerosis /
- Gene /
- Mutation

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图 1 TSC1/2突变组与未突变组患者生存情况

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表 1 TSC1/2基因突变患者临床特征比较

项目	TSC1				TSC2
项目	突变(n=20)	未突变(n=472)	χ²值	P值	突变(n=41)	未突变(n=451)	χ²值	P值
性别[例(%)]			0.80	＞0.05			1.08	＞0.05
男	14(70)	344(73)			27(66)	331(73)
女	6(30)	128(27)			14(34)	120(27)
年龄[例(%)]			0.01	＞0.05			0.12	＞0.05
40~60岁	12(60)	284(61)			25(61)	271(60)
60~75岁	8(40)	188(39)			16(39)	180(40)
肿瘤大小[例(%)]			1.92	＞0.05			0.25	＞0.05
≥5个	13(65)	309(65)			26(63)	296(66)
＜5个	7(35)	163(35)			15(37)	155(34)
肿瘤个数[例(%)]			29.90	＜0.05			47.5	＜0.05
单个	1(05)	130(28)			5(12)	126(28)
多个	19(95)	342(72)			36(88)	325(72)
肝外转移[例(%)]			10.91	＜0.05			7.56	＜0.05
否	7(35)	394(83)			17(41)	384(85)
是	13(65)	78(17)			24(59)	67(15)
PS评分[例(%)]			4.58	＜0.05			4.19	＜0.05
0~2分	14(70)	410(87)			31(76)	393(87)
3~4分	6(30)	62(13)			10(24)	58(13)
Child-Pugh分级[例(%)]			4.39	＞0.05			2.51	＞0.05
A级	1(5)	100(22)			8(10)	93(20)
B级	14(70)	309(65)			24(68)	299(67)
C级	5(25)	63(13)			9(22)	59(13)

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表 2 随访的TSC1/2突变组与未突变组患者基本情况比较

项目	TSC1/2未突变(n=35)	TSC1/2突变(n=35)	χ²值	P值
性别[例(%)]			2.20	＞0.05
男	25(71)	19(54)
女	10(29)	16(46)
年龄[例(%)]			1.43	＞0.05
≥40岁且＜60岁	21(60)	16(46)
≥60岁且＜75岁	14(40)	19(54)
一级亲属[例(%)]			1.29	＞0.05
患肝癌	6(17)	10(29)
无肝癌	29(83)	25(71)
二级亲属[例(%)]			1.75	＞0.05
患肝癌	5(14)	2(6)
无肝癌	30(86)	33(94)
吸烟史[例(%)]			0.58	＞0.05
有	20(57)	19(54)
无	15(43)	16(46)
饮酒史[例(%)]			0.01	＞0.05
有	27(77)	23(66)
无	8(23)	12(34)
治疗方式[例(%)]			0.86	＞0.05
手术治疗	12(34)	15(43)
介入治疗	18(51)	17(49)
药物治疗	5(15)	3(8)
肝病病程[例(%)]			2.69	＞0.05
≤10年	6(17)	12(34)
＞10年	29(83)	23(66)

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