基于时钟基因启动子区甲基化的胃癌患者预后预测模型的建立与验证

黄一波; 牛英群; 黄国强; 胡如英

doi:10.16766/j.cnki.issn.1674-4152.002272

基于时钟基因启动子区甲基化的胃癌患者预后预测模型的建立与验证

doi: 10.16766/j.cnki.issn.1674-4152.002272

1.
浙江中医药大学附属二院普外科，浙江杭州 310005
2.
浙江中医药大学附属二院胃肠外科，浙江杭州 310005

基金项目:

浙江省医药卫生科技计划项目 2017KY517

浙江省医药卫生科技计划项目 2014KYB180

详细信息

通讯作者:
牛英群，E-mail：niuyingqun@163.com

中图分类号: R735.2 R730.4
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- 文章访问数: 152
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- 被引次数: 0
出版历程
- 收稿日期: 2020-07-09
- 网络出版日期: 2022-03-03

Establishment and verification of a prognostic model for patients with gastric cancer based on clock gene promoter methylation

1.
Department of General Surgery, the Second Affiliated Hospital of Zhejiang University of Traditional Chinese Medicine, Hangzhou, Zhejiang 310005, China

摘要

摘要: 目的建立基于时钟基因启动子区甲基化的胃癌患者预后的预测模型并验证其效能。方法选取2015年1月—2018年1月浙江中医药大学附属二院收治的胃癌患者459例，术后随访2年，根据复发情况分为复发组和未复发组。对比2组患者一般资料、手术相关资料、时钟基因启动子区甲基化情况，行多因素logistic回归分析研究复发的独立影响因素，使用R软件建立复发的预测模型，并验证其效能。结果随访过程中5例患者失访，剩余454例患者中，217例肿瘤复发列为复发组，其余237例未复发列为非复发组，胃癌复发率为47.80%(217/454)。2组分化程度、淋巴结转移、肿瘤生长方式以及per1、per2、cry1、clock时钟基因启动子区甲基化差异有统计学意义(均P < 0.05)。多因素logistic回归分析结果显示，分化程度(OR=0.519，P=0.006)、淋巴结转移(OR=2.365，P＜0.001)、肿瘤生长方式(OR=0.616，P=0.036)、per1(OR=24.108，P＜0.001)、per2(OR=2.152，P=0.008)、cry1(OR=3.131，P＜0.001)、clock(OR=1.676，P=0.024)是胃癌复发的独立影响因素。预测模型预测复发发生的一致性指数为0.906(95% CI：0.879~0.938)。结论分化程度、淋巴结转移、肿瘤生长方式及per1、per2、cry1、clock时钟基因启动子区甲基化作为影响因素建立的预测模型可有效预测胃癌的复发，并具有较好的应用价值。
- 胃癌 /
- 时钟基因 /
- 启动子区 /
- 甲基化 /
- 预测模型
Abstract: Objective To establish and certificate a prognostic model for gastric cancer patients based on methylation of the promoter region of the clock gene. Methods A total of 459 patients with gastric cancer admitted to the Second Affiliated Hospital of Zhejiang University of Traditional Chinese Medicine from January 2015 to January 2018 were selected. They were followed up for 2 years after operation and were divided into the recurrence group and non-recurrence group according to the recurrence. The differences in the general data, surgery-related data and methylation frequency of the clock gene promoter region between the two groups were compared. Multivariate logistic regression analysis was performed to determine the independent influencing factors of recurrence, and R software was used to establish a predictive model of recurrence and verify its efficacy. Results During follow-up, 5 cases were lost to follow-up. Among the remaining 454 patients, 217 had recurrence and were classified as the recurrence group, and the remaining 237 cases without recurrence were classified as the non-recurrence group. The recurrence rate of gastric cancer was 47.80% (217/454). There were statistically significant differences in the degree of differentiation, lymph node metastasis, tumour growth pattern and methylation frequency of the per1, per2, cry1 and clock gene promoter regions between the two groups (P < 0.05). Multivariate logistic regression analysis showed that the degree of differentiation (OR=0.519, P < 0.05), lymph node metastasis (OR=2.365, P < 0.05), tumour growth pattern (OR=0.616, P < 0.05), per1 (OR=24.108, P < 0.05), per2 (OR=2.152, P < 0.05), cry1 (OR=3.131, P < 0.05) and clock (OR=1.676, P < 0.05) were independent factors affecting gastric cancer recurrence. The prediction model showed that the consistency index of recurrence was 0.906 (95% CI: 0.879-0.938). Conclusion The degree of differentiation, lymph node metastasis, tumour growth pattern and methylation of the per1, per2, cry1 and clock gene promoter regions as influencing factors can effectively predict the recurrence of gastric cancer, and have good application value.
- Gastric cancer /
- Clock gene /
- Promoter /
- Methylation /
- Prediction model

HTML全文

图 1 胃癌复发的预测模型

下载: 全尺寸图片幻灯片

图 2 胃癌复发的校正曲线

下载: 全尺寸图片幻灯片

表 1 2组胃癌患者一般资料比较

组别	例数	性别(例)		年龄(x ±s, 岁)	BMI(x ±s)	高血压(例)		长期吸烟(例)		长期饮酒(例)
组别	例数	男性	女性	年龄(x ±s, 岁)	BMI(x ±s)	否	是	否	是	否	是
复发组	217	148	69	51.37±7.34	20.19±3.46	158	59	136	81	130	87
非复发组	237	157	80	52.42±8.52	20.53±2.99	185	52	165	72	154	83
统计量		0.197^a		1.401^b	1.123^b	1.689^a		2.447^a		1.244^a
P值		0.657		0.162	0.262	0.194		0.118		0.265
注：^a为χ²值，^b为t值。

下载: 导出CSV

表 2 2组胃癌患者手术相关情况比较

组别	例数	TNM分期(例)		分化程度(例)		病灶直径 (x ±s, cm)	淋巴结转移(例)		肿瘤部位(例)			肿瘤生长方式(例)
组别	例数	Ⅰ/Ⅱ期	Ⅲ/Ⅳ期	高+中	低	病灶直径 (x ±s, cm)	否	是	胃窦	贲门部	胃体部	膨胀型	浸润型
复发组	217	121	106	128	89	4.78±1.12	112	105	113	71	33	74	143
非复发组	237	136	101	176	61	4.91±1.27	154	83	126	83	28	120	117
统计量		0.122^a		11.948^a		1.152^b	8.341^a		1.173^a			12.651^a
P值		0.727		＜0.001		0.250	0.004		0.556			＜0.001
注：^a为χ²值，^b为t值。

下载: 导出CSV

表 3 2组胃癌患者时钟基因启动子区甲基化情况比较(例)

组别	例数	per1		per2		cry1		cry2		clock		bmal1		npas2
组别	例数	否	是	否	是	否	是	否	是	否	是	否	是	否	是
复发组	217	152	65	158	59	162	55	191	26	166	51	169	48	180	37
非复发组	237	223	14	210	27	214	23	206	31	207	30	198	39	207	30
χ²值		45.574		18.409		19.476		0.125		9.088		2.346		1.737
P值		＜0.001		＜0.001		＜0.001		0.724		0.003		0.126		0.187

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表 4 胃癌患者复发的多因素logistic回归分析

项目	B	SE	Wald χ²	P值	OR值	95% CI
分化程度	-0.657	0.240	7.519	0.006	0.519	0.324~0.829
淋巴结转移	0.861	0.230	14.046	< 0.001	2.365	1.508~3.710
肿瘤生长方式	-0.484	0.231	4.406	0.036	0.616	0.392~0.968
per1	3.183	0.451	49.690	< 0.001	24.108	9.951~58.407
per2	0.767	0.287	7.115	0.008	2.152	1.225~3.781
cry1	1.141	0.292	15.234	< 0.001	3.131	1.765~5.553
clock	0.517	0.229	5.110	0.024	1.676	1.071~2.623

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参考文献(19)

[1]	左婷婷, 郑荣寿, 曾红梅, 等. 中国胃癌流行病学现状[J]. 中国肿瘤临床, 2017, 44(1): 52-58. https://www.cnki.com.cn/Article/CJFDTOTAL-ZGZL201701015.htm
[2]	刘苗, 王英南, 赵群, 等. 不同Lauren分型胃癌的临床病理特征及影响胃癌根治术后复发的危险因素分析[J]. 中国肿瘤, 2019, 28(12): 941-950. doi: 10.11735/j.issn.1004-0242.2019.12.A011
[3]	WU X D, WANG X G, WANG Y, et al. Comparison of clinical efficacy between laparotomy and laparoscopic radical surgery for gastric cancer and their effects on CRP, CEA and insulin resistance[J]. J BUON, 2020, 25(1): 255-261.
[4]	HERNANDEZ-ROSAS F, HERNANDEZ-OLIVERAS A, FLORES-PEREDO L, et al. Histone deacetylase inhibitors induce the expression of tumor suppressor genes Per1 and Per2 in human gastric cancer cells[J]. Oncol Lett, 2018, 16(2): 1981-1990.
[5]	MAO Y D, ZHAO Q H, YIN S, et al. Genome-wide expression profiling and bioinformatics analysis of deregulated genes in human gastric cancer tissue after gastroscopy[J]. Asia Pac J Clin Oncol, 2018, 14(2): e29-e36. doi: 10.1111/ajco.12688
[6]	ROSSI M A. Postresective outcome nomograms: A patient-specific prediction tool for the clinic?[J]. Epilepsy Curr, 2015, 15(5): 257-259. doi: 10.5698/1535-7511-15.5.257
[7]	胡祥. 第5版日本《胃癌治疗指南》拔萃[J]. 中国实用外科杂志, 2018, 38(4): 396-406. https://www.cnki.com.cn/Article/CJFDTOTAL-ZGWK201804018.htm
[8]	LIN Q L, DING H, ZHENG Z, et al. Promoter methylation analysis of seven clock genes in Parkinson's disease[J]. Neurosci Lett, 2012, 507(2): 147-150. doi: 10.1016/j.neulet.2011.12.007
[9]	HANNIBAL J, NORN T, GEORG B, et al. Spatiotemporal expression pattern of PERIOD 1 and PERIOD 2 in the mouse SCN is dependent on VIP receptor 2 signaling[J]. Eur J Neurosci, 2019, 50(7): 3115-3132. doi: 10.1111/ejn.14482
[10]	MAO W, ZHAO C, DING H, et al. Pyrosequencing analysis of methylation levels of clock genes in leukocytes from Parkinson's disease patients[J]. Neurosci Lett, 2018, 668: 115-119. doi: 10.1016/j.neulet.2018.01.027
[11]	YANG S L, REN Q G, WEN L, et al. Research progress on circadian clock genes in common abdominal malignant tumors[J]. Oncol Lett, 2017, 14(5): 5091-5098.
[12]	ZHOU Z R, WANG C C, SUN X J, et al. Prognostic factors in breast phyllodes tumors: A nomogram based on a retrospective cohort study of 404 patients[J]. Cancer Med, 2018, 7(4): 1030-1042. doi: 10.1002/cam4.1327
[13]	王力, 沈洪, 宋国栋, 等. 进展期胃癌患者根治术后复发的危险因素分析[J]. 山东医药, 2016, 56(39): 42-44. https://www.cnki.com.cn/Article/CJFDTOTAL-SDYY201639013.htm
[14]	郑南翔, 单廷. 胃癌根治术患者术后早期复发转移的相关危险因素[J]. 中国老年学杂志, 2017, 37(17): 4301-4303. https://www.cnki.com.cn/Article/CJFDTOTAL-ZLXZ201717065.htm
[15]	HU Y F, HUANG C M, SUN Y H, et al. Morbidity and mortality of laparoscopic versus open D2 distal gastrectomy for advanced gastric cancer: A randomized controlled trial[J]. J Clin Oncol, 2016, 34(12): 1350-1357. doi: 10.1200/JCO.2015.63.7215
[16]	YAMASHITA K, SAKURAMOTO S, KIKUCHI S, et al. Laparoscopic versus open distal gastrectomy for early gastric cancer in Japan: Long-term clinical outcomes of a randomized clinical trial[J]. Surg Today, 2016, 46(6): 741-749.
[17]	JUNG Y Y, SUNG J Y, KIM J Y, et al. Down-regulation of B-cell translocation gene 1 by promoter methylation in colorectal carcinoma[J]. Anticancer Res, 2018, 38(2): 691-697.
[18]	CHEN Y, WANG D, SONG Y, et al. Functional polymorphisms in circadian positive feedback loop genes predict postsurgical prognosis of gastric cancer[J]. Cancer Med, 2019, 8(4): 1919-1929.
[19]	QU F, QIAO Q, WANG N, et al. Genetic polymorphisms in circadian negative feedback regulation genes predict overall survival and response to chemotherapy in gastric cancer patients[J]. Scientific Reports, 2016, 6(5): 22424.