Construction of risk model associated with prognosis of lung adenocarcinoma based on a set of microRNAs by analyzing TCGA database

doi:10.3877/cma.j.issn.2095-5820.2018.02.006

Abstract

Abstract:

Objective

To explore the specific prognosis related microRNAs (miRNAs) of lung adenocarcinoma (LUAD), and provide basis for prognosis prediction and individualized treatment.

Methods

The miRNA-Seq data and clinical information of LUAD patients were downloaded from the TCGA database, and the differentially expressed miRNAs between LUAD and adjacent normal tissues were identified by R Language. The LASSO & COX regression was used to develop a miRNA-based model for predicting patients? survival in the training set (n=245) and to carry out LUAD prognostic related miRNAs screening, and to construct a linear risk model based on 7 miRNAs expression profiles. According to the risk values, the patients were divided into high and low risk groups with the median risk value as the boundary, and the effectiveness of the prognosis was verified by the risk model in the test set (n=245) and the total specimens (n=490) respectively. COX regression analysis was used to determine whether the miRNAs risk model was an independent prognostic factor.

Results

Seventy-two differentially expressed miRNAs were identified between LUAD and adjacent normal tissues. forty-five miRNAs were up-regulated and 27 were down-regulated in LUAD tissues. Seven survival-related miRNAs (miR-101-3p, miR-148a-3p, miR-192-5p, miR-193b-3p, miR-505-3p, miR-584-5p, and miR-99a-5p) were identified in the training set and a prognostic model based on the expression of the 7 miRNAs was developed and its coefficient was evaluated. It showed that the overall survival time of the high-risk group was significantly lower than that of the low risk group in the training set, test set and whole cohort (P<0.05). Multivariate cox regression analysis indicated that the risk model was an independent prognostic factor in the training set, test set and whole cohort (training set HR=1.97, P=0.02; test set HR=1.927, P=0.009; overall HR=1.909, P=0.001).

Conclusion

Seven miRNAs are identified to be significantly associated with the prognosis of LUAD patients and the risk model based on the 7 miRNAs could be an independent prognostic factor.

Key words: Lung adenocarcinoma, MicroRNAs, Prognosis, TCGA

Kang Lin, Bei Pan, Xueni Xu, Huiling Sun, Shukui Wang. Construction of risk model associated with prognosis of lung adenocarcinoma based on a set of microRNAs by analyzing TCGA database[J]. Chinese Journal of Clinical Laboratory Management(Electronic Edition), 2018, 06(02): 89-98.

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Figures/Tables 7

References 37

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临床变量			总体(n=490)	训练集(n=245)	测试集(n=245)	检验值	P值
年龄[岁(±s)]			65±10	65±10	66±10	-1.144^a	0.253
?	<=65[岁,n(%)]	?	230(46.94)	121(49.39)	109(44.49)	1.402^b	0.236
?	>65[岁,n(%)]	?	250(51.02)	118(48.16)	132(53.88)	?	?
性别[n(%)]		男	230(46.94)	108(44.08)	122(49.80)	1.606^b	0.205
?	?	女	260(53.06)	137(55.92)	123(50.20)	?	?
吸烟状态[n(%)]		否	69(14.08)	32(13.06)	37(15.10)	0.495^b	0.781
?	?	戒烟	291(59.39)	145(59.18)	146(59.59)	?	?
?	?	是	116(23.67)	60(24.49)	56(22.86)	?	?
肿瘤分期[n(%)]		I期	266(54.29)	140(57.14)	126(51.43)	2.388^b	0.496
?	?	II期	115(23.47)	56(22.86)	59(24.08)	?	?
?	?	III期	79(16.12)	34(13.88)	45(18.37)	?	?
?	?	IV期	23(4.69)	11(4.49)	12(4.90)	?	?
浸润深度[n(%)]		T1	165(33.67)	83(33.88)	82(33.47)	1.554^b	0.670
?	?	T2	261(53.27)	134(54.69)	127(51.84)	?	?
?	?	T3	43(8.78)	18(7.35)	25(10.20)	?	?
?	?	T4	18(3.67)	8(3.27)	10(4.08)	?	?
淋巴结转移[n(%)]		N0	317(64.69)	161(65.71)	156(63.67)	0.432^b	0.962
?	?	N1	92(18.78)	45(18.37)	47(19.18)	?	?
?	?	N2	68(13.88)	33(13.47)	35(14.29)	?	?
?	?	N3	2(0.41)	1(0.41)	1(0.41)	?	?
远处转移[n(%)]		M0	326(66.53)	157(64.08)	167(68.16)	0.074^b	0.785
?	?	M1	22(4.49)	10(4.08)	12(4.90)	?	?
生存状态[n(%)]		存活	324(66.12)	161(65.71)	163(66.53)	0.036^b	0.849
?	?	死亡	166(33.88)	84(34.29)	82(33.47)	?	?
生存时间[月(±s)]			27.08±17.22	27.26±18.32	26.90±16.08	0.231^c	0.818

临床变量			总体(n=490)	训练集(n=245)	测试集(n=245)	检验值	P值
年龄[岁(±s)]			65±10	65±10	66±10	-1.144^a	0.253
?	<=65[岁,n(%)]	?	230(46.94)	121(49.39)	109(44.49)	1.402^b	0.236
?	>65[岁,n(%)]	?	250(51.02)	118(48.16)	132(53.88)	?	?
性别[n(%)]		男	230(46.94)	108(44.08)	122(49.80)	1.606^b	0.205
?	?	女	260(53.06)	137(55.92)	123(50.20)	?	?
吸烟状态[n(%)]		否	69(14.08)	32(13.06)	37(15.10)	0.495^b	0.781
?	?	戒烟	291(59.39)	145(59.18)	146(59.59)	?	?
?	?	是	116(23.67)	60(24.49)	56(22.86)	?	?
肿瘤分期[n(%)]		I期	266(54.29)	140(57.14)	126(51.43)	2.388^b	0.496
?	?	II期	115(23.47)	56(22.86)	59(24.08)	?	?
?	?	III期	79(16.12)	34(13.88)	45(18.37)	?	?
?	?	IV期	23(4.69)	11(4.49)	12(4.90)	?	?
浸润深度[n(%)]		T1	165(33.67)	83(33.88)	82(33.47)	1.554^b	0.670
?	?	T2	261(53.27)	134(54.69)	127(51.84)	?	?
?	?	T3	43(8.78)	18(7.35)	25(10.20)	?	?
?	?	T4	18(3.67)	8(3.27)	10(4.08)	?	?
淋巴结转移[n(%)]		N0	317(64.69)	161(65.71)	156(63.67)	0.432^b	0.962
?	?	N1	92(18.78)	45(18.37)	47(19.18)	?	?
?	?	N2	68(13.88)	33(13.47)	35(14.29)	?	?
?	?	N3	2(0.41)	1(0.41)	1(0.41)	?	?
远处转移[n(%)]		M0	326(66.53)	157(64.08)	167(68.16)	0.074^b	0.785
?	?	M1	22(4.49)	10(4.08)	12(4.90)	?	?
生存状态[n(%)]		存活	324(66.12)	161(65.71)	163(66.53)	0.036^b	0.849
?	?	死亡	166(33.88)	84(34.29)	82(33.47)	?	?
生存时间[月(±s)]			27.08±17.22	27.26±18.32	26.90±16.08	0.231^c	0.818

miRNA分类	log2FC	FDR	miRNA分类	log2FC	FDR	miRNA分类	log2FC	FDR	miRNA分类	log2FC	FDR
miR-210-3p	6.00	2.2E-158	miR-21-3p	2.05	3.08E-47	miR-29b-3p	1.24	1.98E-17	let-7e-5p	-1.41	1.20E-19
miR-9-5p	4.92	1.06E-50	miR-182-5p	2.00	5.03E-38	miR-200c-5p	1.23	4.30E-15	miR-101-3p	-1.41	8.43E-33
miR-205-5p	3.09	3.26E-15	miR-200a-3p	1.83	3.31E-23	miR-429	1.21	8.53E-13	miR-126-5p	-1.50	2.86E-32
miR-708-5p	2.81	3.14E-47	miR-331-3p	1.82	2.25E-36	miR-625-3p	1.19	5.71E-17	miR-374a-5p	-1.69	3.49E-59
miR-192-5p	2.78	1.93E-16	miR-141-5p	1.74	4.48E-29	miR-199a-5p	1.17	1.51E-16	miR-378a-3p	-1.76	9.37E-31
miR-135b-5p	2.70	1.41E-34	miR-339-5p	1.68	1.57E-29	miR-17-5p	1.11	7.45E-14	miR-145-3p	-1.76	1.17E-48
let-7g-3p	2.63	1.03E-57	miR-1307-3p	1.67	1.84E-33	miR-328-3p	1.10	1.06E-14	let-7a-5p	-1.80	9.89E-39
miR-708-3p	2.62	3.36E-53	miR-424-5p	1.67	9.25E-19	miR-501-3p	1.06	1.20E-12	let-7c-5p	-1.86	3.09E-33
miR-193b-3p	2.59	5.56E-36	miR-21-5p	1.62	2.87E-45	miR-191-5p	1.04	2.49E-21	miR-30a-5p	-1.98	9.77E-31
miR-455-3p	2.51	5.30E-47	miR-141-3p	1.48	4.05E-21	miR-584-5p	-1.03	6.11E-06	miR-218-5p	-1.99	1.02E-53
miR-127-5p	2.51	2.62E-26	miR-134-5p	1.45	1.35E-08	miR-99a-5p	-1.06	3.95E-14	let-7f-5p	-2.18	6.85E-36
miR-143-5p	2.40	5.74E-33	miR-532-3p	1.38	9.24E-21	miR-139-5p	-1.09	1.34E-10	miR-195-5p	-2.42	6.51E-68
miR-183-5p	2.39	3.18E-42	miR-93-5p	1.34	1.32E-21	let-7a-3p	-1.10	2.22E-23	miR-30a-3p	-2.72	2.80E-54
miR-375	2.38	1.73E-17	miR-505-3p	1.33	3.40E-28	miR-223-3p	-1.19	9.09E-11	miR-143-3p	-2.82	2.05E-56
miR-200a-5p	2.21	3.12E-41	miR-151a-5p	1.30	8.34E-34	miR-374b-5p	-1.20	2.27E-41	miR-30c-2-3p	-2.89	1.96E-59
miR-194-5p	2.21	1.36E-11	miR-425-5p	1.28	2.05E-19	miR-26a-5p	-1.30	1.40E-33	miR-451a	-2.98	7.90E-37
miR-224-5p	2.19	2.90E-18	miR-423-3p	1.27	1.09E-35	let-7g-5p	-1.32	3.03E-34	miR-486-5p	-3.11	1.58E-39
miR-142-3p	2.09	6.51E-29	miR-148a-3p	1.25	1.23E-17	miR-140-3p	-1.35	4.62E-38	miR-144-5p	-3.42	4.03E-50

miRNA分类	log2FC	FDR	miRNA分类	log2FC	FDR	miRNA分类	log2FC	FDR	miRNA分类	log2FC	FDR
miR-210-3p	6.00	2.2E-158	miR-21-3p	2.05	3.08E-47	miR-29b-3p	1.24	1.98E-17	let-7e-5p	-1.41	1.20E-19
miR-9-5p	4.92	1.06E-50	miR-182-5p	2.00	5.03E-38	miR-200c-5p	1.23	4.30E-15	miR-101-3p	-1.41	8.43E-33
miR-205-5p	3.09	3.26E-15	miR-200a-3p	1.83	3.31E-23	miR-429	1.21	8.53E-13	miR-126-5p	-1.50	2.86E-32
miR-708-5p	2.81	3.14E-47	miR-331-3p	1.82	2.25E-36	miR-625-3p	1.19	5.71E-17	miR-374a-5p	-1.69	3.49E-59
miR-192-5p	2.78	1.93E-16	miR-141-5p	1.74	4.48E-29	miR-199a-5p	1.17	1.51E-16	miR-378a-3p	-1.76	9.37E-31
miR-135b-5p	2.70	1.41E-34	miR-339-5p	1.68	1.57E-29	miR-17-5p	1.11	7.45E-14	miR-145-3p	-1.76	1.17E-48
let-7g-3p	2.63	1.03E-57	miR-1307-3p	1.67	1.84E-33	miR-328-3p	1.10	1.06E-14	let-7a-5p	-1.80	9.89E-39
miR-708-3p	2.62	3.36E-53	miR-424-5p	1.67	9.25E-19	miR-501-3p	1.06	1.20E-12	let-7c-5p	-1.86	3.09E-33
miR-193b-3p	2.59	5.56E-36	miR-21-5p	1.62	2.87E-45	miR-191-5p	1.04	2.49E-21	miR-30a-5p	-1.98	9.77E-31
miR-455-3p	2.51	5.30E-47	miR-141-3p	1.48	4.05E-21	miR-584-5p	-1.03	6.11E-06	miR-218-5p	-1.99	1.02E-53
miR-127-5p	2.51	2.62E-26	miR-134-5p	1.45	1.35E-08	miR-99a-5p	-1.06	3.95E-14	let-7f-5p	-2.18	6.85E-36
miR-143-5p	2.40	5.74E-33	miR-532-3p	1.38	9.24E-21	miR-139-5p	-1.09	1.34E-10	miR-195-5p	-2.42	6.51E-68
miR-183-5p	2.39	3.18E-42	miR-93-5p	1.34	1.32E-21	let-7a-3p	-1.10	2.22E-23	miR-30a-3p	-2.72	2.80E-54
miR-375	2.38	1.73E-17	miR-505-3p	1.33	3.40E-28	miR-223-3p	-1.19	9.09E-11	miR-143-3p	-2.82	2.05E-56
miR-200a-5p	2.21	3.12E-41	miR-151a-5p	1.30	8.34E-34	miR-374b-5p	-1.20	2.27E-41	miR-30c-2-3p	-2.89	1.96E-59
miR-194-5p	2.21	1.36E-11	miR-425-5p	1.28	2.05E-19	miR-26a-5p	-1.30	1.40E-33	miR-451a	-2.98	7.90E-37
miR-224-5p	2.19	2.90E-18	miR-423-3p	1.27	1.09E-35	let-7g-5p	-1.32	3.03E-34	miR-486-5p	-3.11	1.58E-39
miR-142-3p	2.09	6.51E-29	miR-148a-3p	1.25	1.23E-17	miR-140-3p	-1.35	4.62E-38	miR-144-5p	-3.42	4.03E-50

临床变量		变量比较类别	单因素分析		多因素分析
临床变量		变量比较类别	HR(95%CI)	P值	HR(95%CI)	P值
训练集(n=245)
?	年龄	>65岁比≤65岁	1.121(0.727-1.729)	0.606	0.902(0.517-1.573)	0.717
?	性别	男比女	1.101(0.715-1.694)	0.662	0.808(0.436-1.496)	0.498
?	浸润深度	T4＋T3比T2＋T1	2.749(1.536-4.920)	0.001	2.624(1.318-5.221)	0.006
?	淋巴结转移	N3＋N2＋N1比N0	2.343(1.514-3.625)	<0.001	1.817(0.999-3.303)	0.050
?	远处转移	M1比M0	2.678(1.212-5.918)	0.015	1.455(0.516-4.106)	0.479
?	肿瘤分期	IV＋III比II＋I	2.632(1.671-4.148)	<0.001	1.227(0.497-3.026)	0.657
?	风险评估模型	高风险比低风险	2.233(1.436-3.471)	<0.001	1.970(1.112-3.490)	0.020
测试集(n=245)
?	年龄	>65岁比. ≤65岁	1.083(0.701-1.673)	0.720	1.203(0.717-2.018)	0.483
?	性别	男比女	1.005(0.651-1.551)	0.984	0.997(0.617-1.609)	0.989
?	肿瘤浸润深度	T4＋T3比T2＋T1	2.058(1.200-3.528)	0.009	1.652(0.867-3.146)	0.127
?	淋巴结转移	N3＋N2＋N1比N0	2.749(1.772-4.264)	<0.001	1.876(1.084-3.247)	0.025
?	远处转移	M1比M0	2.111(0.961-4.641)	0.063	1.664(0.624-4.434)	0.309
?	肿瘤分期	IV＋III比II＋I	2.867(1.817-4.523)	<0.001	1.977(1.124-3.478)	0.018
?	风险评估模型	高风险比低风险	1.686(1.082-2.626)	0.021	1.927(1.181-3.145)	0.009
总体(n=490)
?	年龄	>65岁比≤65岁	1.103(0.812-1.500)	0.530	1.033(0.717-1.489)	0.862
?	性别	男比女	1.055(0.778-1.432)	0.729	0.920(0.641-1.320)	0.651
?	肿瘤浸润深度	T4＋T3比T2＋T1	2.351(1.583-3.490)	<0.001	1.794(1.103-2.918)	0.019
?	淋巴结转移	N3＋N2＋N1比N0	2.526(1.854-3.440)	<0.001	1.753(1.139-2.699)	0.011
?	远处转移	M1比.M0	2.359(1.350-4.120)	0.003	1.374(0.692-2.728)	0.364
?	肿瘤分期	IV＋III比II＋I	2.733(1.983-3.767)	<0.001	1.605(0.989-2.604)	0.055
?	风险评估模型	高风险比低风险	1.941(1.420-2.653)	<0.001	1.909(1.320-2.760)	0.001

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