KRAS基因突变类型预测结肠直肠癌根治术后异时性远处转移

doi:10.16139/j.1007-9610.2021.01.014

摘要/Abstract

摘要：

目的：研究结肠直肠癌根治术后异时性远处转移与KRAS基因突变的相关性。方法：回顾性分析结肠直肠癌原发灶根治术后异时性远处转移病人和无转移病人。运用PCR和焦磷酸测序检测KRAS基因类型。通过分析两组病人临床病理因素和KRAS基因类型的差异,寻找预测异时性远处转移的相关因素。结果：共186例病人纳入本研究,异时性远处转移组93例,无转移组93例。KRAS基因突变类型与根治术前CEA (P=0.015)和异时性远处转移(P<0.001)显著相关。多因素分析显示,女性(OR=0.426, P=0.020)、原发灶位于直肠(OR=0.408, P=0.040)、原发灶组织学类型黏液腺癌(OR=0.230, P=0.010)是异时性远处转移的3个独立保护因素;术后pN₂分期(OR=4.191, P=0.003)、KRAS基因 p.G12V突变型(OR=10.568, P=0.001)和p.G13D突变型(OR=12.657, P<0.001)是异时性远处转移的2个独立危险因素。以5个独立影响因素建立预测模型,ROC曲线内部效能检验显示预测性能良好,显著优于TNM分期和KRAS基因类型的单因素分析(多因素模型AUC=0.767;TNM分期AUC=0.569;KRAS基因类型AUC=0.628;P<0.001)。结论：KRAS基因p.G12V和p.G13D突变是异时性远处转移的独立危险因素。本研究建立的多因素模型较好预测结肠直肠癌异时性远处转移。

关键词: 结肠直肠癌, 异时性远处转移, KRAS

Abstract:

Objective To explore the relationship between KRAS genotype and metachronous distant metastases in patients with colorectal cancer after radical resections. Methods Patients were analyzed retrospectively with metachronous distant metastases group and non-metastases group. PCR and pyrosequencing were used to detect the genotype of KRAS. Clinicopathological data and the KRAS genotype were analyzed to find the predictor for metachronous distant metastases. Results A total of 186 patients were enrolled in this study: 93 cases in metachronous distant metastases group and 93 cases in non-metastases group. KRAS gene mutation type was significantly associated with preoperative CEA(P=0.015) and metachronous distant metastases (P<0.001). The multivariate analyses showed that female (OR=0.426, P=0.020), tumor located at rectum (OR=0.408, P=0.040) and the type of mucinous adenocarcinoma (OR=0.230, P=0.010) were independent protective factors for metachronous distant metastases. Pathological N₂ stage (OR=4.191, P=0.003), KRAS mutation type of p.G12V (OR=10.568, P=0.001) and p.G13D (OR=12.657, P<0.001) were 2 independent risk factors for metachronous distant metastases. The model of multivariate prediction was gotten based on 5 factors and was significantly better than prediction of single factor with TNM stage or KRAS genotype (multivariate model, AUC=0.767; TNM stage, AUC=0.569; KRAS genotype, AUC=0.628; P<0.001). Conclusions p.G12V and p.G13D mutation type of KRAS gene were independent risk factors for metachronous distant metastases. Multivariate prediction model was constructed for prediction of metachronous colorectal cancer distance metastases.

Key words: Colorectal cancer, Metachronous distant metastases, KRAS

中图分类号:

林松斌, 冯青阳, 许剑民. KRAS基因突变类型预测结肠直肠癌根治术后异时性远处转移[J]. 外科理论与实践, 2021, 26(01): 66-71.

LIN Songbin, FENG Qingyang, XU Jianmin. KRAS genotypes predict metachronous colorectal cancer distant metastases after radical resections[J]. Journal of Surgery Concepts & Practice, 2021, 26(01): 66-71.

图/表 6

表1

表2

KRAS突变类型与临床病理因素的相关性[n（%）]

项目	总体（n=186）	野生型（n=117）	c.35G>A,p.G12D （n=23）	c.35G>T,p.G12V （n=16）	c.38G>A,p.G13D （n=25）	其他突变类型（n=5）	检验值	P值
性别							4.080	0.259
男	110 (59.1)	75 (64.1)	11 (47.8)	7 (43.8)	14 (56.0)	3 (60.0)
女	76 (40.9)	42 (35.9)	12 (52.2)	9 (56.2)	11 (44.0)	2 (40.0)
年龄(岁)							3.436	0.345
≤60	86 (46.2)	58 (49.6)	11 (47.8)	4 (25.0)	12 (48.0)	1 (20.0)
>60	100 (53.8)	59 (50.4)	12 (52.2)	12 (75.0)	13 (52.0)	4 (80.0)
术前CEA(μg/L)							10.330	0.015^a)
<5	113 (60.8)	78 (66.7)	14 (60.9)	4 (25.0)	15 (60.0)	2 (40.0)
≥5	73 (39.2)	39 (33.3)	9 (39.1)	12 (75.0)	10 (40.0)	3 (60.0)
原发灶部位							4.347	0.637^b)
右半结肠	54 (29.0)	34 (29.1)	8 (34.8)	4 (25.0)	6 (24.0)	2 (40.0)
左半结肠	49 (26.3)	35 (29.9)	3 (13.0)	3 (18.8)	8 (32.0)	0
直肠	83 (44.6)	48 (41.0)	12 (52.2)	9 (56.2)	11 (44.0)	3 (60.0)
组织学类型							1.655	0.643^b)
腺癌	155 (83.3)	99 (84.6)	18 (78.3)	15 (93.8)	21 (84.0)	2 (40.0)
黏液腺癌	31 (16.7)	18 (15.4)	5 (21.7)	1 (6.2)	4 (16.0)	3 (60.0)
分化程度							3.145	0.375
高/中分化	109 (58.6)	66 (56.4)	12 (52.2)	11 (68.8)	18 (72.0)	2 (40.0)
低/未分化	77 (41.4)	51 (43.6)	11 (47.8)	5 (31.2)	7 (28.0)	3 (60.0)
pT分期							5.588	0.465^b)
1~2	25 (13.4)	18 (15.4)	1 (4.3)	3 (18.8)	2 (8.0)	1 (20.0)
3	65 (34.9)	36 (30.8)	10 (43.5)	4 (25.0)	12 (48.0)	3 (60.0)
4	96 (51.6)	63 (53.8)	12 (52.2)	9 (56.2)	11 (44.0)	1 (20.0)
pN分期							11.302	0.073^a)b)
0	77 (41.4)	43 (36.8)	12 (52.2)	12 (75.0)	9 (36.0)	1 (20.0)
1	66 (35.5)	41 (35.0)	6 (26.1)	3 (18.8)	12 (48.0)	4 (80.0)
2	43 (23.1)	33 (28.2)	5 (21.7)	1 (6.2)	4 (16.0)	0
异时性远处转移							19.728	<0.001^a)
无	93 (50.0)	68 (58.1)	14 (60.9)	4 (25.0)	4 (16.0)	3 (60.0)
有	93 (50.0)	49 (41.9)	9 (39.1)	12 (75.0)	21 (84.0)	2 (40.0)

表2

表3

图1

图2

图3

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项目	总体	转移组	无转移组
总计	186	93	93
野生型	117 (62.9)	49 (52.7)	68 (73.1)
突变型	69 (37.1)	44 (47.3)	25 (26.9)
c.35G>A, p.G12D	23 (12.4)	9 (9.7)	14 (15.1)
c.35G>T, p.G12V	16 (8.6)	12 (12.9)	4 (4.3)
c.34G>T, p.G12C	2 (1.1)	0	2 (2.2)
c.35G>C, p.G12A	1 (0.5)	1 (1.1)	0
c.34G>A, p.G12S	1 (0.5)	1 (1.1)	0
c.34G>C, p.G12R	1 (0.5)	0	1 (1.1)
c.38G>A, p.G13D	25 (13.4)	21 (22.6)	4 (4.3)

项目	单因素分析			多因素分析
项目	OR	95%CI	P值	OR	95%CI	P值
性别
男	1	-	-	1	-	-
女	0.640	0.355~1.152	0.137	0.426	0.207~0.876	0.020^a)
年龄（岁）
≤60	1	-	-	1	-	-
>60	0.841	0.472~1.498	0.556	0.693	0.336~1.427	0.319
术前CEA（μg/L）
<5	1	-	-	1	-	-
≥5	1.145	0.635~2.063	0.652	0.899	0.444~1.820	0.767
原发灶部位
右半结肠	1	-	-	1	-	-
左半结肠	0.656	0.301~1.429	0.289	0.500	0.200~1.248	0.138
直肠	0.658	0.330~1.312	0.234	0.408	0.173~0.961	0.040^a)
组织学类型
腺癌	1	-	-	1	-	-
黏液腺癌	0.490	0.220~1.090	0.080	0.230	0.075~0.709	0.010^a)
分化程度
高/中分化	1	-	-	1	-	-
低/未分化	0.957	0.534~1.715	0.882	1.377	0.613~3.093	0.439
pT分期
1~2	1	-	-	1	-	-
3	1.645	0.645~4.197	0.297	1.304	0.416~4.086	0.649
4	1.564	0.639~3.826	0.327	1.182	0.397~3.524	0.764
pN分期
0	1	-	-	1	-	-
1	1.190	0.615~2.303	0.605	1.365	0.605~3.083	0.454
2	2.134	0.993~4.585	0.052	4.191	1.643~10.691	0.003^a)
原发灶术后静脉化疗
FOLFOX	1	-	-	1	-	-
XELOX	1.962	0.740~5.198	0.175	1.806	0.590~5.522	0.300
未化疗	0.864	0.338~2.210	0.761	0.580	0.181~1.856	0.359
KRAS基因型
野生型	1	-	-	1	-	-
c.35G>A, p.G12D	0.892	0.358~2.226	0.807	1.258	0.454~3.485	0.658
c.35G>T, p.G12V	4.163	1.267~13.681	0.019^a)	10.568	2.568~43.499	0.001^a)
c.38G>A, p.G13D	7.286	2.352~22.567	0.001^a)	12.657	3.607~44.411	<0.001^a)
其他突变	0.925	0.149~5.747	0.933	2.927	0.381~22.493	0.302