胰腺导管腺癌重要驱动基因突变与临床病理特征、预后间相关性的分析

doi:10.16150/j.1671-2870.2022.05.006

摘要/Abstract

摘要：

目的：探讨胰腺导管腺癌（pancreatic ductal adenocarcinoma, PDAC）重要驱动基因突变特点与临床病理特征间的关系。方法：采用靶向测序技术检测269例PDAC患者中相关基因的突变情况，并分析其中重要驱动基因（KRAS、TP53、SMAD4及CDKN2A）突变状态与包括年龄、肿瘤分化程度、预后等在内的各项临床病理特征之间的关系。结果：在269例PDAC患者中，KRAS、TP53、SMAD4、CDKN2A的突变率分别为82.53%（222/269）、55.02%（148/269）、15.24%（41/269）、11.15%（30/269）。KRAS突变均为错义突变，其中94.59%发生于2号外显子的12位密码子，5.41%则发生于3号外显子的61位密码子。KRAS突变与年龄相关，小于70岁患者中KRAS突变率为80.09%，大于70岁患者中为93.75%（P<0.05）；TP53突变与肿瘤分化程度相关，中、高分化患者中TP53突变率为52.52%，低分化患者中为74.19%（P<0.05）；SMAD4、CDKN2A突变与患者的各项临床病理特征均无关。单因素及多因素生存分析结果显示，TP53突变是影响PDAC患者术后生存的独立危险因素（突变患者的死亡风险为非突变患者的4.3倍）。结论：4种重要驱动基因突变状态中，KRAS、TP53基因突变状态分别与患者年龄、肿瘤分化程度相关，且TP53突变状态可作为预测PDAC术后患者预后的参考指标。

关键词: 胰腺导管腺癌, 驱动基因, 临床病理特征, 预后

Abstract:

Objective: To investigate the relationship between genetic characteristics of pivotal driver genes and clinicopathological features in pancreatic ductal adenocarcinoma(PDAC). Methods: Mutations in related genes in 269 PDAC patients were detected with targeted sequencing, and the relationship between the genetic status of pivotal driver genes (KRAS、TP53、SMAD4 and CDKN2A) and clinicopathological features (including age, tumor differentiation, and prognosis, etc) were analyzed. Results: Among 269 patients, KRAS, TP53, SMAD4 and CDKN2A mutations were identified in 222 cases (82.53%), 148 cases (55.02%), 41 cases (15.24%) and 30 cases (11.15%) respectively. KRAS mutations were missense mutations, of which 94.59% occurred in codon 12 of exon 2 and 5.41% in codon 61 in exon 3. KRAS mutation might be correlated with age, with a mutation rate of 80.09% in patients younger than 70 years old and 93.75% in patients older than 70 years old (P<0.05); TP53 mutation was correlated with the tumor differentiation, with a mutation rate of 52.52% in well/moderately differentiated patients and 74.19% in poorly differentiated patients (P<0.05); SMAD4 or CDKN2A mutations were not significantly associated with the clinicopathological features. Univariate and multivariate analysis showed that TP53 mutation was an independent risk factor for prognosis of PDAC patients. Conclusions: The genetic status of KRAS and TP53 genes are accociated with the age and tumor differentiation respectively, and TP53 mutation can be used as a reference index to predict the prognosis of PDAC patients.

Key words: Pancreatic ductal adenocarcinoma, Driver gene, Clinicopathological feature, Prognosis

中图分类号:

R736.7

谢吻, 梁怀予, 董磊, 袁菲, 王朝夫, 郭滟. 胰腺导管腺癌重要驱动基因突变与临床病理特征、预后间相关性的分析[J]. 诊断学理论与实践, 2022, 21(05): 581-587.

XIE Wen, LIANG Huaiyu, DONG Lei, YUAN Fei, WANG Chaofu, GUO Yan. Analysis of genetic status of pivotal driver genes in pancreatic ductal adenocarcinoma and their correlation with clinicopathologic features[J]. Journal of Diagnostics Concepts & Practice, 2022, 21(05): 581-587.

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临床病理特征	例数（%）
性别
男	180（66.91）
女	89（33.01）
年龄（岁）
≤70	221（82.16）
>70	48（17.84）
肿瘤部位
胰体尾	130（48.33）
胰头	139（51.67）
肿瘤分化程度
高~中分化	238（88.48）
低分化	31（11.52）
存在神经侵犯	255（94.80）
存在脉管内癌栓	104（38.66）
病理T分期
T₁	41（15.24）
T₂	145（53.90）
T₃/T₄	83（30.86）
病理N分期
N₀	128（47.58）
N₁	117（43.50）
N₂	24（8.92）
存在远处转移	42（15.61）
TNM分期
Ⅰ~Ⅱ	190（70.63）
Ⅲ~Ⅳ	79（29.37）

临床病理特征	KRAS				TP53				SMAD4				CDKN2A
临床病理特征	WT	MT	χ²值	P值	WT	MT	χ²值	P值	WT	MT	χ²值	P值	WT	MT	χ²值	P值
性别			3.587	0.058			0.063	0.801			0.268	0.605			0.729	0.393
男	37	143			80	100			154	26			162	18
女	10	79			41	48			74	15			77	12
年龄（岁）			5.103	0.024			1.321	0.250			0.092	0.762			0.032	0.858
≤70	44	177			103	118			188	33			196	25
>70	3	45			18	30			40	8			43	5
肿瘤部位			2.294	0.130			3.362	0.067			0.004	0.950			0.938	0.333
胰体尾	18	112			51	79			110	20			118	12
胰头	29	110			70	69			118	21			121	18
肿瘤分化程度			2.951	0.086			5.206	0.023			0.469	0.594			0.077	1.000
高~中分化	45	193			113	125			203	35			211	27
低分化	2	29			8	23			25	6			28	3
有神经侵犯	43	212	1.262	0.277	113	142	0.883	0.347	214	41	2.656	0.138	225	30	1.854	0.237
有脉管内癌栓 17		87	0.149	0.699	43	61	0.905	0.341	87	17	0.160	0.689	93	11	0.057	0.812
病理T分期			0.224	0.860			2.022	0.364			0.349	0.919			0.724	0.773
T₁	8	33			20	21			36	5			38	3
T₂	24	121			69	76			122	23			128	17
T₃/T₄	15	68			32	51			70	13			73	10
病理N分期			1.791	0.394			5.093	0.078			0.737	0.766			0.649	0.770
N₀	24	104			56	72			106	22			115	13
N₁	17	100			49	68			101	16			102	15
N₂	6	18			16	8			21	3			22	2
远处转移			0.540	0.462			0.408	0.523			0.429	0.512			0.808	0.592
无	38	189			104	123			191	36			200	27
有	9	33			17	25			37	5			39	3
临床分期			0.600	0.482			0.155	0.788			0.128	0.721			0.119	0.730
Ⅰ~Ⅱ	31	159			84	106			162	28			168	22
Ⅲ~Ⅳ	16	63			37	42			66	13			71	8

临床病理特征	例数（n）	单因素分析（P值）	多因素分析
临床病理特征	例数（n）	单因素分析（P值）	HR（95%CI）	P值
性别
男	174	0.061
女	86
年龄（岁）
≤70	212	0.334
>70	48
肿瘤部位
胰体尾	124	0.640
胰头	136
肿瘤分化程度
高~中分化	231	0.345
低分化	29
神经侵犯
无	13	0.011	1.00
有	247		4.92（0.67~36.16）	0.117
脉管内癌栓
无	157	<0.001	1.00
有	103		2.30（0.33~1.33）	<0.001
病理T分期
T₁	40	<0.001	1.00
T₂	140		1.90（0.90~4.01）	0.092
T₃/T₄	80		1.66（0.75~3.69）	0.214
病理N分期
N₀	123	<0.001	1.00
N₁	113		0.90（0.58~1.38）	0.621
N₂	24		0.66（0.33~1.33）	0.241
TNM分期
Ⅰ~Ⅱ	182	<0.001	1.00
Ⅲ~Ⅳ	78		4.19（2.61~6.71）	<0.001
CA19-9（U/mL）
≤37	44	0.032	1.00
37~500	176		2.08（1.12~3.85）	0.021
>500	40		2.63（1.27~5.45）	0.009
KRAS突变
无	45	0.922	1.00
有	215		0.75（0.42~1.33）	0.320
TP53突变
无	117	0.045	1.00
有	143		4.30（1.32~14.04）	0.016
SMAD4突变
无	220	0.319	1.00
有	40		1.29（0.77~2.17）	0.326
CDKN2A突变
无	231	0.497	1.00
有	29		1.32（0.74~2.36）	0.341
基因突变数
0~1个	108	0.257	1.00
2~4个	152		0.30（0.08~1.06）	0.061