诊断学理论与实践 ›› 2022, Vol. 21 ›› Issue (05): 581-587.doi: 10.16150/j.1671-2870.2022.05.006
收稿日期:
2020-07-07
出版日期:
2022-10-25
发布日期:
2023-01-29
通讯作者:
郭滟
E-mail:guoyan@histomed.com
基金资助:
XIE Wen, LIANG Huaiyu, DONG Lei, YUAN Fei, WANG Chaofu, GUO Yan()
Received:
2020-07-07
Online:
2022-10-25
Published:
2023-01-29
Contact:
GUO Yan
E-mail:guoyan@histomed.com
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。
中图分类号:
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.
表1
269例PDAC患者的临床病理特征
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) |
表2
269例PDAC患者重要驱动基因突变状态与临床病理特征间的关系[例(n)]
临床病 理特征 | KRAS | TP53 | SMAD4 | CDKN2A | |||||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
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 |
表3
269例PDAC患者重要驱动基因突变状态与预后的关系分析结果
临床病理特征 | 例数(n) | 单因素分析 (P值) | 多因素分析 | |
---|---|---|---|---|
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 |
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