上海交通大学学报(医学版) ›› 2022, Vol. 42 ›› Issue (11): 1589-1597.doi: 10.3969/j.issn.1674-8115.2022.11.011
• 论著 · 技术与方法 • 上一篇
收稿日期:
2022-05-07
接受日期:
2022-10-18
出版日期:
2022-11-28
发布日期:
2023-01-04
通讯作者:
马晔,郭润生
E-mail:symbuster_1986@163.com;malele2013@sina.com;grs982600@163.com
作者简介:
孙亚蒙(1986—),男,博士,电子信箱: symbuster_1986@163.com。第一联系人:(马晔、郭润生并列第一作者)
基金资助:
SUN Yameng1(), MA Ye2(), GUO Runsheng2()
Received:
2022-05-07
Accepted:
2022-10-18
Online:
2022-11-28
Published:
2023-01-04
Contact:
MA Ye,GUO Runsheng
E-mail:symbuster_1986@163.com;malele2013@sina.com;grs982600@163.com
Supported by:
摘要:
目的·利用微滴式数字PCR系统(droplet digital PCR system,ddPCR)建立乳腺癌组织福尔马林固定石蜡包埋(formalin-fixed paraffin embedded,FFPE)样本和血浆样本中 HER2基因拷贝数检测体系,并对检测体系进行性能评估,为临床辅助诊疗提供科学依据。方法·收集2020年1月—2021年6月就诊于上海健康医学院附属嘉定区中心医院普外科乳腺癌患者组织样本12例及其中4例配对血浆样本用于检测体系评价,同期收集健康志愿者血浆样本24例及就诊的乳腺癌组织切片样本77例,提取核酸,用于建立检测体系空白检测限及性能评价。设计及筛选检测体系,使用ddPCR检测体系的空白检测限、精密度、灵敏度及线性范围,使用高通量测序(next generation sequencing,NGS)验证ddPCR检测一致性,并与荧光原位杂交(fluorescence in situ hybridization,IHC)/免疫组化(immunohistochemistry,FISH)金标准方法比对检测体系准确性。定量资料比较采用 χ 2 检验和配对样本 t检验进行分析,使用Poisson概率函数分析体系空白检测限,变异系数(coefficient of variation,CV)评价灵敏度及精密度,线性回归相关系数( R 2 )评价线性范围。结果·使用ddPCR平台建立了乳腺癌患者组织切片DNA中 HER2基因拷贝数定量和扩增检测体系,配对样本 t检验评价:与NGS方法检测组织核酸和血浆游离核酸样本结果相比,检测拷贝数结果相关系数0.987,扩增判读一致性100%。评估检测体系的批内精密度为6.8%、批间精密度为9.4%,灵敏度为1 ng,线性良好( R 2 >0.98)。与传统的IHC/FISH方法相比,检测体系的灵敏度和特异度分别为84.6%(95% CI 64.3%~95.0%)和76.5%(95% CI 62.2%~86.8%), Kappa为0.57,一致率为79.2%。结论·使用ddPCR建立乳腺癌患者 HER2拷贝数检测体系,临床检测一致性良好,可能为乳腺癌患者的诊疗和预后判断的研究提供辅助手段。
中图分类号:
孙亚蒙, 马晔, 郭润生. 乳腺癌组织样本中 HER2基因拷贝数的检测分析[J]. 上海交通大学学报(医学版), 2022, 42(11): 1589-1597.
SUN Yameng, MA Ye, GUO Runsheng. Detection and analysis of copy number of HER2 gene in breast cancer tissue samples[J]. Journal of Shanghai Jiao Tong University (Medical Science), 2022, 42(11): 1589-1597.
Gene | Forword primer (5′→3′) | Reverse primer (5′→3′) | Probe sequence (5′→3′) |
---|---|---|---|
HER2 | TCACTCATATCCTCCTCTTTCTGC | AATTTTCACATTCTCCCCATCAG | FAM-CAGGGCATCTGGATC-MGB |
EIF2C1 | GCTGCTAGGCTTTCCTGTTC | GCCTATTTTCCTGCATCTTCT | HEX-AGGCCCCAAAACCCTAAAC-MGB |
表1 引物和探针序列信息
Tab 1 List of primers and probe sequences
Gene | Forword primer (5′→3′) | Reverse primer (5′→3′) | Probe sequence (5′→3′) |
---|---|---|---|
HER2 | TCACTCATATCCTCCTCTTTCTGC | AATTTTCACATTCTCCCCATCAG | FAM-CAGGGCATCTGGATC-MGB |
EIF2C1 | GCTGCTAGGCTTTCCTGTTC | GCCTATTTTCCTGCATCTTCT | HEX-AGGCCCCAAAACCCTAAAC-MGB |
Sample | Detection System 1 | BC-HER2-2019 | ||||
---|---|---|---|---|---|---|
HER2 gene copy number (copies) | Reference gene copy number (copies) | Copy amplification [( HER2/Reference)]×2 | HER2 gene copy number (copies) | Reference gene copy number (copies) | Copy amplification [( HER2/Reference)]×2 | |
HV-1 | 2 400 | 1.33 | 3 180 | 1.99 | ||
HV-2 | 2 150 | 1.25 | 3 050 | 1.97 | ||
HV-3 | 2 600 | 1.41 | 3 200 | 2.05 |
表2 健康人 cfDNA中 HER2 基因和内参基因拷贝数及拷贝数比例
Tab 2 Copy number and copy number ratio of HER2 and reference gene in healthy human cfDNA
Sample | Detection System 1 | BC-HER2-2019 | ||||
---|---|---|---|---|---|---|
HER2 gene copy number (copies) | Reference gene copy number (copies) | Copy amplification [( HER2/Reference)]×2 | HER2 gene copy number (copies) | Reference gene copy number (copies) | Copy amplification [( HER2/Reference)]×2 | |
HV-1 | 2 400 | 1.33 | 3 180 | 1.99 | ||
HV-2 | 2 150 | 1.25 | 3 050 | 1.97 | ||
HV-3 | 2 600 | 1.41 | 3 200 | 2.05 |
Sample No. | Concentration/(ng·μL -1) | HER2 Gene copy | Sample No. | Concentration/(ng·μL -1) | HER2 Gene copy |
---|---|---|---|---|---|
1 | 0.44 | 1.80 | 13 | 0.21 | 2.24 |
2 | 0.19 | 2.20 | 14 | 0.10 | 2.20 |
3 | 0.54 | 2.08 | 15 | 0.16 | 2.22 |
4 | 0.26 | 2.01 | 16 | 0.10 | 1.20 |
5 | 0.95 | 2.58 | 17 | 0.38 | 2.37 |
6 | 0.62 | 2.00 | 18 | 0.13 | 1.87 |
7 | 0.23 | 2.90 | 19 | 0.49 | 1.99 |
8 | 0.29 | 2.27 | 20 | 0.32 | 1.62 |
9 | 0.32 | 1.99 | 21 | 0.10 | 2.40 |
10 | 0.21 | 2.28 | 22 | 0.24 | 1.75 |
11 | 0.23 | 2.08 | 23 | 0.19 | 2.19 |
12 | 0.38 | 2.17 | 24 | 0.74 | 1.69 |
表3 24例健康人 cfDNA样本 HER2拷贝数比例
Tab 3 HER2 copy number ratio in 24 healthy human cfDNA samples
Sample No. | Concentration/(ng·μL -1) | HER2 Gene copy | Sample No. | Concentration/(ng·μL -1) | HER2 Gene copy |
---|---|---|---|---|---|
1 | 0.44 | 1.80 | 13 | 0.21 | 2.24 |
2 | 0.19 | 2.20 | 14 | 0.10 | 2.20 |
3 | 0.54 | 2.08 | 15 | 0.16 | 2.22 |
4 | 0.26 | 2.01 | 16 | 0.10 | 1.20 |
5 | 0.95 | 2.58 | 17 | 0.38 | 2.37 |
6 | 0.62 | 2.00 | 18 | 0.13 | 1.87 |
7 | 0.23 | 2.90 | 19 | 0.49 | 1.99 |
8 | 0.29 | 2.27 | 20 | 0.32 | 1.62 |
9 | 0.32 | 1.99 | 21 | 0.10 | 2.40 |
10 | 0.21 | 2.28 | 22 | 0.24 | 1.75 |
11 | 0.23 | 2.08 | 23 | 0.19 | 2.19 |
12 | 0.38 | 2.17 | 24 | 0.74 | 1.69 |
Sample No. | Test date | Copy amplification [( HER2/Reference)]×2 | |||||
---|---|---|---|---|---|---|---|
Batch 1 | Batch 2 | Batch 3 | |||||
Repeat 1 | Repeat 2 | Repeat 1 | Repeat 2 | Repeat 1 | Repeat 2 | ||
1 | Day 1 | 1.74 | 2.14 | 2.16 | 2.14 | 1.82 | 1.94 |
2 | Day 2 | 1.84 | 1.88 | 2.36 | 2.18 | 1.92 | 1.88 |
3 | Day 3 | 2.08 | 1.98 | 2.38 | 2.50 | 2.20 | 1.82 |
4 | Day 4 | 2.12 | 2.26 | 1.83 | 2.14 | 1.80 | 1.90 |
5 | Day 5 | 2.10 | 2.10 | 2.24 | 2.04 | 2.18 | 1.92 |
Xmean | 2.05 | ||||||
Intra batch standard deviation | 0.14 | ||||||
inter batch standard deviation | 0.19 | ||||||
Intra batch precision/% | 6.80 | ||||||
inter batch precision/% | 9.40 |
表4 检测体系的精密度评价
Tab 4 Precision evaluation of the detection system
Sample No. | Test date | Copy amplification [( HER2/Reference)]×2 | |||||
---|---|---|---|---|---|---|---|
Batch 1 | Batch 2 | Batch 3 | |||||
Repeat 1 | Repeat 2 | Repeat 1 | Repeat 2 | Repeat 1 | Repeat 2 | ||
1 | Day 1 | 1.74 | 2.14 | 2.16 | 2.14 | 1.82 | 1.94 |
2 | Day 2 | 1.84 | 1.88 | 2.36 | 2.18 | 1.92 | 1.88 |
3 | Day 3 | 2.08 | 1.98 | 2.38 | 2.50 | 2.20 | 1.82 |
4 | Day 4 | 2.12 | 2.26 | 1.83 | 2.14 | 1.80 | 1.90 |
5 | Day 5 | 2.10 | 2.10 | 2.24 | 2.04 | 2.18 | 1.92 |
Xmean | 2.05 | ||||||
Intra batch standard deviation | 0.14 | ||||||
inter batch standard deviation | 0.19 | ||||||
Intra batch precision/% | 6.80 | ||||||
inter batch precision/% | 9.40 |
图2 灵敏度检测结果
Fig 2 Results of sensitivity detectionNote: A-1/A-2. Results of three duplication holes of HER2 and reference gene by using 10ng. B-1/B-2. Results of three duplication holes of HER2 and reference gene by using 1ng. C-1/C-2. Results of three duplication holes of HER2 and reference gene by using 0.1ng.
Loading quantity | Repeat | HER2 Gene copy number (copies/20 μL) | Reference Gene copy number (copies/20 μL) | Copy amplification [( HER2/Reference)]×2 | CV/% |
---|---|---|---|---|---|
10 ng | 1 | 2 780 | 1.89 | 3.30 | |
2 | 3 100 | 1.99 | |||
3 | 3 160 | 2.01 | |||
1 ng | 1 | 226 | 274 | 1.64 | 12.50 |
2 | 234 | 244 | 1.91 | ||
3 | 276 | 260 | 2.11 | ||
0.1 ng | 1 | 15.20 | 14.00 | 2.20 | 26.00 |
2 | 9.60 | 14.40 | 1.30 | ||
3 | 13.00 | 15.40 | 1.70 |
表5 灵敏度检测拷贝数统计及变异系数
Tab 5 Copy number statistics and CV of sensitivity detection
Loading quantity | Repeat | HER2 Gene copy number (copies/20 μL) | Reference Gene copy number (copies/20 μL) | Copy amplification [( HER2/Reference)]×2 | CV/% |
---|---|---|---|---|---|
10 ng | 1 | 2 780 | 1.89 | 3.30 | |
2 | 3 100 | 1.99 | |||
3 | 3 160 | 2.01 | |||
1 ng | 1 | 226 | 274 | 1.64 | 12.50 |
2 | 234 | 244 | 1.91 | ||
3 | 276 | 260 | 2.11 | ||
0.1 ng | 1 | 15.20 | 14.00 | 2.20 | 26.00 |
2 | 9.60 | 14.40 | 1.30 | ||
3 | 13.00 | 15.40 | 1.70 |
图3 Her2 基因和内参基因的 ddPCR线性检测扩增图谱Note: A. The result of the HER2 copies. B. The result of the reference gene copies.
Fig 3 Linear detection amplification plots of the gene HER2 and reference by ddPCR
HER2∶ reference | Theoretical value | Actual value | |||||
---|---|---|---|---|---|---|---|
HER2 gene copy number (copies/20 μL) | Reference gene copy number (copies/20 μL) | Copy amplification [( HER2/ reference)]×2 | HER2 gene copy number (copies/20 μL) | Reference gene copy number (copies/20 μL) | Copy amplification [( HER2/ reference)]×2 | ||
1∶1 | 3 260 | 2.04 | 3 160 | 1.89 | |||
2∶1 | 5 984 | 3.93 | 6 460 | 2.99 | |||
3∶1 | 8 708 | 6.01 | 8 900 | 3 000 | 5.94 | ||
4∶1 | 13 914 | 7.96 | 16 140 | 8.62 | |||
5∶1 | 14 482 | 2927 | 9.90 | 16 760 | 10.00 |
表6 线性检测拷贝数统计
Tab 6 Copy number statistics of linear detection
HER2∶ reference | Theoretical value | Actual value | |||||
---|---|---|---|---|---|---|---|
HER2 gene copy number (copies/20 μL) | Reference gene copy number (copies/20 μL) | Copy amplification [( HER2/ reference)]×2 | HER2 gene copy number (copies/20 μL) | Reference gene copy number (copies/20 μL) | Copy amplification [( HER2/ reference)]×2 | ||
1∶1 | 3 260 | 2.04 | 3 160 | 1.89 | |||
2∶1 | 5 984 | 3.93 | 6 460 | 2.99 | |||
3∶1 | 8 708 | 6.01 | 8 900 | 3 000 | 5.94 | ||
4∶1 | 13 914 | 7.96 | 16 140 | 8.62 | |||
5∶1 | 14 482 | 2927 | 9.90 | 16 760 | 10.00 |
No. | NGS copy amplification | ddPCR copy amplification |
---|---|---|
1 a | 1.90 | 1.62 |
2 a | 1.90 | 1.86 |
3 a | 1.90 | 1.62 |
4 a | 5.00 | 4.27 |
5 a | 6.00 | 4.21 |
6 a | 13.10 | 14.10 |
7 a | 8.00 | 6.64 |
8 a | 18.00 | 16.00 |
9 a | 2.40 | 1.73 |
9 b | 2.10 | 1.84 |
10 a | 2.20 | 1.77 |
10 b | 1.80 | 1.41 |
11 a | 5.00 | 3.50 |
11 b | 1.80 | 1.49 |
12 a | 5.00 | 3.85 |
12 b | 1.70 | 1.20 |
表7 NGS检测拷贝数与 ddPCR检测对比
Tab 7 Copy number results by NGS comparison of ddPCR
No. | NGS copy amplification | ddPCR copy amplification |
---|---|---|
1 a | 1.90 | 1.62 |
2 a | 1.90 | 1.86 |
3 a | 1.90 | 1.62 |
4 a | 5.00 | 4.27 |
5 a | 6.00 | 4.21 |
6 a | 13.10 | 14.10 |
7 a | 8.00 | 6.64 |
8 a | 18.00 | 16.00 |
9 a | 2.40 | 1.73 |
9 b | 2.10 | 1.84 |
10 a | 2.20 | 1.77 |
10 b | 1.80 | 1.41 |
11 a | 5.00 | 3.50 |
11 b | 1.80 | 1.49 |
12 a | 5.00 | 3.85 |
12 b | 1.70 | 1.20 |
ddPCR | FISH | Specificity [% (95% CI)] | Sensitivity [% (95% CI)] | Kappa value | |
---|---|---|---|---|---|
Positive | Negative | ||||
Positive | 22 | 12 | 76.5 (62.2—86.8) | 84.6 (64.3—95.0) | 0.57 |
Negative | 4 | 39 |
表8 以 FISH为金标准评价 ddPCR方法检测 HER2 拷贝数
Tab 8 Gold standard FISH to evaluate the HER2 copy number detected by ddPCR
ddPCR | FISH | Specificity [% (95% CI)] | Sensitivity [% (95% CI)] | Kappa value | |
---|---|---|---|---|---|
Positive | Negative | ||||
Positive | 22 | 12 | 76.5 (62.2—86.8) | 84.6 (64.3—95.0) | 0.57 |
Negative | 4 | 39 |
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