A Prehepatectomy Circulating Exosomal microRNA Signature Predicts the Prognosis and Adjuvant Chemotherapeutic Benefits in Colorectal Liver Metastasis
Abstract
:Simple Summary
Abstract
1. Introduction
2. Materials and Methods
2.1. Study Design and Patients
2.2. Extraction and Quantification of Exosomal miRNAs
2.3. Circulating Exosomal microRNA Signature Construction and Validation
2.4. Origin Identification of Circulating Exosomal miRNAs
2.5. Statistical Analysis
3. Results
3.1. Identification of Differentially Expressed Exosomal miRNAs
3.2. Construction and Validation of a Circulating Exosomal miRNA Signature
3.3. Merged Score Based on the CRS and Exosomal miRNA Signature
3.4. Candidate Factors Identifying the Benefit of Adjuvant Chemotherapy
3.5. Origin and Mechanism of the Model-Included miRNAs
4. Discussion
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Training Cohort | Internal Validation Cohort | External Validation Cohort | |||||||
---|---|---|---|---|---|---|---|---|---|
Low | High | p-Value | Low | High | p-Value | Low | High | p-Value | |
Age (years) | |||||||||
≥70 | 8 (22.2) | 5 (6.5) | 0.0342 | 5 (7.8) | 6 (12.0) | 0.531 2 | 1 (8.3) | 11 (7.1) | 1.000 2 |
<70 | 28 (77.8) | 72 (93.5) | 59 (92.2) | 44 (88.0) | 11 (91.7) | 144 (92.9) | |||
Gender | |||||||||
Male | 26 (72.2) | 46 (59.7) | 0.199 | 43 (67.2) | 33 (66.0) | 0.894 | 9 (75.0) | 109 (70.3) | 1.000 2 |
Female | 10 (27.8) | 31 (40.3) | 21 (32.8) | 17 (34.0) | 3 (25.0) | 46 (29.7) | |||
Tumor grade | |||||||||
G3 | 5 (15.6) | 21 (27.6) | 0.183 | 14 (21.9) | 8 (16.0) | 0.430 | 1 (10.0) | 13 (8.7) | 1.000 2 |
G1–2 | 27 (84.4) | 55 (72.4) | 50 (78.1) | 42 (84.0) | 9 (90.0) | 136 (91.3) | |||
Primary tumor | |||||||||
Rectal | 17 (47.2) | 29 (38.2) | 0.362 | 21 (32.8) | 13 (26.0) | 0.430 | 3 (25.0) | 62 (40.5) | 0.368 2 |
Colon | 19 (52.8) | 47 (61.8) | 43 (67.2) | 37 (74.0) | 9 (75.0) | 91 (59.5) | |||
T-stage 1 | |||||||||
Tis-2 | 3 (9.1) | 10 (13.7) | 0.750 2 | 2 (3.2) | 6 (12.5) | 0.077 2 | 1 (11.1) | 12 (8.2) | 0.553 2 |
T3–4 | 30 (90.9) | 63 (86.3) | 60 (96.8) | 42 (87.5) | 8 (88.9) | 135 (91.8) | |||
N-stage 1 | |||||||||
N0 | 18 (51.4) | 31 (44.3) | 0.489 | 25 (39.7) | 20 (42.6) | 0.762 | 5 (55.6) | 51 (35.2) | 0.287 2 |
N1–2 | 17 (48.6) | 39 (55.7) | 38 (60.3) | 27 (57.4) | 4 (44.4) | 94 (64.8) | |||
Interval to liver metastases 3 (months) | |||||||||
>12 | 27 (75.0) | 63 (82.9) | 0.326 | 52 (81.3) | 40 (80.0) | 0.867 | 6 (50.0) | 3 (19.4) | 0.0232 |
≤12 | 9 (25.0) | 13 (17.1) | 12 (18.8) | 10 (20.0) | 6 (50.0) | 125 (80.6) | |||
Resection | |||||||||
R0 | 28 (84.8) | 49 (66.2) | 0.048 | 51 (79.7) | 40 (83.3) | 0.625 | 12 (100.0) | 138 (89.6) | 0.609 2 |
R1–2 | 5 (15.2) | 25 (33.8) | 13 (20.3) | 8 (16.7) | 0 (0.0) | 16 (10.4) | |||
Ablation | |||||||||
Yes | 1 (2.8) | 11 (14.3) | 0.099 2 | 10 (15.6) | 7 (14.0) | 0.809 | 1 (8.3) | 10 (6.5) | 0.571 2 |
No | 35 (97.2) | 66 (85.7) | 54 (84.4) | 43 (86.0) | 11 (91.7) | 145 (93.5) | |||
Number of metastases per patient | |||||||||
>1 | 19 (52.8) | 47 (61.0) | 0.406 | 45 (70.3) | 30 (60.0) | 0.249 | 5 (41.7) | 103 (66.5) | 0.116 2 |
≤1 | 17 (47.2) | 30 (39.0) | 19 (29.7) | 20 (40.0) | 7 (58.3) | 52 (33.5) | |||
Size of the max metastases (cm) | |||||||||
>5 | 9 (25.0) | 15 (19.5) | 0.504 | 10 (15.6) | 10 (20.0) | 0.542 | 1 (8.3) | 24 (15.5) | 1.000 2 |
≤5 | 27 (75.0) | 62 (80.5) | 54 (84.4) | 40 (80.0) | 11 (91.7) | 131 (84.5) | |||
Preoperative CEA (ng/mL) | |||||||||
>200 | 2 (5.6) | 2 (2.6) | 0.591 2 | 3 (4.7) | 3 (6.1) | 1.000 2 | 1 (8.3) | 9 (5.8) | 0.536 2 |
≤200 | 34 (94.4) | 75 (97.4) | 61 (95.3) | 46 (93.9) | 11 (91.7) | 146 (94.2) | |||
CRS | |||||||||
0–2 | 24 (68.6) | 40 (57.1) | 0.258 | 36 (57.1) | 27 (58.7) | 0.871 | 7 (77.8) | 78 (53.8) | 0.188 2 |
3–5 | 11 (31.4) | 30 (42.9) | 27 (42.9) | 19 (41.3) | 2 (22.2) | 67 (46.2) | |||
Preoperative chemotherapy | |||||||||
Yes | 16 (44.4) | 47 (61.0) | 0.098 | 40 (62.5) | 37 (74.0) | 0.193 | 8 (66.7) | 113 (72.9) | 0.738 2 |
No | 20 (55.6) | 30 (39.0) | 24 (37.5) | 13 (26.0) | 4 (33.3) | 42 (27.1) | |||
Postoperative chemotherapy | |||||||||
Yes | 27 (75.0) | 48 (62.3) | 0.184 | 51 (79.7) | 31 (62.0) | 0.037 | 9 (75.0) | 89 (57.4) | 0.363 2 |
No | 9 (25.0) | 29 (37.7) | 13 (20.3) | 19 (38.0) | 3 (25.0) | 66 (42.6) |
Training Cohort | Internal Validation Cohort | External Validation Cohort | ||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|
RFS | OS | RFS | OS | RFS | OS | |||||||
HR (95% CI) | p-Value | HR (95% CI) | p-Value | HR (95% CI) | p-Value | HR (95% CI) | p-Value | HR (95% CI) | p-Value | HR (95% CI) | p-Value | |
Age | ||||||||||||
≥70 vs. <70 years | 0.82 (0.42–1.58) | 0.553 | 0.98 (0.49–1.95) | 0.944 | 1.00 (0.50–2.00) | 0.994 | 1.46 (0.66–3.20) | 0.348 | 0.53 (0.23–1.21) | 0.131 | 1.04 (0.41–2.61) | 0.932 |
Gender | ||||||||||||
Male vs. female | 0.82 (0.54–1.26) | 0.368 | 0.83 (0.53–1.31) | 0.429 | 1.09 (0.69–1.70) | 0.719 | 1.15 (0.68–1.96) | 0.598 | 0.93 (0.63–1.38) | 0.723 | 0.91 (0.53–1.56) | 0.739 |
Tumor grade | ||||||||||||
G3 vs. G1–2 | 1.64 (1.02–2.64) | 0.043 | 2.10 (1.27–3.48) | 0.004 | 1.18 (0.69–2.00) | 0.547 | 1.55 (0.87–2.76) | 0.14 | 1.68 (0.94–3.02) | 0.083 | 1.58 (0.71–3.50) | 0.263 |
Primary tumor | ||||||||||||
Rectal vs. colon | 1.08 (0.71–1.63) | 0.728 | 0.96 (0.62–1.50) | 0.865 | 1.47 (0.95–2.29) | 0.084 | 1.20 (0.72–2.01) | 0.489 | 0.99 (0.69–1.44) | 0.972 | 1.10 (0.65–1.85) | 0.719 |
T-stage | ||||||||||||
T3–4 vs. Tis-2 | 0.92 (0.49–1.73) | 0.798 | 0.96 (0.49–1.86) | 0.894 | 0.86 (0.39–1.85) | 0.692 | 0.59 (0.25–1.37) | 0.217 | 1.36 (0.66–2.79) | 0.403 | 1.47 (0.53–4.07) | 0.460 |
N-stage | ||||||||||||
N1–2 vs. N0 | 1.23 (0.80–1.89) | 0.35 | 1.95 (1.22–3.13) | 0.006 | 1.32 (0.84–2.07) | 0.224 | 1.33 (0.79–2.25) | 0.287 | 1.16 (0.78–1.72) | 0.465 | 1.15 (0.65–2.02) | 0.636 |
Interval to liver metastases 1 | ||||||||||||
>12 vs. ≤12 months | 1.58 (0.92–2.72) | 0.099 | 1.42 (0.78–2.58) | 0.247 | 0.70 (0.42–1.17) | 0.171 | 0.77 (0.42–1.39) | 0.385 | 1.30 (0.84–2.01) | 0.238 | 0.93 (0.52–1.68) | 0.818 |
Resection | ||||||||||||
R1–2 vs. R0 | 2.14 (1.36–3.37) | 0.001 | 3.60 (2.21–5.85) | <0.001 | 2.30 (1.38–3.82) | 0.001 | 1.88 (1.06–3.32) | 0.031 | 1.53 (0.88–2.68) | 0.135 | 2.11 (0.99–4.50) | 0.053 |
Ablation | ||||||||||||
Yes vs. no | 2.01 (1.07–3.79) | 0.03 | 1.95 (1.02–3.70) | 0.042 | 1.77 (1.01–3.09) | 0.045 | 1.62 (0.88–2.99) | 0.121 | 3.06 (1.62–5.79) | 0.001 | 0.5(0.13–2.20) | 0.385 |
Number of metastases per patient | ||||||||||||
>1 vs. ≤1 | 1.97 (1.28–3.03) | 0.002 | 1.97 (1.24–3.14) | 0.004 | 1.68 (1.07–2.63) | 0.024 | 1.78 (1.02–3.10) | 0.042 | 1.95 (1.31–2.90) | 0.001 | 1.00 (0.59–1.69) | 0.994 |
Size of the max metastases | ||||||||||||
>5 vs. ≤5 cm | 0.92 (0.55–1.54) | 0.749 | 1.06 (0.62–1.81) | 0.842 | 1.32 (0.77–2.27) | 0.312 | 2.08 (1.14–3.78) | 0.016 | 1.21 (0.75–1.93) | 0.436 | 1.89 (1.06–3.36) | 0.030 |
Preoperative CEA | ||||||||||||
>200 vs. ≤200 ng/mL | 1.22 (0.38–3.87) | 0.736 | 1.97 (0.62–6.26) | 0.253 | 3.03 (1.29–7.10) | 0.011 | 3.22 (1.27–8.14) | 0.013 | 1.72 (0.84–3.55) | 0.138 | 1.35 (0.54–3.39) | 0.519 |
CRS | ||||||||||||
1.27 (1.03–1.58) | 0.027 | 1.42 (1.13–1.79) | 0.003 | 1.28 (1.03–1.59) | 0.029 | 1.48 (1.12–1.95) | 0.005 | 1.31 (1.07–1.60) | 0.008 | 1.09 (0.83–1.44) | 0.528 | |
Risk score | ||||||||||||
High vs. low | 3.11 (1.88–5.15) | <0.001 | 3.65 (2.06–6.46) | <0.001 | 1.67 (1.10–2.54) | 0.016 | 2.39 (1.45–3.95) | 0.001 | 3.33 (1.35–8.21) | 0.009 | 4.61 (1.11–19.03) | 0.035 |
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Wang, Y.; Chen, X.; Lin, H.; Sun, X.; Fong, W.P.; Wu, X.; Pan, Z.; Yuan, Y.; Liang, J.; Wang, D.; et al. A Prehepatectomy Circulating Exosomal microRNA Signature Predicts the Prognosis and Adjuvant Chemotherapeutic Benefits in Colorectal Liver Metastasis. Cancers 2021, 13, 4258. https://doi.org/10.3390/cancers13174258
Wang Y, Chen X, Lin H, Sun X, Fong WP, Wu X, Pan Z, Yuan Y, Liang J, Wang D, et al. A Prehepatectomy Circulating Exosomal microRNA Signature Predicts the Prognosis and Adjuvant Chemotherapeutic Benefits in Colorectal Liver Metastasis. Cancers. 2021; 13(17):4258. https://doi.org/10.3390/cancers13174258
Chicago/Turabian StyleWang, Yun, Xiuxing Chen, Haocheng Lin, Xiaoqiang Sun, William Pat Fong, Xiaojun Wu, Zhizhong Pan, Yunfei Yuan, Jieying Liang, Deshen Wang, and et al. 2021. "A Prehepatectomy Circulating Exosomal microRNA Signature Predicts the Prognosis and Adjuvant Chemotherapeutic Benefits in Colorectal Liver Metastasis" Cancers 13, no. 17: 4258. https://doi.org/10.3390/cancers13174258