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Serum miRNA expression profile as a prognostic biomarker of stage II/III colorectal adenocarcinoma.

Li J, Liu Y, Wang C, Deng T, Liang H, Wang Y, Huang D, Fan Q, Wang X, Ning T, Liu R, Zhang CY, Zen K, Chen X, Ba Y - Sci Rep (2015)

Bottom Line: Using individual RT-qPCR verification in 175 stage II/III CRC patients, we identified that miR-145, miR-106a and miR-17-3p were significantly differentially expressed between pre- and post-operative CRC patients and between pre-operative CRC patients and normal controls (P < 0.0001).Furthermore, using the Kaplan-Meier method and Cox proportional hazards analysis, we found that miR-17-3p and miR-106a were powerful and independent prognostic indicators and that high levels of these miRNAs were associated with shorter disease-free survival (DFS) (P < 0.0001 for miR-17-3p and P = 0.001 for miR-106a).The present study reveals novel serum-miRNA-based biomarkers for monitoring tumor dynamics as well as for predicting disease recurrence in patients with stage II/III CRC.

View Article: PubMed Central - PubMed

Affiliation: 1] Tianjin Medical University Cancer Institute and Hospital, Key Laboratory of Cancer Prevention and Therapy, Huanhuxi Rd., Tiyuanbei, Tianjin 300060, China [2] Jiangsu Engineering Research Center for microRNA Biology and Biotechnology, State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, 22 Hankou Rd., Nanjing 210093, Nanjing, China.

ABSTRACT
We sought to identify a serum miRNA expression profile to improve disease surveillance and to predict post-operative disease recurrence for stage II/III colorectal cancer (CRC) patients. Using the TaqMan Low-Density Array (TLDA), we performed an initial survey to analyze 749 miRNAs in the pooled serum of 20 paired pre- and post-operative CRC patients and 20 matched normal subjects. Using individual RT-qPCR verification in 175 stage II/III CRC patients, we identified that miR-145, miR-106a and miR-17-3p were significantly differentially expressed between pre- and post-operative CRC patients and between pre-operative CRC patients and normal controls (P < 0.0001). The area under the ROC curve (AUC) for the three-miRNA panel was 0.886 (95% CI 0.850-0.921) for discriminating between pre-operative CRC patients and normal subjects and 0.850 (95% CI 0.809-0.891) for discriminating between pre- and post-operative CRC patients. Furthermore, using the Kaplan-Meier method and Cox proportional hazards analysis, we found that miR-17-3p and miR-106a were powerful and independent prognostic indicators and that high levels of these miRNAs were associated with shorter disease-free survival (DFS) (P < 0.0001 for miR-17-3p and P = 0.001 for miR-106a). The present study reveals novel serum-miRNA-based biomarkers for monitoring tumor dynamics as well as for predicting disease recurrence in patients with stage II/III CRC.

No MeSH data available.


Related in: MedlinePlus

A Kaplan–Meier curve estimates the association of miRNAs and the survival of patients with stage II/III colorectal cancer.(A–C) The miR-17-3p high-level group (greater than the cutoff value) compared with the low-level group (less than the cutoff value) in both cohorts. (D–E) The miR-106a high-level group compared with the low-level group in both cohorts.
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f4: A Kaplan–Meier curve estimates the association of miRNAs and the survival of patients with stage II/III colorectal cancer.(A–C) The miR-17-3p high-level group (greater than the cutoff value) compared with the low-level group (less than the cutoff value) in both cohorts. (D–E) The miR-106a high-level group compared with the low-level group in both cohorts.

Mentions: We then performed an analysis to identify whether the three selected miRNAs were associated with cancer recurrence. We analyzed the expression level of each individual miRNA for an association with poor prognosis in both the Tianjin cohort and the Xiangya cohort using Kaplan–Meier DFS curves for all of the recruited CRC patients. The median follow-up period was 36 months for the Tianjin cohort and 32 months for the Xiangya cohort. We categorized these patients into patients at high risk of disease recurrence (high-risk group) and patients at low risk of disease recurrence (low-risk group) based on the expression levels of each miRNA. When we assessed the distribution of the expression levels of each miRNA and survival status, we found similar results for the prognostic values in both the Tianjin cohort and the Xiangya cohort. In the Tianjin cohort, patients with lower levels of miR-17-3p and miR-106a generally had better survival than patients with higher levels (log-rank test: P = 0.005 and P = 0.028, respectively) (Fig. 4A,B). In the Xiangya cohort, we also found consistent correlations between the expression level of each miRNA and survival status (log-rank test: P = 0.013 for miR-17-3p and P = 0.017 for miR-106a) (Fig. 4C,D). Similar results were found in all 175 patients (log-rank test: P < 0.0001 for miR-17-3p and P = 0.001 for miR-106a) (Fig. 4E,F). Subsequently, we performed univariate and multivariate Cox proportional hazards regression analyses to determine the influence of serum miRNA levels and clinicopathological characteristics on patient survival. In the univariate analysis for the Tianjin test cohort, we found that high expression of miR-17-3p and miR-106a as well as TNM stage was significantly correlated with DFS (P = 0.002, P = 0.03 and P = 0.001, respectively). Similar results were also observed in an independent validation of miR-17-3p and miR-106a levels as well as TNM stage for the Xiangya cohort (P = 0.009, P = 0.023 and P = 0.007, respectively). After multivariable adjustment by clinicopathological variables, miR-17-3p, miR-106a and the TNM stage remained independent risk factors in the entire cohort of all 175 patients (HR 2.24, 95% CI 1.28-3.92, P = 0.035; HR 3.02, 95% CI 1.36-6.73, P = 0.007; and HR 4.13, 95% CI 1.66-10.2, P = 0.002, respectively). We also found similar results in the combined training and internal validation set (P = 0.012, P = 0.013 and P  = 0.001, respectively) and in the independent validation set (P = 0.011, P = 0.01 and P  = 0.002, respectively) (Table 2). These data indicate that miR-17-3p and miR-106a may be prognostic biomarkers for CRC patients with localized disease who underwent surgery.


Serum miRNA expression profile as a prognostic biomarker of stage II/III colorectal adenocarcinoma.

Li J, Liu Y, Wang C, Deng T, Liang H, Wang Y, Huang D, Fan Q, Wang X, Ning T, Liu R, Zhang CY, Zen K, Chen X, Ba Y - Sci Rep (2015)

A Kaplan–Meier curve estimates the association of miRNAs and the survival of patients with stage II/III colorectal cancer.(A–C) The miR-17-3p high-level group (greater than the cutoff value) compared with the low-level group (less than the cutoff value) in both cohorts. (D–E) The miR-106a high-level group compared with the low-level group in both cohorts.
© Copyright Policy - open-access
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4528229&req=5

f4: A Kaplan–Meier curve estimates the association of miRNAs and the survival of patients with stage II/III colorectal cancer.(A–C) The miR-17-3p high-level group (greater than the cutoff value) compared with the low-level group (less than the cutoff value) in both cohorts. (D–E) The miR-106a high-level group compared with the low-level group in both cohorts.
Mentions: We then performed an analysis to identify whether the three selected miRNAs were associated with cancer recurrence. We analyzed the expression level of each individual miRNA for an association with poor prognosis in both the Tianjin cohort and the Xiangya cohort using Kaplan–Meier DFS curves for all of the recruited CRC patients. The median follow-up period was 36 months for the Tianjin cohort and 32 months for the Xiangya cohort. We categorized these patients into patients at high risk of disease recurrence (high-risk group) and patients at low risk of disease recurrence (low-risk group) based on the expression levels of each miRNA. When we assessed the distribution of the expression levels of each miRNA and survival status, we found similar results for the prognostic values in both the Tianjin cohort and the Xiangya cohort. In the Tianjin cohort, patients with lower levels of miR-17-3p and miR-106a generally had better survival than patients with higher levels (log-rank test: P = 0.005 and P = 0.028, respectively) (Fig. 4A,B). In the Xiangya cohort, we also found consistent correlations between the expression level of each miRNA and survival status (log-rank test: P = 0.013 for miR-17-3p and P = 0.017 for miR-106a) (Fig. 4C,D). Similar results were found in all 175 patients (log-rank test: P < 0.0001 for miR-17-3p and P = 0.001 for miR-106a) (Fig. 4E,F). Subsequently, we performed univariate and multivariate Cox proportional hazards regression analyses to determine the influence of serum miRNA levels and clinicopathological characteristics on patient survival. In the univariate analysis for the Tianjin test cohort, we found that high expression of miR-17-3p and miR-106a as well as TNM stage was significantly correlated with DFS (P = 0.002, P = 0.03 and P = 0.001, respectively). Similar results were also observed in an independent validation of miR-17-3p and miR-106a levels as well as TNM stage for the Xiangya cohort (P = 0.009, P = 0.023 and P = 0.007, respectively). After multivariable adjustment by clinicopathological variables, miR-17-3p, miR-106a and the TNM stage remained independent risk factors in the entire cohort of all 175 patients (HR 2.24, 95% CI 1.28-3.92, P = 0.035; HR 3.02, 95% CI 1.36-6.73, P = 0.007; and HR 4.13, 95% CI 1.66-10.2, P = 0.002, respectively). We also found similar results in the combined training and internal validation set (P = 0.012, P = 0.013 and P  = 0.001, respectively) and in the independent validation set (P = 0.011, P = 0.01 and P  = 0.002, respectively) (Table 2). These data indicate that miR-17-3p and miR-106a may be prognostic biomarkers for CRC patients with localized disease who underwent surgery.

Bottom Line: Using individual RT-qPCR verification in 175 stage II/III CRC patients, we identified that miR-145, miR-106a and miR-17-3p were significantly differentially expressed between pre- and post-operative CRC patients and between pre-operative CRC patients and normal controls (P < 0.0001).Furthermore, using the Kaplan-Meier method and Cox proportional hazards analysis, we found that miR-17-3p and miR-106a were powerful and independent prognostic indicators and that high levels of these miRNAs were associated with shorter disease-free survival (DFS) (P < 0.0001 for miR-17-3p and P = 0.001 for miR-106a).The present study reveals novel serum-miRNA-based biomarkers for monitoring tumor dynamics as well as for predicting disease recurrence in patients with stage II/III CRC.

View Article: PubMed Central - PubMed

Affiliation: 1] Tianjin Medical University Cancer Institute and Hospital, Key Laboratory of Cancer Prevention and Therapy, Huanhuxi Rd., Tiyuanbei, Tianjin 300060, China [2] Jiangsu Engineering Research Center for microRNA Biology and Biotechnology, State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, 22 Hankou Rd., Nanjing 210093, Nanjing, China.

ABSTRACT
We sought to identify a serum miRNA expression profile to improve disease surveillance and to predict post-operative disease recurrence for stage II/III colorectal cancer (CRC) patients. Using the TaqMan Low-Density Array (TLDA), we performed an initial survey to analyze 749 miRNAs in the pooled serum of 20 paired pre- and post-operative CRC patients and 20 matched normal subjects. Using individual RT-qPCR verification in 175 stage II/III CRC patients, we identified that miR-145, miR-106a and miR-17-3p were significantly differentially expressed between pre- and post-operative CRC patients and between pre-operative CRC patients and normal controls (P < 0.0001). The area under the ROC curve (AUC) for the three-miRNA panel was 0.886 (95% CI 0.850-0.921) for discriminating between pre-operative CRC patients and normal subjects and 0.850 (95% CI 0.809-0.891) for discriminating between pre- and post-operative CRC patients. Furthermore, using the Kaplan-Meier method and Cox proportional hazards analysis, we found that miR-17-3p and miR-106a were powerful and independent prognostic indicators and that high levels of these miRNAs were associated with shorter disease-free survival (DFS) (P < 0.0001 for miR-17-3p and P = 0.001 for miR-106a). The present study reveals novel serum-miRNA-based biomarkers for monitoring tumor dynamics as well as for predicting disease recurrence in patients with stage II/III CRC.

No MeSH data available.


Related in: MedlinePlus