Prognostic and predictive value of a microRNA signature in stage II colon cancer: a microRNA expression analysis.
BACKGROUND
Current staging methods do not accurately predict the risk of disease recurrence and benefit of adjuvant chemotherapy for patients who have had surgery for stage II colon cancer. We postulated that expression patterns of multiple microRNAs (miRNAs) could, if combined into a single model, improve postoperative risk stratification and prediction of chemotherapy benefit for these patients.


METHODS
Using miRNA microarrays, we analysed 40 paired stage II colon cancer tumours and adjacent normal mucosa tissues, and identified 35 miRNAs that were differentially expressed between tumours and normal tissue. Using paraffin-embedded specimens from a further 138 patients with stage II colon cancer, we confirmed differential expression of these miRNAs using qRT-PCR. We then built a six-miRNA-based classifier using the LASSO Cox regression model, based on the association between the expression of every miRNA and the duration of individual patients' disease-free survival. We validated the prognostic and predictive accuracy of this classifier in both the internal testing group of 138 patients, and an external independent group of 460 patients.


RESULTS
Using the LASSO model, we built a classifier based on the six miRNAs: miR-21-5p, miR-20a-5p, miR-103a-3p, miR-106b-5p, miR-143-5p, and miR-215. Using this tool, we were able to classify patients between those at high risk of disease progression (high-risk group), and those at low risk of disease progression (low-risk group). Disease-free survival was significantly different between these groups in every set of patients. In the initial training group of patients, 5-year disease-free survival was 89% (95% CI 77·3-94·4) for the low-risk group, and 60% (46·3-71·0) for the high-risk group (hazard ratio [HR] 4·24, 95% CI 2·13-8·47; p<0·0001). In the internal testing set of patients, 5-year disease-free survival was 85% (95% CI 74·3-91·8) for the low-risk group, and 57% (42·8-68·5) for the high-risk group (HR 3·63, 1·86-7·01; p<0·0001), and in the independent validation set of patients, was 85% (79·6-89·0) for the low-risk group and 54% (46·4-61·1) for the high-risk group (HR 3·70, 2·56-5·35; p<0·0001). The six-miRNA-based classifier was an independent prognostic factor for, and had better prognostic value than, clinicopathological risk factors and mismatch repair status. In an ad-hoc analysis, the patients in the high-risk group were found to have a favourable response to adjuvant chemotherapy (HR 1·69, 1·17-2·45; p=0·0054). We developed two nomograms for clinical use that integrated the six-miRNA-based classifier and four clinicopathological risk factors to predict which patients might benefit from adjuvant chemotherapy after surgery for stage II colon cancer.


CONCLUSIONS
Our six-miRNA-based classifier is a reliable prognostic and predictive tool for disease recurrence in patients with stage II colon cancer, and might be able to predict which patients benefit from adjuvant chemotherapy. It might facilitate patient counselling and individualise management of patients with this disease.


BACKGROUND
Natural Science Foundation of China.
First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
Jia-Xing
JX
Zhang
Wu
W
Song
Zhen-Hua
ZH
Chen
Jin-Huan
JH
Wei
Yi-Ji
YJ
Liao
Jian
J
Lei
Ming
M
Hu
Geng-Zhen
GZ
Chen
Bing
B
Liao
Jian
J
Lu
Hong-Wei
HW
Zhao
Wei
W
Chen
Yu-Long
YL
He
Hui-Yun
HY
Wang
Dan
D
Xie
Jun-Hang
JH
Luo
D000368:Aged; D014408:Biomarkers, Tumor / Q000032:analysis*; D017024:Chemotherapy, Adjuvant; D002681:China; D003110:Colonic Neoplasms / Q000737:chemistry* / Q000188:drug therapy / Q000235:genetics / Q000473:pathology* / Q000601:surgery; D053843:DNA Mismatch Repair; D018450:Disease Progression; D018572:Disease-Free Survival; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D035683:MicroRNAs / Q000032:analysis*; D008875:Middle Aged; D060787:Neoplasm Grading; D009367:Neoplasm Staging; D049451:Nomograms; D057285:Precision Medicine; D011237:Predictive Value of Tests; D011379:Prognosis; D016016:Proportional Hazards Models; D015203:Reproducibility of Results; D012307:Risk Factors
D014408:Biomarkers, Tumor; C544749:MIRN103 microRNA, human; C542541:MIRN106 microRNA, human; C542359:MIRN143 microRNA, human; C534451:MIRN20a microRNA, human; C524940:MIRN21 microRNA, human; C553667:MIRN215 microRNA, human; D035683:MicroRNAs