Gene Signature in Non-Small-Cell Lung Cancer: Application of Gene Expression Profile and MicroRNA in Clinical Outcome
Date Issued
2007
Date
2007
Author(s)
Chen, Hsuan-Yu
DOI
en-US
Abstract
Current clinical staging system can not accurately predict patients’ outcome. In this study, microarray technology and real time RT-PCR were carried out to assay the gene expressions, including gene expression profile and microRNA signature. This disser- tation included two studies of non-small-cell lung cancer. One is “Gene Expression Signature Predicts Clinical Outcomes in NSCLC” and another is “microRNA Expre- ssion Profile and Clinical Outcomes in NSCLC”.
Study 1: Gene Expression Signature Predicts Clinical Outcomes in NSCLC
Background: Using molecular profiling approach to predict patients’ outcome is better than current staging method. of non-small cell lung carcinoma (NSCLC). In this study, a model based on few number of gene will be established and predicted survival in NSCLC. Methods: Gene expression in surgical specimens of 125 samples of surgi- cally resected NSCLC was studied by microarray and real-time reverse transcriptase polymerase chain reaction (RT-PCR), and the results were compared with survival. We used the risk score and decision tree methods to develop a gene-expression model to predict the outcome of NSCLC. The results were validated in an independent cohort from 60 patients and published dataset from 86 samples. Results: Sixteen genes that correlated with survival in patients with NSCLC were identified using microarray and risk score analysis. We selected 5 genes (DUSP6, MMD, STAT1, ERBB3 and LCK) and developed a risk predictive model based on RT-PCR and a decision tree analysis. The 5-gene signature is an independent predictor of cancer recurrence and overall survival of NSCLC patients (hazard ratio [HR] =2.82, 95% CI= 1.38-5.78). We validated the model in an independent cohort of 60 NSCLC patients (HR=3.36, 95% CI= 1.35-8.35) and in a set of published microarray data of 86 patients (HR=4.36, 95% CI= 1.01-18.76). Conclusions: A 5-gene signature can predict survival and relapse of NSCLC patients.
Study 2: microRNA Expression Profile and Clinical Outcomes in NSCLC
Background: MicroRNAs are a new class of small non-protein-coding RNAs that function as endogenous negative gene-regulators and can act as oncogenes or tumor- suppressors. An microRNA signature will be developed and significantly associated with survival of NSCLC patients. Methods: Using real-time reverse transcriptase polymerase chain reaction (RT-PCR), we studied microRNA expression in tumor-specimens of 112 patients who had undergone surgical resection of NSCLC. Results were correlated with patients’ survival. We used Cox regression and risk-score analysis to develop a microRNA signature for the prediction of treatment outcome of NSCLC. Results: We identified a 5- microRNA signature (hsa-let-7a, hsa-miR-221, hsa-miR-137, hsa-miR-372 and hsa-miR -182*) associated with survival of 56 NSCLC patients each in the training and testing sets. We reconfirmed the findings in an independent cohort of 62 NSCLC patients. NSCLC pa- tients with high-expression of the 5-microRNA signature had reduced overall survival (adjusted HR=2.81, 95%CI=1.13-7.01, p=0.026) and disease-free survival (adjusted HR= 2.39, 95%CI=1.12-5.10, p=0.024) compared to low-expression patients, even after stratify- ing patients by stage I, II, III, adenocarcinoma or squamous cell carcinoma subgroups. The 5-microRNA signature was more effective to predict survival of NSCLC patients compared to less-than-five or single-microRNA signatures (p<0.05, log-rank tests).Conclusions: An unique microRNA signature can predict cancer relapse and survival of NSCLC patients. MicroRNAs may have implications in molecular-pathogenesis of NSCLC, selection of high-risk patients for adjuvant chemotherapy or development of new targeted-therapy for NSCLC.
In conclusion, our results indicate that using a gene signature composed of relatively small number of genes, either a five-gene or 5-microRNA signature, can predict the recurrence as well as overall survival of NSCLC and further validation of these findings in a prospective cohort of large sample size is warranted.
Subjects
非小細胞肺癌
基因印記
微小核甘核酸
微陣列晶片
即時反轉錄聚合酶
連鎖反應
風險分數
決策樹
non-small-cell lung cancer
gene signature
microRNA
microarray
reverse- transcription polymerase chain reaction (RT-PCR)
risk score
decision tree
SDGs
Type
thesis