Carcinogenesis Advance Access originally published online on September 7, 2009
Carcinogenesis 2009 30(11):1903-1909; doi:10.1093/carcin/bgp219
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miR-34a as a prognostic marker of relapse in surgically resected non-small-cell lung cancer
Department of Medical Oncology, Hospital Clinic, Institut d'Investigacions Biomèdiques, Agust Pi i Sunyer, 08036 Barcelona, Spain
1 Human Anatomy and Embryology Unit, Molecular Oncology and Embryology Laboratory, School of Medicine, University of Barcelona, Institut d'Investigacions Biomèdiques, Agust Pi i Sunyer, C/Casanova 143, 08036 Barcelona, Spain
2 Department of Pneumology, Hospital Clinic, Institut d'Investigacions Biomèdiques, Agust Pi i Sunyer Ciberes (06/06/0028), 08036 Barcelona, Spain
3 Department of Pathology, Hospital Clinic, Institut d'Investigacions Biomèdiques, Agust Pi i Sunyer Ciberes, 08036 Barcelona, Spain
4 Laboratory of Pharmacogenomics, Center for Applied Medical Research, University of Navarra, 31008 Pamplona, Spain
5 Present address: Department of Medical Oncology, Hospital Clínico Universitario, 15706 Santiago de Compostela, Spain
* To whom correspondence should be addressed. Tel: +34 93 402 19 03; Fax: +34 93 403 52 63; Email: mmonzo{at}ub.edu
MicroRNAs (miRNAs) have been identified as promising prognostic markers in non-small-cell lung cancer (NSCLC) since they play an important role in oncogenesis. The miR-34 family is composed of three miRNAs (miR-34a, miR-34b and miR-34c) that are part of the p53 network and whose expression is directly induced by p53 in response to DNA damage or oncogenic stress. We have analyzed the impact of miR-34 expression on relapse and overall survival in surgically resected NSCLC patients. For this purpose, we used stem-loop reverse transcription–polymerase chain reaction to analyze the expression of the miR-34 family in paired tumor and normal tissue from 70 surgically resected NSCLC patients who received no postsurgical treatment until relapse. In addition, in patients with sufficient tumor tissue, we assessed p53 mutations and the methylation status of the MIRN34A gene promoter region and correlated these findings with miR-34a expression. Molecular findings were correlated with relapse and overall survival. The miR-34 family was downregulated in tumor compared with normal tissue, and low levels of miR-34a expression were correlated with a high probability of relapse (P = 0.04). A relation was also found between MIRN34A methylation and miR-34a expression (P = 0.008). Patients with both p53 mutations and low miR-34a levels had the highest probability of relapse (P = 0.001). In the multivariate analysis, miR-34a expression emerged as an independent prognostic marker for relapse. In summary, we have identified miR-34a as a novel prognostic marker in NSCLC patients, providing a potential mechanism for estimating a patient's risk of disease recurrence and a useful tool to help guide treatment decisions.
Abbreviations: miRNA, microRNA; MSP, methylation-specific polymerase chain reaction; NSCLC, non-small-cell lung cancer; PCR, polymerase chain reaction
These authors contributed equally to this work Received June 12, 2009; revised September 1, 2009; accepted September 3, 2009.