Research Article: Aberrant DNA Methylation of OLIG1, a Novel Prognostic Factor in Non-Small Cell Lung Cancer

Date Published: March 27, 2007

Publisher: Public Library of Science

Author(s): Romulo M Brena, Carl Morrison, Sandya Liyanarachchi, David Jarjoura, Ramana V Davuluri, Gregory A Otterson, David Reisman, Selina Glaros, Laura J Rush, Christoph Plass, Naftali Kaminski

Abstract: BackgroundLung cancer is the leading cause of cancer-related death worldwide. Currently, tumor, node, metastasis (TNM) staging provides the most accurate prognostic parameter for patients with non-small cell lung cancer (NSCLC). However, the overall survival of patients with resectable tumors varies significantly, indicating the need for additional prognostic factors to better predict the outcome of the disease, particularly within a given TNM subset.Methods and FindingsIn this study, we investigated whether adenocarcinomas and squamous cell carcinomas could be differentiated based on their global aberrant DNA methylation patterns. We performed restriction landmark genomic scanning on 40 patient samples and identified 47 DNA methylation targets that together could distinguish the two lung cancer subgroups. The protein expression of one of those targets, oligodendrocyte transcription factor 1 (OLIG1), significantly correlated with survival in NSCLC patients, as shown by univariate and multivariate analyses. Furthermore, the hazard ratio for patients negative for OLIG1 protein was significantly higher than the one for those patients expressing the protein, even at low levels.ConclusionsMultivariate analyses of our data confirmed that OLIG1 protein expression significantly correlates with overall survival in NSCLC patients, with a relative risk of 0.84 (95% confidence interval 0.77–0.91, p < 0.001) along with T and N stages, as indicated by a Cox proportional hazard model. Taken together, our results suggests that OLIG1 protein expression could be utilized as a novel prognostic factor, which could aid in deciding which NSCLC patients might benefit from more aggressive therapy. This is potentially of great significance, as the addition of postoperative adjuvant chemotherapy in T2N0 NSCLC patients is still controversial.

Partial Text: Lung cancer is the leading cause of cancer-related death worldwide [1]. It is estimated that over 1.2 million people are diagnosed with lung cancer annually, and 1.1 million die from the disease [2]. Despite intensive research over the past decades, the five-year survival of lung cancer patients remains poor [3]. Currently, the most accurate prognostic factor for patients with non-small cell lung cancer (NSCLC) is tumor, node, metastasis (TNM) clinico-pathologic staging [4]. Nevertheless, patients with early-stage lung cancer exhibit a wide spectrum of survival, indicating the need for additional prognostic parameters to better predict the outcome of the disease [5]. Thus, much effort has been dedicated to identifying molecular markers that might improve the classification of NSCLC. Such markers not only should give prognostic information, but could help identify patients that would benefit from novel therapeutic strategies or, alternatively, those for which additional treatment is not needed. A recent example of the utility of such markers is the identification of gene expression profiles that predict high risk of recurrence of localized lung cancer [6].

In this study we have demonstrated that lung adenocarcinomas and SCCs can be distinguished by the DNA methylation status of 47 discrete loci. This is a remarkable observation, since it not only lends further support to the fact that aberrant CpG island methylation is nonrandom [10], but it also indicates that different subtypes of neoplasias arising from the same organ can potentially be distinguished by their aberrant DNA methylation patterns.



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