Original article
General thoracic
Methylated DLX4 Predicts Response to Pathologic Stage I Non-Small Cell Lung Cancer Resection

Presented at the Poster Session of the Fiftieth Annual Meeting of The Society of Thoracic Surgeons, Orlando, FL, Jan 25–29, 2014.
https://doi.org/10.1016/j.athoracsur.2014.12.058Get rights and content

Background

Surgery with curative intent is the standard treatment for patients with stage I non-small cell lung cancer (NSCLC). Even after curative resection, however, many patients have recurrent disease. Thus, there is a need to identify molecular biomarkers for the biological characteristics and prognosis of tumors.

Methods

Methylation-specific polymerase chain reaction analysis was performed for the distal-less homeobox 4 (DLX4) gene in cancer tissues from 109 patients who underwent curative resection for pathologic stage I NSCLC from June 2005 to November 2011. We investigated possible correlations between DLX4 methylation status and disease outcome.

Results

Methylated DLX4 was detected in 54 of 109 patients (49.5%). No significant relationship between DLX4 methylation status and clinicopathologic features was found. Multivariate logistic regression analysis revealed that DLX4 methylation was an independent risk factor for recurrence (p < 0.0001). Patients with DLX4 methylation showed significantly poorer recurrence-free, cancer-specific, and overall survival than patients without DLX4 methylation (p < 0.0001, p = 0.0001, p = 0.0004, respectively). Cox’s proportional hazard regression analysis revealed that DLX4 methylation was an independent risk factor for poor prognosis regarding recurrence-free, cancer-specific, and overall survival (p < 0.0001, p = 0.0005, p = 0.0018, respectively).

Conclusions

Methylated DLX4 is a potential biomarker that predicts poor prognosis after curative resection of pathologic stage I NSCLC. Identification of patients with methylated DLX4 may assist stratification for appropriate adjuvant treatment strategies.

Section snippets

Study Population

Written informed consent was obtained from all enrolled patients, and the protocol used for this study was approved by the Institutional Review Boards. In total, 109 patients who underwent complete resection for pathologic stage I NSCLC between June 2005 and November 2011 were enrolled. The end of the follow-up period was June 2014. The mean follow-up time of all enrolled patients was 1,514 ± 660 days. Patients treated with neoadjuvant therapy were not included. Patients with large cell tumors

Association of DLX4 Methylation Status With Clinicopathologic Features

The DLX4 methylation status in cancerous specimens and adjacent normal lung tissue is shown in Figure 1A. Methylated DLX4 was also detected in LK-2 and SK-LU-1 cells (American Type Culture Collection, Rockville, MD), clearly indicating that this epigenetic modification occurs in lung cancer cell lines (Fig 1A). The overall frequency of DLX4 promoter methylation was 49.5% (54 of 109). Demographics and clinical characteristics relating to DLX4 methylation status are shown in Table 1. No

Comment

Aberrant DNA methylation of gene promoters can suppress gene expression and inactivate tumor suppressor genes, contributing to cancer initiation and progression [24]. The methylation patterns of several genes are now used as molecular markers to facilitate diagnosis, prognosis, and therapy [10]. In stage I lung cancer, putative associations between gene methylation and early recurrence have been demonstrated 7, 8, 9. Rauch and colleagues [25] demonstrated that DLX4 was methylated in more than

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