Aberrant Promoter Methylation Of ESR1 Gene Is Associated With Inferior Survival In Surgically Resected Non-Small Cell Lung Cancer (NSCLC)

Milica KONTIC, Clinical Center of Serbia, Serbia
JOVANOVIC D. 1,2 , BOJIC S. 3 , STOJSIC J. 4 , SAVIC M. 5 , NELSON H. 6 , OGNJANOVIC M. 7 , OGNJANOVIC S. 8

1 Clinic for Pulmonology, Clinical Center of Serbia, Belgrade, Serbia
2 School of Medicine, University of Belgrade, Belgrade, Serbia
3 Institute for Medical Statistics and Informatics, School of Medicine, Belgrade, Serbia
4 Institute for Pathology, Clinical Center of Serbia, Belgrade, Serbia
5 Clinic for Thoracic Surgery, Clinical Center of Serbia, Belgrade, Serbia
6 Division of Epidemiology and Community Health, University of Minnesota, Minneapolis, USA
7 International Organization for Cancer Prevention and Research (IOCPR), Belgrade, Serbia
8 Mayo Graduate School, Mayo Clinic, Rochester, USA

Purpose: We have previously reported that the aberrant promoter methylation in several tumor suppressor genes in NCSLC tumor tissue was associated with clinico-pathological features of NSCLC. The aim of the current study was to assess whether promoter methylation in these genes was associated with 5-year survival in this population.
Methods: Primary tumor samples (n=65) and corresponding nonmalignant lung tissues (n=65) were obtained from NSCLC patients who underwent curative surgery at the Institute for lung diseases, Clinical Center of Serbia. DNA was extracted and the samples were shipped to the University of Minnesota, where promoter methylation in seven genes (RASSF1A, CDH13, MGMT, ESR1, DAPK, SOX1 and HOXA9) was analyzed by using bisulfite pyrosequencing. Cox proportional hazards models were used to analyze the associations between gene methylation status and overall patient survival.
Results: In the Cox proportional hazards model, ESR1 methylation in tumor tissue was associated with significantly poorer survival, with hazard ratio of 1.09 (95% confidence interval 1.02-1.16, p=0.01). This effect was independent of TNM stage, which was also a predictor of survival. No significant survival differences were associated with methylation in other genes tested in either of the two tissue types.
Conclusion: Our study suggests that high ESR1 promoter methylation may be associated with inferior survival in NSCLC patients. Caution is warranted due to small sample size and a modest effect observed. Further studies are needed to confirm whether ESR1 promoter methylation could be utilized as a prognostic biomarker of NSCLC survival.

Funding source: International Organization for Cancer Prevention and Research (IOCPR)