Genetic Variants in Histone Modification Regions Predict Clinical Outcomes of Pemetrexed Chemotherapy in Lung Adenocarcinoma

Abstract

<b><i>Objective:</i></b> This study was conducted to investigate the association between genetic variants in histone modification regions and clinical outcomes of PEM chemotherapy in patients with lung adenocarcinoma. <b><i>Methods:</i></b> Potentially functional SNPs were selected using integrated analysis of ChIP-seq and RNA-seq. The associations of 279 SNPs with chemotherapy response and overall survival (OS) were analyzed in 314 lung adenocarcinoma patients who underwent PEM chemotherapy. <b><i>Results:</i></b> Among the SNPs investigated, 18 were significantly associated with response to chemotherapy, while 28 with OS. Of these SNPs, rs549794A&#x3e;G in an enhancer which is expected to regulate the expression of <i>ribosomal protein S3</i> (<i>RPS3</i>) gene was significantly associated with both worse response to chemotherapy and worse OS (adjusted odds ratio = 0.59, 95% CI = 0.36–0.97, <i>p</i> = 0.04; adjusted hazard ratio = 1.44, 95% CI = 1.09–1.91, <i>p</i> = 0.01, respectively). Previous studies suggested that RPS3, a multi-functional protein with various extraribosomal activities, may play a role in chemotherapy resistance. Therefore, it is postulated that rs549794-induced change in the expression level of RPS3 may affect the response to PEM chemotherapy and consequently the survival outcomes in lung adenocarcinoma patients. <b><i>Conclusion:</i></b> This study suggests that genetic variants in the histone modification regions may be useful for the prediction of clinical outcomes of PEM chemotherapy in advanced lung adenocarcinoma.