Polymorphisms of HIF1A gene are associated with prognosis of early stage non-small-cell lung cancer patients after surgery

Boya Liu,Yunjie Wang,Qingchun Liu,Haichuan Su,Zhipei Zhang,Xiaofei Li,Yang Song,Shaogui Wan

doi:10.1007/s12032-014-0877-8

Abstract

Hypoxia-inducible factor 1α (HIF1α) activates the transcription of genes that are involved in angiogenesis and cell survival. Over-expression of HIF1α caused by intratumoral hypoxia and its genetic alterations are associated with increased mortality in several cancer types including non-small-cell lung cancer (NSCLC). The aim of this study was to investigate the predictive role of single nucleotide polymorphisms (SNPs) in HIF1A gene in NSCLC outcomes. We genotyped two functional SNPs (rs2057482 and rs2301113) in HIF1A gene and assessed their associations with clinicopathological parameters and prognosis of 494 NSCLC patients by Cox proportional hazard model. There was no significant association between the SNPs and clinical outcomes of NSCLC for overall analysis. However, in stratified analysis for NSCLC patients at early stage (I/II), we observed a protective effect conferred by variant genotype of rs2057482 on overall survival (OS) (HR 0.42, 95 % CI 0.22–0.80) and recurrence-free survival (RFS) (HR 0.60, 95 % CI 0.36–0.97) in a dominant model. Additionally, multivariate Cox analysis based on dominant model indicated that significant increased death and recurrence risks were observed in patients with early T-stage (T1 and T2) tumors, who carrying variant-containing genotype of rs2301113, as well as in patients without lymph node involvement (N0 stage) for rs2057482. Genetic variations on HIF1A gene are significantly associated with NSCLC outcomes in patients with early stage disease.Electronic supplementary materialThe online version of this article (doi:10.1007/s12032-014-0877-8) contains supplementary material, which is available to authorized users.

Highlights

Lung cancer is the leading cause of cancer-related death worldwide
We evaluated the effects of 2 functional single nucleotide polymorphisms (SNPs) in HIF1A on the prognosis of non-small-cell lung cancer (NSCLC) patients
There was no statistical significant association to be found in the primary analyses, significant associations were observed in the stratified analysis between variantcontaining genotypes of SNPs and reduced death or recurrence risk in patients with early TNM stage (I ? II)

Summary

Introduction

Lung cancer is the leading cause of cancer-related death worldwide. Non-small-cell lung cancer (NSCLC) represents 75–85 % of all lung cancer cases. The median survival time of patients with untreated metastatic NSCLC is only 4–5 months, with a 1-year survival rate of only 10 % [1, 2]. The prediction of NSCLC prognosis largely depends on the conventional prognostic factors such as disease stage and performance status. NSCLC patients with the same pathological features, have dramatically distinct response to chemotherapies and have different survival outcomes, suggesting the importance of novel biomarkers for the prognosis of NSCLC [3]. Hypoxia-inducible factor-1 (HIF1) is a key regulator of cellular response to hypoxia and plays essential roles in regulating angiogenesis, cell adhesion, energy metabolism, 877 Page 2 of 9

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