Effects of single-nucleotide polymorphisms in the mTORC1 pathway on the risk of brain metastasis in patients with non-small cell lung cancer

Yiquan Xu,Yi Huang,Lihong Weng,Yunan Zhao,Yina Huang,Jiankun Zheng,Yusheng Chen,Ying Lin,Hongru Li

doi:10.1007/s00432-019-03059-y

Abstract

PurposeThe mammalian target of rapamycin complex 1 (mTORC1) signaling pathway plays a vital role in cancer development and progression. This study aimed to investigate the relationship between genotype variants in mTORC1 pathway and the risk of brain metastasis (BM) in patients with non-small cell lung cancer (NSCLC).MethodsWe extracted genomic DNA from blood samples of 501 NSCLC patients and genotyped eight single-nucleotide polymorphisms (SNPs) in three core genes [mammalian target of rapamycin (mTOR), mammalian lethal with sec-13 protein 8 (mLST8) and regulatory-associated protein of mTOR (RPTOR)] of the mTORC1 pathway. The associations between these SNPs and the risk of BM development were assessed.ResultsThe AG/GG genotype of mLST8:rs26865 and TC/CC genotype of mLST8:rs3160 were associated with an increased risk of BM [hazard ratios (HR) 2.938, 95% confidence interval (CI) 1.664–5.189, p < 0.001 and HR = 2.490, 95% CI = 1.543–4.016, p < 0.001, respectively]. These risk polymorphisms had a cumulative effect on BM risk, with two risk genotypes exhibiting the highest increased risk (p < 0.001). Furthermore, these risk SNPs were associated with the lymph node metastasis (N2/3), body mass index (BMI) (≥ 25 kg/m2), high level of squamous cell carcinoma (SCC) antigen and Ki-67 proliferation index. Moreover, patients with AG/GG genotype of mLST8:rs26865 had significantly lower median overall survival than those with AA genotype (12.1 months versus 21.6 months, p = 0.04).ConclusionsOur results indicate that polymorphisms in mTORC1 pathway were significantly associated with increased risk of BM and may be valuable biomarkers to identify NSCLC patients with a high risk of BM.

Highlights

Primary lung cancer is among the most common malignant tumors with the highest mortality worldwide (Chen et al 2016; Siegel et al 2016)
We attempted to identify the molecular markers of brain metastasis (BM) by analyzing the association between eight potential functional polymorphisms of three genes in the mammalian target of rapamycin complex 1 (mTORC1) pathways and the risk of BM
Two single-nucleotide polymorphisms (SNPs) associated with BM risk were located in mammalian lethal with sec-13 protein 8 (mLST8), which mapped to chromosome 16p13.3 and was composed of 11 exons. mLST8 binds to the catalytic domain of mammalian target of rapamycin (mTOR) and is among the crucial component proteins of the mTORC1 pathway (Yang et al 2013)

Summary

Introduction

Primary lung cancer is among the most common malignant tumors with the highest mortality worldwide (Chen et al 2016; Siegel et al 2016). Despite great progress in systemic therapy including surgery, radiotherapy, chemotherapy, and targeted therapy, the prognosis of BM patients remains generally poor, with a median survival time of approximately 13.7 months (Baek et al 2018). Without any treatments, this further decreases to approximately less. BM has become an important cause of lung cancer morbidity and mortality (Nayak et al 2012). Identifying predictive factors of BM is essential for its prevention and improving patient survival

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