Polymorphisms in mitotic checkpoint-related genes can influence survival outcomes of early-stage non-small cell lung cancer.

Hyo Gyoung Kang,Hyun Jung Kim,Sukki Cho,Chang Ho Kim,Sun Ha Choi,Won Kee Lee,Jaehee Lee,Mi Jeong Hong,Jae Yong Park,Soyoun Kim,Eungbae Lee,So Yeon Lee,Shin Yup Lee,Yangki Seok,Jin Eun Choi,Seung Soo Yoo,Sanghoon Jheon,Sook Kyung ,Seung Ick ,Cheng Jin

doi:10.18632/oncotarget.18693

Hyo Gyoung Kang, Hyun Jung Kim + Show 18 more

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https://doi.org/10.18632/oncotarget.18693

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Abstract

This study was conducted to investigate the association between variants in mitotic checkpoint-related genes and clinical outcomes of non-small cell lung cancer (NSCLC). A total of 766 patients with NSCLC who underwent curative surgery were enrolled. Among the 73 variants evaluated, 4 variants were related with survival outcomes. BUB3 rs7897156C>T was associated with worse overall survival under a recessive model (adjusted hazard ratio = 1.58, 95% confidence interval = 1.07–2.33, P = 0.02). AURKB rs1059476G>A was associated with better overall survival under a recessive model (adjusted hazard ratio = 0.64, 95% confidence interval = 0.41–0.99, P = 0.05). PTTG1 rs1895320T>C and RAD21 rs1374297C>G were associated with worse disease-free survival. In the functional study, relative luciferase activity was higher at the BUB3 rs7897156T allele compared to that at the C allele. Western blot showed that the phosphorylation of AKT and mTOR in the AURKB variant-type (M298) was significantly lower than in the AURKB wild-type (T298). We found that 4 variants of mitotic checkpoint-related genes were associated with survival outcomes in patients with surgically resected NSCLC. Particularly, our results suggest that BUB3 rs7897156C>T and AURKB rs1059476G>A are functional variants.

Highlights

Accurate segregation of chromosomes during mitosis is important to the survival of human cells
BUB3 rs7897156C>T was associated with worse overall survival under a recessive model (CC+CT (88.2%) vs. TT (11.8%), adjusted hazard ratio [aHR] = 1.58, 95% confidence interval [confidence intervals (CIs)] = 1.07– 2.33, P = 0.02; Table 2 and Figure 1)
Aurora kinase B (AURKB) rs1059476G>A was associated with better overall survival under a recessive model (GG+GA (84.6%) vs. AA (15.4%), aHR = 0.64, 95% CI = 0.41–0.99, P = 0.05; Table 2 and Figure 1)

Summary

Introduction

Accurate segregation of chromosomes during mitosis is important to the survival of human cells. Errors in mitosis result in cells with an abnormal number of chromosomes, known as aneuploidy, which can lead to cell-cycle arrest, cell death, or tumorigenesis [1, 2]. Chromosome instability, defined as a high rate of either gain or loss of whole chromosomes and causing aneuploidy, is one of the hallmarks of human solid tumors [2, 5]. A number of genes, such as mitotic arrest deficient (MAD) 1–3 and budding uninhibited by benzimidazole (BUB) 1–3, are related to mitotic checkpoints to guarantee accurate chromosome segregation [8,9,10,11]. Defects in mitotic checkpoints can cause chromosome instability, which contributes to tumorigenesis. Defects in mitotic checkpoints can cause chromosome instability, which contributes to tumorigenesis. [12, 13]

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