A Functional Polymorphism (rs10817938) in the XPA Promoter Region Is Associated with Poor Prognosis of Oral Squamous Cell Carcinoma in a Chinese Han Population.

Chunhai Gao,Chong Li,Jinzhu Wang,Wei Zhang,Guoxia Liu,Qing-Yi Wei

doi:10.1371/journal.pone.0160801

Chunhai Gao, Chong Li + Show 4 more

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https://doi.org/10.1371/journal.pone.0160801

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Journal: PloS one	Publication Date: Sep 13, 2016
Citations: 7	License type: CC BY 4.0

Affiliation: Linyi People's Hospital, Jinan Stomatological Hospital

Abstract

Single nucleotide polymorphisms of XPA gene have been studied in several cancers such as rs10817938, rs2808668. However, the role of XPA polymorphisms in patients with oral squamous cell carcinoma (OSCC) remains unclear. Thus, we analyzed the association of XPA polymorphisms with OSCC risk, clinicopathological characteristics and prognosis in the present study. TaqMan genotyping was used to evaluate the frequency of rs10817938, rs2808668 polymorphisms in OSCC patients. The prognostic significance of these polymorphisms was evaluated using Kaplan-Meier curves, Log-Rank analyses, and the Cox proportional hazard model. Luciferase reporter assay, RT-PCR and western blot were used to determine whether rs10817938 could influence transcription activity and XPA expression. The results showed that individuals carrying TC and CC genotypes had significantly greater risk of developing OSCC (OR = 1.42, 95% CI 1.04–1.93; OR = 2.75, 95% CI 1.32–5.71, respectively) when compared with wild-type TT genotype at rs10817938. OSCC patients with C allele at rs10817938 were more susceptible to lymph metastases, poor pathological differentiation and late TNM stage (OR = 1.67, 95% CI 1.17–2.37; OR = 1.64, 95% CI 1.18–2.28; OR = 1.54, 95% CI 1.11–2.14; respectively). A significant gene-environment interaction between smoking and CC genotype at rs10817938 was observed (COR = 3.60, 95% CI 1.20–10.9) and data also showed that OSCC patients with CC genotype and C allele had worse survival (p<0.001 for both). The T to C substitution at rs10817938 significantly decreased transcription activity of XPA gene, XPA mRNA and protein were also decreased in individuals with C allele at rs10817938. In addition, no significant association of rs2808668 polymorphism with OSCC risk, prognosis could be observed. In conclusion, the present study showed that XPA rs10817938 polymorphism is a functional SNP in vitro and in vivo and a biomarker for poor prognosis in OSCC patients.

Highlights

Oral squamous cell carcinoma (OSCC), one of the most lethal malignancies, remains the most common oral cavity cancer, accounting for >274,000 newly diagnosed cancer cases annually worldwide[1]
Previous studies demonstrated that polymorphisms in xeroderma pigmentosum A (XPA) genes could modulate nucleotide excision repair (NER) efficiency and contribute to carcinogenesis [25]
We found the significant association of a novel XPA functional polymorphism and OSCC risk, poor prognosis

Summary

Introduction

Oral squamous cell carcinoma (OSCC), one of the most lethal malignancies, remains the most common oral cavity cancer, accounting for >274,000 newly diagnosed cancer cases annually worldwide[1]. Due to late detection and later stages when diagnosed, OSCC is frequently accompanied by metastasis, high recurrence and poor prognosis[2]. Despite progress in early detection and treatment, mortality is largely unchanged and the 5-year survival rate worldwide for OSCC remains ~50%[3]. The combination of the susceptible genetic background and environmental factors is identified to contribute to the development of OSCC. Smoking and drinking are well-established risk factors, OSCC could develop in the absence of tobacco and alcohol use[4]. Genetic susceptibility to OSCC should be further investigated and paid more attention. An impaired ability to repair DAN damaged by mutagens was identified to play a important role in OSCC pathogenesis[4]

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