Association between genetic polymorphisms in DNA mismatch repair-related genes with risk and prognosis of head and neck squamous cell carcinoma

Abstract

We examined the influence of MLH1 c.293G>A, MSH2 c.211 1 9C>G, MSH3 c.3133G>A and EXO1 c.1765G>A polymorphisms, involved in DNA mismatch repair (MMR), on head and neck (HN) squamous cell carcinoma (SCC) risk and prognosis. Aiming to identify genotypes, DNA from 450 HNSCC patients and 450 controls was analyzed by PCR-RFLP or real time PCR. MSH2 GG plus MSH3 GG (31.7% vs. 18.7%, p 5 0.003) genotypes were higher in laryngeal SCC (LSCC) patients than in controls. Carriers of the respective combined genotype were under a 3.69 (95% CI: 1.54-8.81)-fold increased risk of LSCC. Interactions of tobacco and tobacco plus all the above-mentioned polymorphisms on HNSCC and LSCC risk were also evident in study (p 5 0.001). At 60 months of follow-up, relapse-free survival (RFS) was shorter in patients with EXO1 GG genotype (54.8% vs. 61.1%, p 5 0.03) and overall survival (OS) was shorter in patients with MSH3 GG genotype (42.8% vs. 52.5%, p 5 0.02) compared to those with other genotypes, respectively. After multivariate Cox analysis, patients with EXO1 GG and MSH3 GG genotypes had worst RFS (HR: 1.50, 95% CI: 1.03-2.20, p 5 0.03) and OS (HR: 1.59, 95% CI: 1.19-2.13, P 5 0.002) than those with the remaining genotypes, respectively. Our data present, for the first time, evidence that inherited MLH1 c.-93G>A, MSH2 c.211 1 9C>G, MSH3 c.3133G>A, and EXO1 c.1765G>A abnormalities of DNA MMR pathway are important determinants of HNSCC, particularly among smokers, and predictors of patient outcomes.Exposure to tobacco smoke is considered the most important etiological factor in the development of head and neck (HN) squamous cell carcinoma (SCC). 1 Carcinogens present in tobacco, such as benzo(a)pyrene, could bind to DNA from epithelial cells of the upper aerodigestive tract, forming covalent DNA adducts and inducing replication errors, which can be associated with HNSCC origin. 2,3 However, not all smokers develop HNSCC suggesting that individual genetic background may also participate in the tumor etiology. 4 DNA mismatch repair (MMR) pathway contributes to maintain genetic stability. 5 MutL homolog 1 (MLH1), MutS homolog 2 (MSH2), MutS homolog 3 (MSH3) and exonuclease 1 (EXO1) proteins play important roles in this process, recognizing DNA damage induced by carcinogens from tobacco, and enabling its excision. 6,7 The ability to promote DNA repair of damaged cells is variable in humans, since several DNA repair proteins, such as MLH1, MSH2, MSH3 and EXO1, are encoded by polymorphic genes. 8,9 Variant alleles of MLH1 c.293G>A, 10 MSH2 c.211 1 9C>G 11 and EXO1 c.1765G>A 12 single nucleotide polymorphisms (SNPs) reduce the expression of encoded proteins when compared with the respective wild-type alleles, and have decrease in DNA repair as consequence. The role of MSH3 c.3133G>A in protein activity is not totally clarified. 13-15 GG genotype of MLH1 c.293G>A and variant allele A of EXO1 c.1765G>A SNP were associated with increased risk of oral SCC only in India 16 and Taiwan, 17 respectively. To the best of our knowledge, the roles of the ...

Significant association of the EXO1 rs851797 polymorphism with clinical outcome of ovarian cancer

“…We here reported a potentially functional variant in EXO1 (rs851797) that involved in the process of ovarian cancer progression and prognosis. Unlike the findings from head and neck squamous cell carcinoma15 and non-small cell lung cancer,16 we did not observe predictive values of rs1047840 and rs9350 polymorphisms in EOC survival. It might be caused by the heterogeneity among various types of human cancer.…”

“…For example, EXO1 N279S13 and R354H14 could predict the overall survival in pancreatic cancer patients. EXO1 K589E (rs1047840) might be a prognostic biomarker for relapse-free survival in head and neck squamous cell carcinoma 15. Recently, EXO1 rs9350 was reported to be associated with poor survival of non-small cell lung cancer patients who were treated by platinum-based chemotherapy 16.…”

XPD c.934G>A polymorphism of nucleotide excision repair pathway in outcome of head and neck squamous cell carcinoma patients treated with cisplatin chemoradiation

“…Concurrent single daily fractionated radiation (2 Gy/day) during 35 days and intravenous CDDP at initial dose of 80-100 mg/m 2 on days 1, 22 and 43 was administered to patients; patients with consistent side effects during treatment received CDDP at lower dose [3, 48]. RR to chemoradiotherapy was assessed using Response Evaluation Criteria in Solid Tumors (RECIST) guidelines version 1.1 [49].…”

Association between polymorphisms in genes related to DNA base-excision repair with risk and prognosis of oropharyngeal squamous cell carcinoma

“…The patients were treated according to the institutional protocol, based on conventional procedures (Nogueira et al 2015). Patients with advanced resectable locoregional tumors received neoadjuvant treatment (n = 15) or adjuvant treatment (n = 12) with 35 sessions of radiation, 2 Gy per session, with concurrent intravenous cisplatin at a dose of 80-100 mg/m 2 or carboplatin area under the curve of 5 on days 1, 22 and 43, before or after surgery, respectively.…”