Genetic variants in CHEK1 gene are associated with the prognosis of thoracic esophageal squamous cell carcinoma patients treated with radical resection

Abstract

CHEK1 gene is known to play an important role in tumor progression by cell cycle control. However, the association between CHEK1 and the prognosis of esophageal squamous cell carcinoma (ESCC) is unclear. In this study, we explored the association between genetic variants in CHEK1 gene and prognosis of ESCC patients treated with radical resection. A total of 131 thoracic ESCC patients who underwent radical resection were included in this retrospective study and genotyped using the MassArray method. According to the univariate Cox hazard analysis, the GT/TT genotype of CHEK1 rs555752 was shown to be strongly related to a decreased overall survival (OS) (HR=2.560, 95% CI: 1.415–4.631, P=0.002) and disease-free survival (DFS) (HR=2.160, 95% CI: 1.258–3.710, P=0.005). Furthermore, according to the multivariate Cox hazard analysis and multiple testing, patients with the GT/TT genotype of CHEK1 rs555752 had a notably decreased OS (HR=2.735, 95% CI: 1.468–5.096, P=0.002, Pc=0.006) and DFS (HR=2.282, 95% CI: 1.292–4.023, P=0.004, Pc=0.012). In conclusion, genetic variants of the CHEK1 gene are significantly related to OS and DFS of ESCC patients, and may therefore be predictors of the prognosis of thoracic ESCC after surgery.

Keywords

esophageal squamous cell carcinoma / CHEK1 / single nucleotide polymorphism / prognostic factor / overall survival / disease-free survival

References

[1] ChenW, ZhengR, BaadePD, et al. . Cancer statistics in China, 2015. CA Cancer J Clin, 2016, 66(2): 115-132 PMID: 26808342

[2] JemalA, BrayF, CenterMM, et al. . Global cancer statistics. CA Cancer J Clin, 2011, 61(2): 69-90 PMID: 21296855

[3] AdhamM, BaulieuxJ, MornexF, et al. . Combined chemotherapy and radiotherapy followed by surgery in the treatment of patients with squamous cell carcinoma of the esophagus. Cancer, 2000, 89(5): 946-954 PMID: 10964323

[4] AndoN, OzawaS, KitagawaY, et al. . Improvement in the results of surgical treatment of advanced squamous esophageal carcinoma during 15 consecutive years. Ann Surg, 2000, 232(2): 225-232 PMID: 10903602 PMCID: 1421135

[5] ChengTH, HsuPK, LiAF, et al. . Correlation of p53, MDM2 and p14(ARF) protein expression in human esophageal squamous cell carcinoma. J Cancer Res Clin Oncol, 2009, 135(11): 1577-1582 PMID: 19488782

[6] KleinbergL, ForastiereAA. Chemoradiation in the management of esophageal cancer. J Clin Oncol, 2007, 25(26): 4110-4117 PMID: 17827461

[7] AjaniJA. Carcinoma of the esophagus: is biology screaming in my deaf ears?. J Clin Oncol, 2005, 23(19): 4256-4258 PMID: 15781878

[8] CesconDW, BradburyPA, AsomaningK, et al. . p53 Arg72Pro and MDM2 T309G polymorphisms, histology, and esophageal cancer prognosis. Clin Cancer Res, 2009, 15(9): 3103-3109 PMID: 19383811 PMCID: 3081782

[9] ZhangJ, XuZ, YuL, et al. . Assessment of the potential diagnostic value of serum p53 antibody for cancer: a meta-analysis. PLoS One, 2014, 9(6): 99255

[10] PrivesC, HallPA. The p53 pathway. J Pathol, 1999, 187(1): 112-126 PMID: 10341712

[11] PablaN, BhattK, DongZ. Checkpoint kinase 1 (Chk1)-short is a splice variant and endogenous inhibitor of Chk1 that regulates cell cycle and DNA damage checkpoints. Proc Natl Acad Sci USA, 2012, 109(1): 197-202 PMID: 22184239

[12] SyljuasenRG, SorensenCS, HansenLT, et al. . Inhibition of human Chk1 causes increased initiation of DNA replication, phosphorylation of ATR targets, and DNA breakage. Mol Cell Biol, 2005, 25(9): 3553-3562 PMID: 15831461 PMCID: 1084285

[13] WalworthNC, BernardsR. Rad-dependent response of the chk1-encoded protein kinase at the DNA damage checkpoint. Science, 1996, 271(5247): 353-356 PMID: 8553071

[14] BartekJ, LukasJ. Chk1 and Chk2 kinases in checkpoint control and cancer. Cancer Cell, 2003, 3(5): 421-429 PMID: 12781359

[15] SorensenCS, HansenLT, DziegielewskiJ, et al. . The cell-cycle checkpoint kinase Chk1 is required for mammalian homologous recombination repair. Nat Cell Biol, 2005, 7(2): 195-201 PMID: 15665856

[16] YangJ, LiuB, LiW, et al. . Association of p53 and MDM2 polymorphisms with risk of human papillomavirus (HPV)-related esophageal squamous cell carcinoma (ESCC). Cancer Epidemiol, 2013, 37(5): 629-633 PMID: 23837945

[17] RajaramanP, WangSS, RothmanN, et al. . Polymorphisms in apoptosis and cell cycle control genes and risk of brain tumors in adults. Cancer Epidemiol Biomarkers Prev, 2007, 16(8): 1655-1661 PMID: 17684142

[18] LinWY, BrockIW, ConnleyD, et al. . Associations of ATR and CHEK1 single nucleotide polymorphisms with breast cancer. PLoS One, 2013, 8(7): 68578

[19] ColeKA, HugginsJ, LaquagliaM, et al. . RNAi screen of the protein kinome identifies checkpoint kinase 1 (CHK1) as a therapeutic target in neuroblastoma. Proc Natl Acad Sci USA, 2011, 108(8): 3336-3341 PMID: 21289283 PMCID: 3044382

[20] SanchezY, BachantJ, WangH, et al. . Control of the DNA damage checkpoint by chk1 and rad53 protein kinases through distinct mechanisms. Science, 1999, 286(5442): 1166-1171 PMID: 10550056