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(EZH2) Genotypes with Bladder Cancer Risk in Taiwan

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ANTICANCER RESEARCH 36 : 4509-4514 (2016) doi:10.21873/anticanres.10997 Association of Enhancer of Zeste 2 ( EZH2 ) Genotypes with Bladder Cancer Risk in Taiwan WEN-SHIN CHANG 1,2* , CHENG-HSI LIAO 1,2,3,8* , CHIA-WEN TSAI 2* , PEI-SHIN HU 2,4 , HSI-CHIN WU 2, SHIH-WEI HSU 1,2,3,8 , CHIEH-LUN HSIAO 1,2 , CHANG-HSIEN HSU 5, YI-WEN HUNG 6 and DA-TIAN BAU 1,2,7 1Graduate Institute of Clinical Medical Science, China Medical University, Taichung, Taiwan, R.O.C.; 2Terry Fox Cancer Research Laboratory, China Medical University Hospital, Taichung, Taiwan, R.O.C.; 3Taichung Armed Forces General Hospital, Taichung, Taiwan, R.O.C.; 4Department of Ophthalmology, Changhua Christian Hospital, Changhua, Taiwan, R.O.C.; Departments of 5Business Administration, and 7Bioinformatics and Medical Engineering, Asia University, Taichung, Taiwan, R.O.C.; 6Department of Medicine Research, Taichung Veterans General Hospital, Taichung, Taiwan, R.O.C.; 8National Defence Medical Center, Taipei, Taiwan, R.O.C. Abstract. Aim: Bladder cancer is the sixth most common associated with the lower risk of bladder cancer development, cancer worldwide and its incidence is particularly high in especially among non-smokers. many developed regions including southwestern Taiwan. However, the genetic contribution to the etiology of bladder Bladder cancer is the most serious urinary neoplasm cancer is not well-understood. The aim of this study was to worldwide, with high incidence rates of approximately evaluate the association of the enhancer of zeste homolog 2 10/100,000 and 3/100,000 in more and less developed (EZH2) genotypes with Taiwan bladder cancer risk. Materials regions, respectively (1). According to the statistical data and Methods: Three polymorphic variants of EZH2 were provided by the International Agency for Research on analyzed regarding their association with bladder cancer Cancer, there were an estimated 429,800 new cases of risk, and three hundred and seventy-five patients with bladder bladder cancer and 165,100 deaths occurred in 2012 cancer and same number of age- and gender-matched healthy worldwide (1, 2). In Taiwan, bladder cancer ranks seventh in controls recruited were genotyped by the PCR-RFLP method. incidence and mortality among common carcinomas (3). Results: Among the three polymorphic sites examined, the Carcinogenesis of cancer is a complex, multistep and genotypes of EZH2 rs887569 (C to T), but not rs41277434 (A multifactorial process being the result of interactions of to C) or rs3757441 (T to C), were positively associated with lifestyle, environmental and genetic factors (3-8). bladder cancer risk (p for trend =0.0146). Individuals with The enhancer of zeste homolog 2 (EZH2), embryonic the EZH2 rs887569 TT genotypes were associated with ectoderm development (EED), and suppressor of zeste 12 decreased cancer risk than those with wild-type CC genotype. homolog (SUZ12) are polycomb group proteins which are The stratified analyses showed that EZH2 rs887569 TT important epigenetic chromatin modifiers, cell-cycle genotypes had protective effects on non-smokers but regulators, and believed to be involved in carcinogenesis. obviously not on smokers. Conclusion: Our findings provide EZH2 is reported to serve as a histone methyl transferase, evidence that the T allele of EZH2 rs887569 may be playing a crucial role in methylation of H3K27 and recruiting of protein regulator of cytokinesis 1 (PRC1), leading to initiation of gene silencing (9-11). In the early twentieth century, EZH2 overexpression was firstly reported *These Authors contributed equally to this study. in hematological malignancies (12, 13). In recent years, an increasing number of studies have reported overexpression Correspondence to: Da-Tian Bau, Terry Fox Cancer Research of EZH2 to be associated with poor prognosis in several Laboratory, China Medical University Hospital, 2 Yuh-Der Road, types of cancers including oesophageal (14), breast (15), Taichung, 404 Taiwan, R.O.C. Tel: +886 422052121 Ext. 7534, e-mail: [email protected]; [email protected] endometrial (16), gastric (17-21), colorectal (22, 23), hepatocellular (24), pancreatic (25) and oral (26) cancer. Key Words: Bladder cancer, EZH2 , genotype, polymorphism, In bladder cancer, the mRNA levels of EZH2 were found Taiwan. to be higher in bladder cancer specimens than non-tumor 0250-7005/2016 $2.00+.40 4509 ANTICANCER RESEARCH 36 : 4509-4514 (2016) Table I. Primer sequences, polymerase chain reaction and restriction fragment length polymorphism (PCR-RFLP) conditions for the genotyping of enhancer of zeste homolog 2 (EZH2). Polymorphism Primer sequences (5’ to 3’) Restriction enzyme Allele type Product size (bp) rs887569 F: 5’-TTGCATATTCAGGCTGGCCT-3’ Bsr I C 345 R: 5’-ATCAGGATGCTTAGGCCTGA-3’ T 185+160 rs41277434 F: 5’-CTGGATGGCTCTCTTGGCAA -3’ Kpn I A 391 R: 5’-CCTGAAGAACTGTAACCAGT-3’ C 206+185 rs3757441 F: 5’-TTGCATATTCAGGCTGGCCT-3’ Direct sequencing T – R: 5’-TTGCATATTCAGGCTGGCCT-3’ C *F and R indicate forward and reverse primers, respectively. bladder specimens, and EZH2 mRNA overexpression was for 30 s, and 72˚C for 30 s, and a final extension at 72˚C for 10 min detected in 100% of high-grade and invasive bladder tumors using BIO-RAD Mycycler PCR machine (BIO-RAD, Hercules, CA, (27). However, the contribution of EZH2 genotypes to USA). The primers for rs887569 and rs41277434 genotyping were all designed by our team, and the PCR primer sequences in addition susceptibility for abnormal expression of EZH2 and bladder to each responsive restriction enzyme for each DNA product are carcinogenesis is unknown. The current work focused on listed in Table I. Amplified and digested DNA products for rs887569 revealing the association of genotypes of EZH2 at rs887569 and rs41277434 were monitored by electrophoresis on 3% agarose (C to T), rs41277434 (A to C) and rs3757441 (T to C) gels, stained with ethidium bromide and imaged under UV among 375 bladder cancer and 375 healthy controls in irradiation. The sequencing for rs3757441 were 100% consistent Taiwan, a highly genetically-conserved population. between the results using forward and reverse primers. Materials and Methods Statistical analyses. Pearson’s Chi-square test or Fisher’s exact test (when the expected number in any cell was less than five) was used to compare the distribution of the EZH2 genotypic and allelic Study population and sample collection. Our study was approved by frequencies between case and control groups. The odds ratios (OR) the Institutional Review Board of China Medical University Hospital together with 95% confidence intervals (CI) were calculated to (DMR104-IRB-158), and all clinical investigations were conducted assess the relative risk conferred by a particular allele and genotype. according to the principles expressed in the Declaration of Helsinki. Demographic and clinical data between groups were compared by Three hundred and seventy-five patients diagnosed with bladder Chi-square test and by Student’s t-test. Data was assumed as cancer were enrolled at the outpatient clinics of general surgery significant at a statistical level when the p-value was less than 0.05. between 2003 to 2009 at the China Medical University Hospital, Taichung, Taiwan, Republic of China. All patients who voluntarily participated completed a self-administered questionnaire and Results provided their peripheral blood samples. The clinical characteristics The demographic characteristics of patients with bladder cancer of patients including histological details were all graded and defined by expert surgeons. An equal number of non-cancer healthy controls and the non-cancer controls are summarized in Table II. There were selected by matching for age and gender after initial random were no significant differences between groups regarding their sampling from the Health Examination Cohort of the hospital. The age, gender, cigarette smoking and alcohol drinking status exclusion criteria of the control group included previous malignancy, (Table II). metastasized cancer from other or unknown origin, and any familial The analysis for the distribution frequencies of the genotypes or genetic diseases. Both groups completed a short questionnaire and alleles of EZH2 rs887569 in the bladder cancer and control which included personal habits. Smokers were defined as daily or groups are summarized in Table III. Firstly, there was a almost daily smokers who had smoked at least five packs of cigarettes per year in their lifetime. Age of smoking initiation, significant difference between bladder cancer and control whether they were currently smoking or had already quit, and if so, groups in the distribution of genotypic frequency ( p for when they had quit, and on average, how many cigarettes they trend=0.0146), and the ORs for those with CT and TT genotype smoked or had smoked daily were recorded for smokers. were 0.78 (95% CI=0.58-1.06) and 0.47 (95% CI=0.27-0.80) compared to that for those with the CC wild-type genotype. Genotyping conditions. Each participant provided 3-5 ml venous Secondly, we performed dominant and recessive comparisons, blood. Genomic DNA was prepared within two days from their finding that the ORs of the CC+CT versus TT and CC versus peripheral blood leucocytes with the protocol of a QIAamp Blood Mini Kit (Blossom, Taipei, Taiwan) and further processed and stored CT+TT were 0.53 (95% CI=0.31-0.89, p= 0.0212) and 0.72 according to our regular methodology (28-32). The polymerase chain (95% CI=0.54-0.96, p= 0.0329), respectively. Lastly, from the reaction (PCR)
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  • Association of XRCC3 and XRCC4 Gene Polymorphisms, Family History

    Association of XRCC3 and XRCC4 Gene Polymorphisms, Family History

    Journal of Human Genetics (2013) 58, 679–685 & 2013 The Japan Society of Human Genetics All rights reserved 1434-5161/13 www.nature.com/jhg ORIGINAL ARTICLE Association of XRCC3 and XRCC4 gene polymorphisms, family history of cancer and tobacco smoking with non-small-cell lung cancer in a Chinese population: a case–control study Fei He1, Shen-Chih Chang2, Gina Maria Wallar2, Zuo-Feng Zhang2 and Lin Cai1 Single-nucleotide polymorphisms (SNPs) of DNA repair genes have been reported to modify cancer risk. This study aimed to determine SNPs of the DNA repair genes X-ray repair cross-complementing group 3 (XRCC3) and X-ray cross-complementing group 4 (XRCC4) and their association with non-small-cell lung cancer (NSCLC) susceptibility in a Chinese population. A total of 507 NSCLC patients and 662 healthy controls were recruited for genotyping. Epidemiological and clinical data were also collected for association studies. The data showed that the rs1799794 G allele in the XRCC3 gene and minor allele carriers of XRCC4, including rs1056503 and rs9293337, were inversely associated with NSCLC risk (GG vs homozygote AA), whereas the rs861537 AG or AA genotype and XRCC4 rs6869366 had a significantly increased NSCLC risk. Furthermore, tobacco smoking over 26 pack-years, a family history of lung cancer, exposure to environmental tobacco smoke (ETS) and negative mental status were risk factors for developing NSCLC. This study suggests that SNPs of XRCC3 and XRCC4 and other environmental factors are risk factors for developing NSCLC in this Chinese Han population. Journal of Human Genetics (2013) 58, 679–685; doi:10.1038/jhg.2013.78; published online 8 August 2013 Keywords: case–control study; non-small-cell lung cancer; single-nucleotide polymorphism; XRCC3 and XRCC4 INTRODUCTION homologous recombination and non-homologous end-joining DNA Lung cancer was the most commonly diagnosed cancer and the repairs.
  • RAD51, XRCC3, and XRCC2 Mutation Screening in Finnish

    RAD51, XRCC3, and XRCC2 Mutation Screening in Finnish

    Pelttari et al. SpringerPlus (2015) 4:92 DOI 10.1186/s40064-015-0880-3 a SpringerOpen Journal RESEARCH Open Access RAD51, XRCC3, and XRCC2 mutation screening in Finnish breast cancer families Liisa M Pelttari1,JohannaIKiiski1, Salla Ranta1, Sara Vilske1,CarlBlomqvist2, Kristiina Aittomäki3 and Heli Nevanlinna1* Abstract Majority of the known breast cancer susceptibility genes have a role in DNA repair and the most important high-risk genes BRCA1 and BRCA2 are specifically involved in the homologous recombination repair (HRR) of DNA double-strand breaks. A central player in HRR is RAD51 that binds DNA at the damage site. The RAD51 paralogs RAD51B, RAD51C, RAD51D, XRCC2, and XRCC3 facilitate the binding of RAD51 to DNA. While germline mutations in RAD51C and RAD51D are associated with high ovarian cancer risk and RAD51B polymorphisms with breast cancer, the contribution of RAD51, XRCC3, and XRCC2 is more unclear. To investigate the role of RAD51, XRCC3, and XRCC2 in breast cancer predisposition and to identify putative recurrent founder mutations in the Finnish population where such mutations have been observed in most of the currently known susceptibility genes, we screened 182 familial Finnish breast or ovarian cancer patients for germline variation in the RAD51and XRCC3 genes and 342 patients for variation in XRCC2, with a subset of the patients selected on the basis of decreased RAD51 protein expression on tumors. We also performed haplotype analyses for 1516 breast cancer cases and 1234 controls to assess the common variation in these genes. No pathogenic mutations were detected in any of the genes and the distribution of haplotypes was similar between cases and controls.
  • Differential Mechanisms of Tolerance to Extreme Environmental

    Differential Mechanisms of Tolerance to Extreme Environmental

    www.nature.com/scientificreports OPEN Diferential mechanisms of tolerance to extreme environmental conditions in tardigrades Dido Carrero*, José G. Pérez-Silva , Víctor Quesada & Carlos López-Otín * Tardigrades, also known as water bears, are small aquatic animals that inhabit marine, fresh water or limno-terrestrial environments. While all tardigrades require surrounding water to grow and reproduce, species living in limno-terrestrial environments (e.g. Ramazzottius varieornatus) are able to undergo almost complete dehydration by entering an arrested state known as anhydrobiosis, which allows them to tolerate ionic radiation, extreme temperatures and intense pressure. Previous studies based on comparison of the genomes of R. varieornatus and Hypsibius dujardini - a less tolerant tardigrade - have pointed to potential mechanisms that may partially contribute to their remarkable ability to resist extreme physical conditions. In this work, we have further annotated the genomes of both tardigrades using a guided approach in search for novel mechanisms underlying the extremotolerance of R. varieornatus. We have found specifc amplifcations of several genes, including MRE11 and XPC, and numerous missense variants exclusive of R. varieornatus in CHEK1, POLK, UNG and TERT, all of them involved in important pathways for DNA repair and telomere maintenance. Taken collectively, these results point to genomic features that may contribute to the enhanced ability to resist extreme environmental conditions shown by R. varieornatus. Tardigrades are small