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Nucleotide Excision Repair Gene ERCC2 and ERCC5 Variants Increase Risk of Uterine Cervical Cancer

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Nucleotide Excision Repair Gene ERCC2 and ERCC5 Variants Increase Risk of Uterine Cervical Cancer pISSN 1598-2998, eISSN 2005-9256 Cancer Res Treat. 2016;48(2):708-714 http://dx.doi.org/10.4143/crt.2015.098 Original Article Open Access Nucleotide Excision Repair Gene ERCC2 and ERCC5 Variants Increase Risk of Uterine Cervical Cancer Jungnam Joo, PhD1 Purpose Kyong-Ah Yoon, PhD2 Defects in the DNA damage repair process can cause genomic instability and play an important role in cervical carcinogenesis. The purpose of this study was to analyze the Tomonori Hayashi, PhD3 association of 29 candidate single nucleotide polymorphisms (SNPs) in genes in the DNA MD, PhD4 Sun-Young Kong, repair pathway, TP53, and TP53BP1 with the risk of cervical cancer. Hye-Jin Shin, MS5 Boram Park, MS1 Materials and Methods Young Min Kim, PhD6 Twenty-nine SNPs in four genes in the DNA repair pathway (ERCC2, ERCC5, NBS1, and XRCC1), TP53, and TP53BP1 were genotyped for 478 cervical cancer patients and 922 Sang-Hyun Hwang, MD, PhD7 healthy control subjects, and their effects on cervical carcinogenesis were analyzed. Jeongseon Kim, PhD8 Aesun Shin, MD, PhD8,9 Results Joo-Young Kim, MD, PhD5,10 The most significant association was found for rs17655 in ERCC5, with an age-adjusted p-value < 0.0001, for which a strong additive effect of the risk allele C was observed (odds ratio, 2.01 for CC to GG). On the other hand, another significant polymorphism rs454421 1Biometric Research Branch, in ERCC2 showed a dominant effect (odds ratio, 1.68 for GA+AA to GG) with an age-adjusted 2Lung Cancer Branch, National Cancer Center, p-value of 0.0009. The association of these polymorphisms remained significant regardless Goyang, Korea, 3Department of Radiobiology and Molecular Epidemiology, of the age of onset. The significant result for rs17655 was also consistent for subgroups of Radiation E!ects Research Foundation, patients defined by histology and human papillomavirus (HPV) types. However, for Hiroshima, Japan, rs454421, the association was observed only in patients with squamous cell carcinoma 4 Translational Epidemiology Research Branch and non-HPV 18 type. and Department of Laboratory Medicine, 5 Radiation Medicine Branch, Conclusion National Cancer Center, Goyang, Korea, 6Department of Statistics, The results of this study show a novel association of cervical cancer and the genes involved Radiation E!ects Research Foundation, in the nucleotide excision pathway in the Korean population. Hiroshima, Japan, 7Hematologic Malignancy Branch and Department of Laboratory Medicine, 8Molecular Epidemiology Branch, National Cancer Center, Goyang, 9Department of Preventive Medicine, Seoul National University College of Medicine, Seoul, 10Center for Proton Therapy, Research Institute and Hospital, National Cancer Center, Goyang, Korea Key words ERCC, Single nucleotide polymorphism, Uterine cervical neoplasms + C +o r +re s+p o +n d +e n +c e :+ J o +o - Y+o u+n +g K +i m +, M+ D +, P +h D + + + + R +e s +ea r+c h + I n +st i+tu t+e a +n d + H +o s p+i t +al , + + + + + + + + N +a t+io n+a l+ C a+n c+e r +C e +n t e+r , +1 1 +1 J u+n g+b a+l s a+n -+r o +, + + + I l+s a +nd +on +g- g+u ,+ G o+y a+n g+ 1 0+4 0+8 , +K o +re a+ + + + + + + + + + + + + + + + + + + + + + + + + + + T +e l :+ 8 2 +-3 1+- 9 +20 -+1 7 +24 + + + + + + + + + + + + + F +a x +: 8 2+- 3 +1- 9 +2 0 +-0 1+4 9 + + + + + + + + + + + + + E +-m +a i l+: j o+o y +o u +n g +c a +sa @+n +cc .r+e . k+r + + + + + + + + + + + + + + + + + + + + + + + + + + + + R +e c +ei v +e d + M +a r+c h + 6 , +2 0 +15 + + + + + + + + + + + A +c c +ep +te d + M +a y+ 1 +1, 2+0 1+5 + + + + + + + + + + + P +u b +li s +h e d+ O +n l+in e+ J +u n +e 2 +2 , +20 1+5 + + + + + + + + + + + + + + + + + + + + + + + + + + + + * +Ju n+g n+a m + J +oo +a n +d K+y o+n g+- A +h +Y o +o n + c o +n t +ri b +u t e+d + + e +q u +al l+y t +o t h+i s + w +or k+. + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + 708 Copyright ⓒ 2016 by the Korean Cancer Association │ http://www.e-crt.org │ This is an Open-Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. Jungnam Joo, ERCC2 and ERCC5 Variants Increase Cervical Cancer Risk Introduction with genetic instability as well as cancer risk [10]. Several common and putative functional single nucleotide polymorphisms (SNPs) of these DNA repair genes were The incidence of invasive cervical cancer has been decreas- reported as genetic factors associated with HPV persistence ing (annual percent change [APC] in age-adjusted rates and cervical cancer progression [11]. In the current study, of –4.2%), however cervical neoplasm is still a major health 29 genetic polymorphisms associated with four genes in the problem in Korea. According to the National Cancer Regis- DNA repair pathways, TP53 and TP53BP1 were examined to tration statistics in Korea, the age-standardized incidence determine their effects on development of cervical cancer. rate of cervical cancer was 14.9 per 100,000 in 2011, and the age standardized incidence rate for cervical carcinoma in situ increased from 7.5 in 1993 to 19.0 per 100,000 females in 2009 (APC, 5.7; 95% confidence interval [CI], 4.8 to 6.7) [1]. The Materials and Methods incidence of adenocarcinoma has remained stable despite the decreased incidence of squamous cell carcinoma. Eighty per- cent of infections of human papillomavirus (HPV) clear 1. Study population within 3 years, and persistence of viral DNA is reported in 5%-15% of infected women [2]. Finally, only 3%-5% of The study was designed as a hospital based case-control women with persistent HPV infection reach the stage of cer- study. A total of 479 cervical cancer patients who visited the vical intraepithelial neoplasm (CIN). With this background, National Cancer Center, Korea between July 2003 and March we need to define the subset of the population that is vulner- 2011 were recruited. The control group was selected from able to persistent HPV infection and progression to epithelial a cohort recruited at the Center for Early Detection and abnormality. Use of tobacco and estrogen-derivatives are Prevention at the same hospital between August 2002 and known as external factors associated with progression to cer- August 2011. A total of 8,291 women who provided informed vical cancer [3]. However, reports of familial aggregation of consent completed a questionnaire to collect information on cervical cancer from Swedish and Latin American cohort demographics and cancer risk factors, and provided blood studies suggest that host genetic factors may contribute to samples; 4,005 women had DNA samples available in an cervical carcinogenesis, although shared environmental adequate amount (! 10 µg). Among them, 1,000 consecutive factors in childhood may be partly responsible for familial control subjects with informed consent were selected in aggregation [4,5]. chronological order starting from August 2002. Those who In cervical cancer, HPV integration into the genome of host had missing genotypes due to inadequate DNA quality were cells initiates E6 and E7 oncoprotein expression, which in excluded (1 case and 4 controls); those with history of other turn drives differentiating cells into S or G2/M phases to types of cancer (72 subjects) were also excluded from control induce amplification of the viral genome. Once viral genetic samples. As a result, 478 cases and 922 control subjects were material is introduced in the host genome, it is considered as used in the analysis. The study was approved by the Institu- "damage," which causes activation of cellular DNA repair tional Review Board of the National Cancer Center in Korea machinery [6]. As a result of attempts at unordered replica- (IRB No. NCCNCS 10-412). tion of cells, formation of multiple sites of stalled replication forks occurs along with activation of DNA damage repair 2. Selection and genotyping of 29 SNPs pathways. Activated DNA repair pathways that prevent DNA damage and mutagenesis included in these repair After an intensive literature review, six genes (ERCC2, pathways are the base excision repair (BER) pathway, the ERCC5, NBS1, TP53, TP53BP1, and XRCC1) involved in the nucleotide excision repair (NER) pathway, DNA single DNA damage repair pathway were selected. The candidate strand break (SSB), and the double strand break repair (DSB) polymorphisms in the six genes, including eight non-synony- pathways [7]. X-ray repair cross-complementing (XRCC) 1 in mous SNPs, were selected on the basis of previously the BER pathway and excision repair cross-complementing reported associations with cancer risk or prognosis. Five (ERCC) 2 and ERCC5 in the NER systems were previously SNPs of TP53 and TP53BP1 were selected because they are studied as risk factors for epithelial cancer [8]. Viral E6 and frequently studied as cancer predisposing factors. The minor E7 activate the ataxia telangiectasia mutated (ATM) DNA allele frequency (> 5%) in the Asian population was an damage response necessary for the differentiation-dependent additional filter for selection of target SNPs. Genomic DNA amplification of viral genomes [9]. TP53 is a major activator was extracted from peripheral blood samples using a of ATM upon DNA damage signal, and functional polymor- QIAamp DNA Blood Mini Kit (Qiagen, Valencia, CA) in phisms in TP53 and TP53BP1 are known to be associated accordance with the manufacturer’s instructions. The Taq- VOLUME 48 NUMBER 2 APRIL 2016 709 Cancer Res Treat.
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