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A Rare CHD5 Haplotype and Its Interactions with Environmental

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A Rare CHD5 Haplotype and Its Interactions with Environmental Xiao et al. BMC Cancer (2018) 18:658 https://doi.org/10.1186/s12885-018-4551-y RESEARCHARTICLE Open Access ArareCHD5 haplotype and its interactions with environmental factors predicting hepatocellular carcinoma risk Qin Xiao1,2†, Lianzhou Chen3†, Haiqing Luo1,4†, Hongmei Li1,5†, Qingming Kong6, Fei Jiao7, Shifeng Pang1, Ming Zhang8, Feifei Lan9, Wenguo Fan10, Hui Luo1*, Tao Tao8* and Xiao Zhu1* Abstract Background: CHD5 is a conventional tumour-suppressing gene in many tumours. The aim of this study was to determine whether CHD5 variants contribute to the risk of hepatocellular carcinoma (HCC). Methods: Gene variants were identified using next-generation sequencing targeted on referenced mutations followed by TaqMan genotyping in two case-control studies. Results: We discovered a rare variant (haplotype AG) in CHD5 (rs12564469-rs9434711) that was markedly associated with the risk of HCC in a Chinese population. A logistical regression model and permutation test confirmed the association. Indeed, the association quality increased in a gene dose-dependent manner as the number of samples increased. In the stratified analysis, this haplotype risk effect was statistically significant in a subgroup of alcohol drinkers. The false-positive report probability and multifactor dimensionality reduction further supported the finding. Conclusions: Our results suggest that the rare CHD5 gene haplotype and alcohol intake contribute to the risk of HCC. Our findings can be valuable to researchers of cancer precision medicine looking to improve diagnosis and treatment of HCC. Keywords: CHD5, Gene haplotype, Hepatocellular carcinoma, Alcohol intake, Risk Background is one of the nine members of the CHD-binding en- Hepatocellular carcinoma (HCC) is the most common zymes and belongs to the snf2 DNA helicase/methylase primary liver cancer and has the worst prognoses of all superfamily [2]. CHD5 consists of 42 exons coding for a malignancies. The etiological background of HCC pa- 223 kDa protein. Based on its protein sequence, it con- tients differs between patients from different regions. In tains two PHD zinc fingers, two chromodomains and a China, chronic hepatitis B virus (HBV) infection is the helicase/ATPase domain. most important risk factor for HCC; two-thirds of the Evidence that CHD5 functions as a tumour suppressor worldwide HBV carriers are Chinese, and approximately in human cancers has emerged principally from studies 20% of them have a chronic HBV infection [1]. of neuroblastoma, wherein loss of the CHD5 locus on Chromodomain helicase DNA-binding protein 5 chromosome 1p36.3 is very common. CHD5 has (CHD5) is on the Homo sapiens chromosome 1p36.31. It garnered considerable interest owing to its ability to severely impact clonogenicity and tumourigenecity. Although its expression was thought to be restricted to * Correspondence: [email protected]; [email protected]; neural-related tissues, it was subsequently found to be a [email protected] †Qin Xiao, Lianzhou Chen, Haiqing Luo and Hongmei Li contributed equally tumour suppressor in neuroblastoma [3], melanoma [4], to this work. lung cancer [5], breast cancer [6], ovarian cancer [7], 1 Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics, gastric cancer [8], colorectal cancer [9] and HCC [10]. Dongguan Scientific Research Center, Guangdong Medical University, Dongguan, China CHD5 loss leads to a wide range of cellular conse- 8Department of Gastroenterology, Zibo Central Hospital, Zibo, China quences, and it, therefore, remains a promising Full list of author information is available at the end of the article © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Xiao et al. BMC Cancer (2018) 18:658 Page 2 of 11 candidate for further investigation in HCC. In this study, treatment. All samples were included in the combined we tested the hypothesis that single-nucleotide polymor- study. Genomic DNA was extracted from peripheral phisms (SNPs) in the 1p36 region of CHD5 are associ- whole blood cells using the QIAamp system (QIAGEN ated with HCC. Co.). Genomic DNA from 255 controls and 280 HCC pa- tients were randomly sheared by sonication to an average Methods size of 250 bp per fragment. Target enrichment technol- Study subjects ogy was used as described by Anna Kiialainen et al. [16]. First, 280 unrelated HCC patients and 255 healthy con- The enriched libraries were loaded onto the HiSeq system trols (admitted to the Zibo Central Hospital in North 2000 and approximately 90-bp paired-end reads were pro- China between 2006 and 2010) were recruited for our duced using the NGS technology (Illumina Genome study. Then, 549 HCC patients and 510 controls (admit- Analyzer). We will use fastq short reads to align the NCBI ted to the Peking University Shenzhen Hospital between build 37.1 hg19 [17]. Single-nucleotide variants (SNV) 2007 and 2010, the First Affiliated Hospital at the Sun that obey the criteria that a. P for Hardy–Weinberg equi- − Yat-Sen University between 2007 and 2015, and the librium (HWE, <10 4), b. duplicated paired-end reads, c. Cancer Hospital of Guangzhou Medical University be- overall depth ≤ 8×, d. SNP within 10 bp of a gap, or e. copy tween 2009 and 2011 in South China) were enrolled in number variant ≥2werethenfiltered[18]. For these the replication study. The selection criteria for the con- concerns, only qualified SNPs were considered for this trols included no individual/family history of cancer or evaluation, so a 164-SNP set was used for the primary diabetes; no history of HBV, HCV, tuberculosis or HIV in- case-control study. Plink was used to calculate fection and frequency of age (± 5 years) and sex matching single-nucleotide variants [19], and the Haploview was those of the patients. All patients were newly diagnosed, used to perform visualisation [20]. previously untreated (no radiotherapy or chemotherapy) and were proven to have no other tumours. We used pub- Population risk evaluation, linkage disequilibrium (LD) lished diagnostic criteria for HCC [11, 12]. The definition mapping and gene–gene interactions of ‘Ever or current smokers’ is those who had smoked We used the chi-square and Mann–Whitney U tests to more than 100 cigarettes, which is equal to five packs in compare and evaluate the clinical data between the pa- their whole life before the date they were diagnosed with tients and controls in discovery, replication and the cancer or before the date they were interviewed for the combined groups. The risk evaluation was assessed using controls [13, 14]. The definition of ‘Ever or current the Pearson chi-square test. Because 164 SNPs were ge- drinkers’ were those who have consumed alcoholic bever- notyped, the Bonferroni-corrected P value for associ- ages ≥one time per week for 6 months or more previously; ation studies is 0.05/164 = 0.0003 for single SNPs. otherwise, they were defined as non-drinkers [15]. The A gene–gene interaction in this study is defined as an purpose of frequency matching was to control confound- SNP–SNP interaction and was conducted with LD map- ing factors while evaluating the main effect of CHD5 poly- ping. To estimate the degree of LD between pairs of loci, morphisms. All patients and controls were Han Chinese the standardised disequilibrium coefficient (D′) was cal- in origin and lived in China. Relevant biographical features culated and haplotype blocks were defined using the of the subjects are summarised in Table 1. Haploview programme [20]. The haplotypic imputation, The committee of ethics in Guangdong Medical Uni- reconstruction and frequency estimations were con- versity authorised the experimental and research proto- ducted with an expectation–maximisation algorithm 2 cols of this study. Experiments on humans were [21]. ne =1/∑Pi was used to calculate the number of ef- performed in accordance with relevant guidelines and fective haplotypes, and Pi was the estimate of individual regulations. After clearly explaining the purpose of the haplotype frequency [22]. Pi was calculated because the study to the participants, all controls and patients (or phase of the genotype was known and it was chosen in relatives of patients who already died) provided written compliance with the homologous probabilities of occur- informed consent. The study also adhered to tenets in rence that had a higher likelihood (>0.95 as cut-point). the Helsinki declaration. All potential participants who declined to participate or ended up not participating Permutation test and quantile–quantile (Q–Q) analysis were eligible for treatment, and non-participation did We performed permutation tests for 105 permutations, in not result in any disadvantages for patients. which subjects’ phenotypes were randomly realigned. P values (permutation or empirical P values) were specified Targeted next-generation sequencing (NGS) and as permutation values that were at least as extreme as the identification of genetic variants original statistics divided by the total permutation num- Aliquots of buffy coat
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