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Targeted Sequencing of Cancer-Associated Genes in Hepatocellular Carcinoma Using Next Generation Sequencing

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Targeted Sequencing of Cancer-Associated Genes in Hepatocellular Carcinoma Using Next Generation Sequencing 4678 MOLECULAR MEDICINE REPORTS 12: 4678-4682, 2015 Targeted sequencing of cancer-associated genes in hepatocellular carcinoma using next generation sequencing JIANGUO LU1*, JIKAI YIN1*, RUI DONG1, TAO YANG1, LIJUAN YUAN1, LI ZANG1, CHENG XU2, BO PENG2, JIANGMAN ZHAO2 and XILIN DU1 1Department of General Surgery, Tangdu Hospital, Fourth Military Medical University, Xi'an, Shaanxi 710038; 2Department of Medicine, Shanghai Zhangjiang Translational Medicine Research Center, Shanghai 201203, P.R. China Received August 4, 2014; Accepted April 20, 2015 DOI: 10.3892/mmr.2015.3952 Abstract. Liver cancer is one of the most common causes it is estimated that >600,000 cases of HCC are newly diag- of cancer-associated mortality. Hepatocellular carcinoma nosed each year worldwide, >50% of which are in China (1,2). (HCC) is the major histological subtype among types of Despite advances in diagnosis and multimodality therapies for primary liver cancer. China is an area of high incidence HCC, the prognosis of the disease remains poor, with a 5-year of HCC, and >50% of the cases of HCC worldwide are in overall survival rate of <14% (3). China. At present, the mechanism underlying the develop- The environmental risk factors for HCC include hepa- ment of HCC remains to be fully elucidated, and previous titis B virus (HBV) and hepatitis C virus (HCV) infection, studies have predominantly focused on HCC in southern food aflatoxin contaminants, alcohol intake and smoking (2). and eastern China, with molecular data of the HCC cases in HBV infection is the dominant global attributable risk factor, Western China remains limited. In the present study, a panel accounting for >80% of the cases of HCC in China (2). HBV of 372 cancer-associated genes were screened using a next is small enveloped DNA virus, belonging to the hepadna- generation sequencing platform, which included a total of virus family, which is capable of integrating into and altering 12 cases from western China. The results confirmed muta- the host genome. A total of four overlapping open reading tions in previously identified HCC drivers, including p53 frames, encoding for the surface protein, core protein, poly- and Kras. Additionally, mutations in several cancer genes, merase protein and X protein (HBX), have been identified which had not been previously associated with HCC, were in the small 3.2 kb DNA of HBV (4,5). HBX is the regula- identified, including RUNX1 and JAK3. The present study tory protein of the virus, and is frequently detected in the provided a mutation spectrum of HCC tissue in cases from tumor tissues of patients with HBV-associated HCC (4,5). western China, assisting in the investigation of the mecha- HBX transgenic mice have been reported to exhibit a posi- nism of liver carcinogenesis. tive correlation between the expression levels of HBX and the development of HCC (6,7). Consuming food containing Introduction aflatoxin is another high environmental risk factor for HCC. Aflatoxin B1 is the most abundant form of aflatoxin, produced Liver cancer is one of the most common types of cancer by the fungus Aspergillus flavus, which contaminates food, and is the third most frequent cause of cancer-associated particularly under hot and humid conditions (8-10). The mortality. Hepatocellular carcinoma (HCC) is the major metabolites of Aflatoxin B1 can form a DNA adduct at the histological subtype among types of primary liver cancer, and third base of codon 249 in the TP53 gene, inducing a G>T transversion and an R249S mutation, which is the most frequently altered type of TP53 in HCC tissues (8-10). Alterations in multiple signaling pathways and patterns of host gene expression have been documented following HBV Correspondence to: Professor Jianguo Lu or Dr Xilin Du, infections. Somatic mutations, which trigger oncogenes or Department of General Surgery, Tangdu Hospital, Fourth Military inactivate tumor suppressor genes, contribute to the develop- Medical University, 569 Xinsi Road, Xi'an, Shaanxi 710038, ment of HCC. Previous studies using several strategies have P. R. Ch i na demonstrated that certain genetic alterations occur in HCC E-mail: [email protected] E-mail: [email protected] cells, including TP53, CTNNB1, Axin1 and ARID1A high frequency mutation genes and Kras and APC low frequency *Contributed equally mutation genes (11-13). The development of next generation sequencing (NGS) has led to an increase in the number of Key words: hepatocellular carcinoma, mutations, next generation mutations identified in HCC tissues. Huang et al (14) inves- sequencing tigated the spectrum of molecular aberrations in liver cancer using whole exome sequencing, and identified 356 candidate somatic single nucleotide variants (SNVs) within 347 genes. Tangdu Hospital, Tangdu the Ethics by Committee also approved was study present of printed Medical (Declaration Association Helsinki), of theWorld performed was in accordance The with Ethics Code of of and theand investigation patient, writteneach of consent and drinkinghistory, history acquired was questionnaire. by platform then the sequenced andIlluminausing were the samples HiSeq preparation, sample Prep TruSeq used Sample kit for was DNA (Illumina,tions San Inc., Enrichment 372 of region to capture the exon updated Illumina edition. used was technology TruSeq the 2011 http: from 372 of all exons The targeted included regions Germany). Dusseldorf, (Qiagen, (cat. no. 51306), Mini QIAamp a extracted using DNA was kit GenomicDNA Target China). Optical Instrument Shanghai Tuming Co., microscope light a histochemical using ( analysis cally 33 (range 11 of carriers. chronic HBV were The consisted population study tion was ~0.2x0.2x0.2 extrac DNA used The for samples tissue size of extraction. following non‑cancerous and analyzed in the study. present non the study. present December Fourth Military Medical University Hospital, Tangdu at HCC surgery had undergone for who Tissue methods and Materials HCC. the molecular alterations associated with understanding aimed resources for to provide investigation spectrummutation from samples western China. HCC of The performedan using alterations. gene of in characteristic HCC western Chinawith exhibit may patterns limited. Due to the molecular data in from samples western China HCC remains from s samples HCC on predominantly focus investigations In addition, elucidated. HBV of and progression the molecular mechanismsHCC, leading to the development the and diagnosis treatment of efforts to improve Despite Research Center (Shanghai, China). Research Center (Shanghai, The experiments were performedThe experiments were the with understanding targeted 372 of sequencing In the study, present - // cancerous (minimum, tissues 3 the www.sanger.ac.uk confirmed. males and 1 samples. enrichment in Information regarding family history, smoking Information smoking regarding familyhistory, Catalogue - at 65 surgery the 2010 and September 2010 Trial Shanghai years). All histopathologi casesthe were HCC years). LU samples British according A total of 12 patients from patients A total western China, 12 of et Cirrhosis kit, Fourth Military Medical University genes. The targeted genes were selected The selected targeted were genes. genes female, with amedian with 51 of age female, al different environmental factors, patients of NGS platform, in order to investigate the in toorder investigate platform, NGS The and : TARGETED SEQUENCING OF CANCER-ASSOCIATED GENES IN HEPATOCELLULAR CARCINOMA according of Somatic ZhangJiang / Diego, CA Diego, genetics cm. Medical were - then associated remain HCC to be fully genomic patients' outhern and eastern China, while to and The majority of these The of majority the flash stored Mutations to / capsules genes, using a TruSeq Custom aTruSeq using genes, CGP manufacturer's , USA). An Illumina TruSeq , USA). Journal the cancerous frozen 2012, were included in in included were 2012, DNA Translational (Xi'an, / cosmic) database using cosmic) manufacturer's at Both cancerous and cm) were collected collected were cm) the development of ‑80˚C, were in and in (1964) (15). Cancer China) Ltd., Shanghai, liquid and confirmed sequencing. instructions until CDM965; Medicine genes was was genes adjacent (Cosmic; nitrogen between years old years old patients patients instruc . DNA The by - - - Table I. Summary of hepatocellular carcinoma samples. Sample Number of Age AFP NCCN Single or Tumor ID mutations (years) Gender HBV Cirrhosis Metastsis Smoking Drinking (ng/ml) staging T N M multiple size (mm) Capsule H1 7 33 Male + + ‑ ‑ + 9.7 Ⅰ T1 N0 M0 ‑ 8x6x6 + H2 6 42 Male + + ‑ ‑ + 15766 Ⅰ T1 N0 M0 ‑ 10x8x8 + H3 5 47 Male + + ‑ + + 7.9 Ⅱ T1 N0 M0 ‑ 5x5x4 + H4 8 54 Male + + + ‑ ‑ 6568 Ⅳa T3 N1 M0 + 8x6x5 + H5 5 55 Male + + + ‑ ‑ 2.9 Ⅳa T3 N1 M0 ‑ 10x7x6 + H6 7 49 Male + + ‑ + ‑ 81575 Ⅲc T4 N0 M0 ‑ 7x6x6 + H7 10 65 Male ‑ + ‑ ‑ + 81.1 Ⅰ T1 N0 M0 ‑ 5x5x5 + H8 9 35 Male + ‑ ‑ ‑ ‑ 71060 Ⅲa T3 N0 M0 + 8x6x6 + H9 8 60 Female + + ‑ ‑ ‑ 898.4 Ⅳb T3 N0 M1 + 6x5x5 + H10 3 58 Male + + ‑ ‑ + 6.2 Ⅲa T3 N0 M0 ‑ 6x6x6 + H11 6 53 Male + + ‑ + + 7.1 Ⅰ T1 N0 M0 ‑ 4x4x3 + H12 7 35 Male + + ‑ ‑ + 121001 Ⅲc T4 N0 M0 ‑ 9x8x7 + 4679 +, positive; ‑, negative; HBV, hepatitis B virus; AFP, alpha‑fetoprotein; NCCN, National Comprehensive Cancer Network; T, tumor; N, node; M, metastasis. 4680 MOLECULAR MEDICINE REPORTS 12: 4678-4682, 2015 Data analysis. For each patient, DNA was extracted from both Table II. Recurrent mutations in hepatocellular carcinoma tumor tissues and non tumor tissues, and was sequenced at samples. the same time. The SNVs and insertions/deletions were identi- fied using a Genome Analyzer Toolkit (GATK, version 3.0; Mutation Broad Institute, Cambridge, MA, USA). Coverage represents Gene frequency Mutation Sample the number of times that each nucleotide is sequenced at the NGS platform. Effective rate represents the ratio of clean data TP53 5/12 c.G422A:p.R141H, H12 (following removal of low quality and contaminated data) to c.T368C:p.I123T, H8 raw data. To identify somatic mutations, the sequence variants c.A229T:p.R77X, H9 of the non tumor tissues were subtracted from those of the c.G315A:p.M105I, H4 tumor tissues.
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