刘琼茹,杨文丽,蔡育波,梁津杰,余卫东,方晓华,黄辉,陈艳虹,陈仙兰,张鑫,林碧华
LIU Qiongru,YANG Wenli,CAI Yubo,LIANG Jinjie,YU Weidong,FANG Xiaohua,HUANG Hui,CHEN Yanhong,CHEN Xianlan,ZHANG Xin,LIN Bihua

• 1:江门市中心医院病理科
• 2:广东医科大学广东省医学分子诊断重点实验室
• 3:广东医科大学生物化学与分子生物学教研室

摘要(Abstract)：

目的分析与子宫内膜癌化疗反应相关基因的拷贝数变异情况。方法从肿瘤基因组图谱数据库(TCGA)中,获得子宫内膜癌的全基因组拷贝数变异数据和临床用药数据。分析TCGA数据库中患者的用药信息及药物反应情况,并利用GISTIC2.0软件分析患者肿瘤组织中基因组拷贝数变异情况。利用IGV软件定位拷贝数变异热点区域的关键基因,并分析热点基因的拷贝数变异情况与患者临床治疗反应间的相关性。结果截至2017年5月31日,TCGA数据库中有65例子宫内膜癌患者记录了治疗反应情况,其中49例呈完全缓解,为化疗敏感(CS)患者,2例呈部分缓解、2例呈病情稳定及12例呈病情进展,此3类患者合称化疗抵抗(CR)患者。进一步分析发现,22q12.2和Xp11.23区段特异性在CR患者肿瘤组织中扩增,1q44区段是CR患者肿瘤组织特异性缺失区段。其中22q12.2区段的扩增中心是白血病抑制因子(LIF)的编码基因,Xp11.23区段的扩增中心是果蝇Porcupine基因同源基因(PORCN)和依莫帕米结合蛋白(EBP)编码基因,1q44区段的缺失中心是驱动蛋白家族成员26B(KIF26B)的编码基因。此外,LIF的扩增和PORCN/EBP的扩增与患者发生化疗抵抗相关(P<0.05),但是KIF26B的缺失与化疗抵抗不相关(P>0.05)。结论子宫内膜癌组织中22q12.2区段(LIF)和Xp11.23区段(PORCN/EBP)的扩增及1q44区段(KIF26B)的缺失可能与患者化疗的抵抗相关,可以预判患者的化疗反应情况。
OBJECTIVE To investigate the copy number variations( CNV) involved in the chemotherapy of endometrial cancer.METHODS The patients' information and CNV data for endometrial cancer were download from The Cancer Genome Atlas( TCGA).The CNV significant analysis was used by GISTIC2. 0 program,and patients' drug information was analyzed. The hot pot of CNV in genome location was visualized by IGV program,and the correlated with drug respond was analyzed. RESULTS Up to May 31,2017,there were 65 patients 'drug information in TCGA database,including 49 patients with complete response,2 patients with partial response,2 patients with stable diseases,and 12 patients with disease progressed. The patients with complete response were defined as chemotherapy sensitive,while the rest was defined as chemotherapy resistant. The 22 q12. 2 and Xp11. 23 were amplified in patient's cancer tissues with chemotherapy resistant,and the 1 q44 was deleted in patient's cancer tissues with chemotherapy resistant. The hot plot of 22 q12.2 was the gene of leukemia inhibitory factor( LIF),the hot plot of Xp11.23 was genes of porcupine homolog-drosophila( PORCN) and emopamil binding protein( EBP); the hot plot of 1 q44 was the gene of kinesin family member 26 B( KIF26 B). Clinical analysis showed that amplification of LIF and PORCN/EBP on DNA levels was correlated with patients with chemotherapy resistant( P<0.05),while deletion of KIF26 B was not significantly correlation( P>0.05). CONCLUSION Amplification of 22 q12.2( LIF)and Xp11.23( PORCN/EBP) might be involved in the chemotherapy of endometrial cancer.

关键词(KeyWords)： 子宫内膜癌;基因拷贝数变异;22q12.2区段;Xp11.23区段;1q44区段
endometrial carcinoma;copy number variations;22q12.2;Xp11.23;1q44

Abstract:

Keywords:

基金项目(Foundation): 国家自然科学基金项目(81272434);; 广东省医学科研基金项目(A2016395,A2017103);; 广东省中医药局科研项目(2017208520181273);; 东莞市医疗卫生科技计划项目(2016105101292)

作者(Author): 刘琼茹,杨文丽,蔡育波,梁津杰,余卫东,方晓华,黄辉,陈艳虹,陈仙兰,张鑫,林碧华
LIU Qiongru,YANG Wenli,CAI Yubo,LIANG Jinjie,YU Weidong,FANG Xiaohua,HUANG Hui,CHEN Yanhong,CHEN Xianlan,ZHANG Xin,LIN Bihua

参考文献(References)：

• [1]Jemal A,Bray F,Center M M,et al.Global cancer statistics[J].CA Cancer J Clin,2011,61(2):69-90.
• [2]Parkin D M,Bray F,Ferlay J,et al.Global cancer statistics,2002[J].CA Cancer J Clin,2005,55(2):74-108.
• [3]Torre L A,Bray F,Siegel R L,et al.Global cancer statistics,2012[J].CA Cancer J Clin,2015,65(2):87-108.
• [4]曾昭智,张锦红,陆少君.胎盘生长因子抗体对大鼠子宫内膜异位症模型的治疗作用[J].广东药学院学报,2016,32(2):228-230.
• [5]Chen W,Zheng R,Baade P D,et al.Cancer statistics in China,2015[J].CA Cancer J Clin,2016,66(2):115-132.
• [6]Siegel R L,Miller K D,Jemal A.Cancer Statistics,2017[J].CA Cancer J Clin,2017,66(2):115-132.
• [7]林仲秋,谢玲玲,林荣春.《2016 NCCN子宫肿瘤临床实践指南》解读[J].中国实用妇科与产科杂志,2016,32(2):117-122.
• [8]Morice P,Leary A,Creutzberg C,et al.Endometrial cancer[J].Lancet,2016,387(10023):1094-1108.
• [9]Moxley K M,Mc Meekin D S.Endometrial carcinoma:a review of chemotherapy,drug resistance,and the search for new agents[J].Oncologist,2010,15(10):1026-1033.
• [10]Colaprico A,Silva T C,Olsen C,et al.TCGAbiolinks:an R/Bioconductor package for integrative analysis of TCGA data[J].Nucleic Acids Res,2016,44(8):e71.
• [11]林碧华,陈婧,方炳雄,等.miR-21基因单核苷酸多态性与宫颈癌遗传易感的关联研究[J].中华临床医师杂志(电子版),2015,9(10):1835-1840.
• [12]Mermel C H,Schumacher S E,Hill B,et al.GISTIC2.0 facilitates sensitive and confident localization of the targets of focal somatic copy-number alteration in human cancers[J].Genome Biol,2011,12(4):R41.
• [13]Robinson J T,Thorvaldsdottir H,Winckler W,et al.Integrative genomics viewer[J].Nat Biotechnol,2011,29(1):24-26.
• [14]Prat A,Cruz C,Hoadley K A,et al.Molecular features of the basal-like breast cancer subtype based on BRCA1 mutation status[J].Breast Cancer Res Treat,2014,147(1):185-191.
• [15]Janssen E A,Slewa A,Gudlaugsson E,et al.Biologic profiling of lymph node negative breast cancers by means of microRNA expression[J].Mod Pathol,2010,23(12):1567-1576.
• [16]Jazaeri A A,Yee C J,Sotiriou C,et al.Gene expression profiles of BRCA1-linked,BRCA2-linked,and sporadic ovarian cancers[J].J Natl Cancer Inst,2002,94(13):990-1000.
• [17]Roychowdhury A,Samadder S,Das P,et al.Integrative genomic and network analysis identified novel genes associated with the development of advanced cervical squamous cell carcinoma[J].Biochim Biophys Acta,2017,1861(1):2899-2911.
• [18]Nicola N A,Babon J J.Leukemia inhibitory factor(LIF)[J].Cytokine Growth Factor Rev,2015,26(5):533-544.
• [19]Resh M D.Palmitoylation of proteins in cancer[J].Biochem Soc Trans,2017,45(2):409-416.
• [20]Madan B,Ke Z,Harmston N,et al.Wnt addiction of genetically defined cancers reversed by PORCN inhibition[J].Oncogene,2016,35(17):2197-2207.
• [21]Berardi F,Abate C,Ferorelli S,et al.Novel 4-(4-aryl)cyclohexyl-1-(2-pyridyl)piperazines as Delta(8)-Delta(7)sterol isomerase(emopamil binding protein)selective ligands with antiproliferative activity[J].J Med Chem,2008,51(23):7523-7531.
• [22]Hollt V,Kouba M,Dietel M,et al.Stereoisomers of calcium antagonists which differ markedly in their potencies as calcium blockers are equally effective in modulating drug transport by P-glycoprotein[J].Biochem Pharmacol,1992,43(12):2601-2608.
• [23]Wang Q,Zhao Z B,Wang G,et al.High expression of KIF26B in breast cancer associates with poor prognosis[J].PLo S One,2013,8(4):e61640.