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首页> 外文学位 >Genome-wide identification of novel candidate tumor suppressor genes in Hong Kong common tumors through integrative cancer epigenetics and genomics.
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Genome-wide identification of novel candidate tumor suppressor genes in Hong Kong common tumors through integrative cancer epigenetics and genomics.

机译：通过综合的癌症表观遗传学和基因组学，全基因组鉴定香港常见肿瘤中的新型候选肿瘤抑制基因。

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摘要

Cancer is the leading cause of death in Hong Kong (21,300 new cases and 11,500 deaths in 2003), with nasopharyngeal carcinoma (NPC), esophageal cancer (ESCC), and colorectal cancer (CRC) among the common ones. For these tumors, most patients present with advanced stage disease and poor treatment outcome, with an urge of early detection. Epigenetic inactivation of tumor suppressor genes (TSG) by CpG methylation represents an important mechanism of tumorigenesis, in addition to genetic abnormalities. Tumor-specific methylation can also be used as biomarkers for the identification of novel TSGs and for cancer early diagnosis and prognosis prediction.;Modified genomic methylation subtractive approaches using uracil-DNA glycosylase or combined with pharmacological demethylation were developed. GADD45G, PCDH10, ROR2, DLC1L1 were among a series of novel methylated targets identified by these approaches. Methylation-associated silencing of these genes was frequently detected in various types of tumor cell lines and primary tumors including NPC, ESCC and CRC, in a tumor-specific manner. Ectopic expression of these genes strongly suppressed tumor cell growth and colony formation of silenced tumor cells. Epigenetic inactivation of GADD45G is the major mechanism for the loss of its response to environmental stresses. Reintroduction of PCDH10 strongly suppressed tumor cell migration and invasion. Ectopic expression of DLC1L1 in silenced tumor cells resulted in a remarkable suppression of tumor cell clonogenicity, which depends on its GAP activity. Furthermore, DLC1L1, but not its inactivating mutants, inhibited Ras mediated oncogenic transformation. Thus, these identified genes are functional TSGs.;In the second approach, 1-Mb array-based comparative genomic hybridization (aCGH) was carried out to detect DNA copy number aberrations, which contain potential TSG loci, in a panel of NPC and ESCC cell lines. Frequent deletions include: 1p36.3, 3p14-11, 4p16-15, 5p13-q12, 6p21-12, 8p22-cent, 9p, 9q22-31, 10p, 13q12, 14q32, 16q23-24, 17q11.2, 18q in NPC, and 1p21, 4q21, 7p21, 7q35, 8p22-23, 8q11, 10p11, 11q22, 13q31, 14q32, 18q11-23 in ESCC. Several deletions (3p14-11 and 16q23) were further investigated in detail in this study. More than 12 genes were identified to be frequently silenced by methylation in tumors, including FHIT (3p14), WNT5A (3p14), ADAMTS9 (3p14), FEZF2 (3p14), ROBO (3p12), CADM2 (3p12), EPHA3 (3p11), RAB (11q22), ADAMTS18 (16q23), and TUSC8 (16q23), while homozygous deletion of these genes was infrequently detected. Aberrant methylation of these genes was also frequently detected in primary tumors in a tumor-specific manner. The tumor suppressor functions of TUSC8, WNT5A, CADM2 and ROBO were further investigated and validated. Further experiment indicated that induction of tumor cell apoptosis may contribute to the tumor suppressor function of TUSC8.;Finally, for the purpose of development of epigenetic biomarker for cancer molecular diagnosis, I screened gene methylation in the serum samples. Aberrant methylation of PCDH10 and DLC1 was detected in serum samples (2/14 (14%) and 4/14 (29%) respectively) from tumor patients but not in normal controls. It suggests that screening for PCDH10 and DLC1 methylation in sera could be a tumor-specific and non-invasive epigenetic biomarker for molecular diagnosis and prognostics. (Abstract shortened by UMI.)
机译：癌症是香港的主要死因（2003年有21,300例新病例，11,500例死亡），常见的有鼻咽癌（NPC），食道癌（ESCC）和结直肠癌（CRC）。对于这些肿瘤，大多数患者表现出晚期疾病和较差的治疗结果，强烈希望及早发现。 CpG甲基化导致的肿瘤抑制基因（TSG）的表观遗传失活是除了遗传异常外肿瘤发生的重要机制。肿瘤特异性甲基化还可以用作生物标记物，用于鉴定新型TSGs，以及用于癌症的早期诊断和预后预测。;开发了使用尿嘧啶DNA糖基化酶或结合药理脱甲基化的改良基因组甲基化消减方法。 GADD45G，PCDH10，ROR2，DLC1L1属于通过这些方法鉴定出的一系列新型甲基化靶标。在各种类型的肿瘤细胞系和原发性肿瘤（包括NPC，ESCC和CRC）中，经常以肿瘤特异性的方式检测到这些基因的甲基化相关沉默。这些基因的异位表达强烈抑制了肿瘤细胞的生长和沉默肿瘤细胞的集落形成。 GADD45G的表观遗传失活是失去其对环境压力反应的主要机制。 PCDH10的重新引入强烈抑制了肿瘤细胞的迁移和侵袭。 DLC1L1在沉默的肿瘤细胞中异位表达导致肿瘤细胞克隆性的显着抑制，这取决于其GAP活性。此外，DLC1L1抑制Ras介导的致癌转化，但不抑制其失活突变体。因此，这些鉴定出的基因是功能性TSG。在第二种方法中，在NPC和ESCC小组中进行了基于1-Mb阵列的比较基因组杂交（aCGH），以检测包含潜在TSG基因座的DNA拷贝数畸变。细胞系。常见删除包括：1p36.3、3p14-11、4p16-15、5p13-q12、6p21-12、8p22-cent，9p，9q22-31、10p，13q12、14q32、16q23-24、17q11.2、18q in NPC，以及ESCC中的1p21、4q21、7p21、7q35、8p22-23、8q11、10p11、11q22、13q31、14q32、18q11-23。在这项研究中进一步详细研究了几个缺失（3p14-11和16q23）。超过12个基因被确定在肿瘤中经常被甲基化沉默，包括FHIT（3p14），WNT5A（3p14），ADAMTS9（3p14），FEZF2（3p14），ROBO（3p12），CADM2（3p12），EPHA3（3p11） ，RAB（11q22），ADAMTS18（16q23）和TUSC8（16q23），而很少检测到这些基因的纯合缺失。这些基因的异常甲基化也经常以肿瘤特异性方式在原发性肿瘤中检测到。进一步研究并验证了TUSC8，WNT5A，CADM2和ROBO的抑癌功能。进一步的实验表明，诱导肿瘤细胞凋亡可能有助于TUSC8的抑癌功能。最后，为了开发用于癌症分子诊断的表观遗传标记，我从血清样品中筛选了基因甲基化。在来自肿瘤患者的血清样本（分别为2/14（14％）和4/14（29％））中检测到PCDH10和DLC1的异常甲基化，但在正常对照中未检测到。这表明筛查血清中PCDH10和DLC1甲基化可能是肿瘤特异性和非侵入性的表观遗传标记，可用于分子诊断和预后。 （摘要由UMI缩短。）

著录项

  • 作者

    Ying, Jianming.;

  • 作者单位

    The Chinese University of Hong Kong (Hong Kong).;

  • 授予单位 The Chinese University of Hong Kong (Hong Kong).;
  • 学科 Biology Genetics.;Health Sciences Oncology.
  • 学位 Ph.D.
  • 年度 2007
  • 页码 173 p.
  • 总页数 173
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 遗传学;肿瘤学;
  • 关键词

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