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Genome-wide approaches to study genetic alterations in gene families and on human chromosome 8p.

机译：研究基因家族和人类8p染色体上遗传变异的全基因组方法。

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摘要

Recent technical and bioinformatics advances allow unbiased, global approaches for the identification of genetic alterations in human cancers. I have taken two such approaches: genetic analysis of genes that belong to a class and genome wide genetic analysis of a chromosomal arm. Most colorectal cancers are chromosomally unstable. First, we looked for somatic mutations in the coding region of genes involved in repair pathways. We identified 19 mutations from which eight were identified in a novel gene. We also looked for somatic mutations in all known phosphatases. We identified 83 mutations in six genes. Functional assays showed that somatic mutation suppresses growth of human cancer cells. Then, I turned my attention to the short arm of chromosome 8 which is frequently lost or re-arranged in a variety of tumour types. This lead to the hypothesis that chromosome 8p carries a gene or genes involved in the development or progression of cancer. Gene candidate approaches have failed to identify such genes. First, utilizing a chip hybridization method developed for genome-wide identification of mutations, I scanned the entire chromosomal 8p region for somatic mutation in 11 sporadic colorectal tumors with 8p loss of herozygosity (LOH). I identified 151 somatic mutations in that region. None of these genetic alternations clustered in any known gene and understanding their involvement in cancer was not pursued further. However, the data helped in determining the background rate of mutation in human cancer cells. Translocations have pointed out genes involved in cancer developed before. Chromosome 8p is commonly translocated in breast cancer cell lines, as well as in other tumor types. Utilizing a somatic cell hybrid approach, I isolated the chromosome derivatives in the 8p translocation present in the breast cancer cell line T47D. I characterized this translocation to the base-pair resolution. I found that it was a complex unbalanced translocation between Chromosome 8p and Chromosome 14 that involved the deletion and inversion of a region of chromosome 8p. The translocation disrupts a Chromosome 14 gene, STXBP6, which binds components of the SNARE complex and may be involved in regulating SNARE complex formation.
机译：最近的技术和生物信息学的进步为鉴定人类癌症的遗传变异提供了无偏见的全球方法。我采用了两种方法：属于一类的基因的遗传分析和染色体臂的全基因组遗传分析。大多数结直肠癌是染色体不稳定的。首先，我们在涉及修复途径的基因的编码区寻找体细胞突变。我们鉴定出19个突变，其中一个新基因鉴定出8个突变。我们还在所有已知的磷酸酶中寻找体细胞突变。我们在六个基因中鉴定出83个突变。功能测定表明，体细胞突变抑制了人类癌细胞的生长。然后，我将注意力转向了第8号染色体的短臂，该短臂在各种肿瘤类型中经常丢失或重新排列。这导致了一个假设，即染色体8p带有一个或多个参与癌症发展或进程的基因。基因候选方法未能鉴定出此类基因。首先，利用开发用于全基因组突变鉴定的芯片杂交方法，我扫描了整个染色体8p区域中11个散发性结直肠肿瘤中8p丢失性英雄性（LOH）的体细胞突变。我在该区域发现了151个体细胞突变。这些遗传改变都没有聚集在任何已知基因中，也没有进一步了解它们与癌症的关系。但是，这些数据有助于确定人类癌细胞的背景突变率。易位已经指出了参与癌症发展的基因。染色体8p通常在乳腺癌细胞系以及其他肿瘤类型中易位。利用体细胞杂交方法，我分离出了​​乳腺癌细胞系T47D中8p易位的染色体衍生物。我将这种易位特征描述为碱基对分辨率。我发现这是染色体8p和14号染色体之间复杂的不平衡易位，涉及8p染色体区域的缺失和倒置。易位破坏了染色体14基因STXBP6，该基因与SNARE复合物的成分结合，并可能参与调节SNARE复合物的形成。

著录项

  • 作者

    Shen, Dong.;

  • 作者单位

    The Johns Hopkins University.;

  • 授予单位 The Johns Hopkins University.;
  • 学科 Biology Genetics.;Health Sciences Oncology.
  • 学位 Ph.D.
  • 年度 2009
  • 页码 97 p.
  • 总页数 97
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

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