Department of Mathematics and Statistics, University of New Mexico, Albuquerque, NM 87131, USA.
Oncol Rep. 2011 May;25(5):1447-54. doi: 10.3892/or.2011.1186. Epub 2011 Feb 14.
With the advancement of modern genome sequencing technology, thousands of genetic mutations have been identified in human tumors. However, analysis of the role of genetic mutations in tumor development is limited by the need for prevalence information among multiple tumors and by the lack of analytic capability to define the functional contribution of genetic mutations in patients, individually and collectively. To understand the genetic basis of human endometrial cancer, the fourth most common cancer in women, transcriptome sequencing was performed on an endometrial tumor paired with normal cervical tissue. Twenty-six non-synonymous somatic mutations were validated in the tumor genome. A phylogenetic tree illustrating the mutational time-line was developed based upon the distribution of 26 mutations in 30 randomly-selected laser-captured single cells from the tumor sections. Five ubiquitous mutations were identified that are presumed to occur in the cancer founder cell of the tumor, and may collectively play critical roles in endometrial oncogenesis. However, further testing in 10 additional endometrial tumors failed to show overlapping mutations in the cancer founder cells, indicating the lack of a single common oncogenic pathway for these endometrial tumors. The effects of individual mutations in cancer cell proliferation were calculated based on descendant cell number and time span since acquiring each mutation. We have developed a phylogenetic approach to characterize individual genetic mutations in cancer cell proliferation in a single resected patient tumor. This approach provides the capability to study the tumor-specific role of genetic mutations, without relying on prevalence information from other patients.
随着现代基因组测序技术的进步，已经在人类肿瘤中鉴定出数千种基因突变。然而，对遗传突变在肿瘤发展中的作用的分析受到多种肿瘤中流行信息的需求以及缺乏分析能力的限制，无法单独和集体定义遗传突变在患者中的功能贡献。为了了解女性中第四大常见癌症子宫内膜癌的遗传基础，对子宫内膜肿瘤与其配对的正常宫颈组织进行了转录组测序。在肿瘤基因组中验证了 26 个非同义体细胞突变。基于在肿瘤切片中随机选择的 30 个激光捕获的单个细胞中 26 个突变的分布，开发了一个说明突变时间线的系统发育树。鉴定了五个普遍存在的突变，假定它们发生在肿瘤的癌症起始细胞中，并且可能共同在子宫内膜癌变中发挥关键作用。然而，在另外 10 个额外的子宫内膜肿瘤中的进一步测试未能显示癌症起始细胞中的重叠突变，表明这些子宫内膜肿瘤缺乏单一的共同致癌途径。根据获得每个突变后的后代细胞数量和时间跨度，计算了单个突变对癌细胞增殖的影响。我们已经开发了一种系统发育方法来描述单个切除患者肿瘤中癌细胞增殖的个体遗传突变。这种方法提供了研究遗传突变在肿瘤中的特定作用的能力，而无需依赖其他患者的流行信息。
