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PLoS Genet:脑癌细胞系全基因组测序完成

来源:科技日报 2010-02-01 08:58

美国加州大学洛杉矶分校琼森综合癌症研究中心的科学家在1月29日的《公共科学图书馆·遗传学》专刊上发表论文指出,他们首次完成了脑癌细胞系全基因组测序,这也是截至目前对单个癌症细胞系所做的最为彻底的测序分析。通过使用最新技术,此项测序工作得以在一个月内完成,测序成本大约为3.5万美元。

此项研究成果在朝向基于单个癌症之独特生物学签名的个性化治疗方面迈出了新的一步,其所揭示的新分子靶标将有助于开发出更具效力和更少毒性的药物。此项研究对于更好地找到监测脑癌复发的新方法也大有助益,便于医生更早地对脑癌的复发做出诊断和治疗。借助此项发现,临床医生还可测定脑癌细胞被灭活的准确时间,以防止过度使用药物对人体健康造成的损害。

测序工作是在名为U87的成胶质瘤细胞系上完成的,在全世界范围内有超过1000个实验室正在使用U87细胞系开展研究。之所以选择该细胞系,是因为目前对其的研究最为充分。此项测序工作将使那些从事细胞系研究的科学家们对他们的研究发现重新进行阐述,并促使他们提出新的前进方向。

此次测序工作揭示了几乎所有潜在的致癌染色体易位及导致该癌症发展的基因缺失和突变。研究人员从细胞系中取出遗传物质的长链,然后随机地将其截断。该癌症的数十亿个不同的DNA片段可由新一代测序技术同时进行读取,遗传物质经由10亿次以上的分析后就可确保结果具有高灵敏度和精确度。

研究人员表示,此一特殊的信息化工具使用了目前最为先进的技术,将大大提高基因分析工作的成效。以前,科学家无法了解发生在一个癌症中的大部分突变,因为它们是看不见的,而现在,这项新技术将允许科学家们监视每一种癌症,并对其基因组进行完全解码,如此科学家们就不会错失任何一个致癌突变。

知道了是哪些基因发生了突变并驱动了癌症的发展,临床医生就能选择最适于攻击癌症特定分子签名的疗法,从而给患者提供更有效的治疗。该测序工作还可展现出驱动癌症发展的分子异常,揭示出的靶标或将有助于开发出只针对癌细胞进行攻击同时又不损害健康细胞的新疗法。

研究人员还指出,有了癌症全基因测序图,科学家们就能开发出灵敏的分子检测仪,寻找仅可在癌细胞内发现的一个独特的基因突变。只要检测到此一突变即可判定癌症已复发,由此,患者就能在癌症复发的最早阶段得到积极治疗。反过来,这种检测方法也可用以判定癌症是否已被有效消除,从而及时中止有害人体的治疗手段。(生物谷Bioon.com)

癌症基因组研究:

Nature:美科学家首次测序癌症患者基因组

Nature:肺癌和皮肤癌完整基因图谱测序成功

Nature:基因组和转录组随肿瘤转移所发生的变化

Nature Genetics:迄今规模最大的罕见肿瘤基因研究完成

生物谷推荐原始出处:

PLoS Genet 6(1): e1000832. doi:10.1371/journal.pgen.1000832

U87MG Decoded: The Genomic Sequence of a Cytogenetically Aberrant Human Cancer Cell Line

Michael James Clark1#, Nils Homer1,2#, Brian D. O'Connor1#, Zugen Chen1#, Ascia Eskin1, Hane Lee1, Barry Merriman1, Stanley F. Nelson1*

1 Department of Human Genetics, University of California Los Angeles, Los Angeles, California, United States of America, 2 Department of Computer Science, University of California Los Angeles, Los Angeles, California, United States of America

U87MG is a commonly studied grade IV glioma cell line that has been analyzed in at least 1,700 publications over four decades. In order to comprehensively characterize the genome of this cell line and to serve as a model of broad cancer genome sequencing, we have generated greater than 30× genomic sequence coverage using a novel 50-base mate paired strategy with a 1.4kb mean insert library. A total of 1,014,984,286 mate-end and 120,691,623 single-end two-base encoded reads were generated from five slides. All data were aligned using a custom designed tool called BFAST, allowing optimal color space read alignment and accurate identification of DNA variants. The aligned sequence reads and mate-pair information identified 35 interchromosomal translocation events, 1,315 structural variations (>100 bp), 191,743 small (<21 bp) insertions and deletions (indels), and 2,384,470 single nucleotide variations (SNVs). Among these observations, the known homozygous mutation in PTEN was robustly identified, and genes involved in cell adhesion were overrepresented in the mutated gene list. Data were compared to 219,187 heterozygous single nucleotide polymorphisms assayed by Illumina 1M Duo genotyping array to assess accuracy: 93.83% of all SNPs were reliably detected at filtering thresholds that yield greater than 99.99% sequence accuracy. Protein coding sequences were disrupted predominantly in this cancer cell line due to small indels, large deletions, and translocations. In total, 512 genes were homozygously mutated, including 154 by SNVs, 178 by small indels, 145 by large microdeletions, and 35 by interchromosomal translocations to reveal a highly mutated cell line genome. Of the small homozygously mutated variants, 8 SNVs and 99 indels were novel events not present in dbSNP. These data demonstrate that routine generation of broad cancer genome sequence is possible outside of genome centers. The sequence analysis of U87MG provides an unparalleled level of mutational resolution compared to any cell line to date.

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