靶向癌症 直击癌症基因组测序

　　

生物通报道：癌症基因组计划CGAP是一项重要的，多学科参与的研究计划，早在上个世纪一些国家就已经投入巨额进行相关研究，近期来自美国和英国的两个研究小组公布了癌症基因组序列的最新成果。

来自美国加州大学洛杉矶分校的研究人员公布了他们的最新研究成果：脑癌细胞系全基因组测序，这是首次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。这一研究成果公布在《PLoS Genetics》杂志上。

这项测序工作是在U87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。

这一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。

如果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。

另外来自英国的研究人员破译了肺癌、皮肤癌和乳腺癌的基因密码，他们发现肺癌细胞基因组中包含了2.3万个突变基因，皮肤癌中包含了3.3万个突变的基因。大多数突变基因没什么害处，成为基因组的一部分，但是有些突变基因则会扣动癌症的扳机。

完全破解肺癌、皮肤癌和乳腺癌的基因，这让科学家们发现这些病变的肿瘤之下，是多么混乱的基因错误造成的。肺癌和皮肤癌的产生看起来是如乱码般衍生的变异基因在作祟，乳腺癌则复杂得多。在破译乳腺癌基因序列的过程中，研究者发现无数断裂了，又重新组合的基因序列，这令乳腺癌看起来不是一种疾病，而是二十几种潜在疾病的集合——因为不同的组合很有可能造成不同的结果，症状不同，治疗方法也不应该相同。

除此之外，研究人员还发现了与恶性前列腺癌患病风险相关的基因变异。尽管这项成果的临床应用仍比较有限，但将来有潜力与其他患病风险因素一道用来尽早预测哪类男性更易患恶性前列腺癌。这一研究成果公布在PNAS杂志上。

他们对4849名已发生扩散的恶性前列腺癌患者以及12205名病情发展缓慢的前列腺癌患者的遗传信息进行了对比分析。结果发现，一种名为rs4054823的基因如果发生变异，患恶性前列腺癌的风险将提高四分之一。

这项研究表明，人类基因组中的某些基因变异确实会提高男性患恶性癌的风险。如果将来能够发现更多患病风险因素，医生就能尽早确定男性患恶性前列腺癌的具体风险。

（生物通：万纹）

原文摘要：

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

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.