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应用 Mutation Surveyor 软件检测突变的 Science 和 Nature 论文
1. High frequency of mutations of the PIK3CA gene in human cancers.
SCIENCE. 2004 Apr 23;304(5670):554. Epub 2004 Mar 11. PMID: 1501696
 
Samuels Y, Wang Z, Bardelli A, Silliman N, Ptak J, Szabo S, Yan H, Gazdar A, Powell SM, Riggins GJ, Willson JK, Markowitz S, Kinzler KW, Vogelstein B, Velculescu VE.
 
WASHINGTON (Reuters) - U.S. scientists said on Thursday they had tracked down another gene involved in several different cancers, which seems to become active just before a tumor begins to spread. They hope the gene, called PIK3CA, might be a good "marker" for diagnosing cancer, or a target for new cancer drugs. The gene was found by a team that included some of the country's leading experts in the genetics of cancer at Johns Hopkins University in Baltimore. Led by Dr. Victor Velculescu, the researchers found PIK3CA mutations in 74 of 234 colon cancer patients, or 32 percent of them. Mutations in the gene were found in 27 percent of patients with brain tumors known as glioblastomas, 25 percent of stomach cancer patients and 8 percent of breast cancer patients. They found 92 mutations in all. "The sheer number of mutations observed in this gene strongly suggests that they are functionally important," the researchers wrote in their report, published in this week's issue of the journal Science. The mutations seem to come about late in tumor development, just as a benign tumor becomes invasive cancer, they said. Many different cancer genes have been found, from the p53 gene found in dozens of cancers to the BRCA genes linked with breast and ovarian cancer. Experts note cancer is a complex disease, caused by the interaction of possibly hundreds of genes and the environment.
 
译文
 
PIK3CA基因在人类肿瘤中的高频突变
 
华盛顿（路透社）：美国科学家3月11日表示，他们又发现一种与多种癌症有关的基因。据观察，该基因会在肿瘤扩散前开始活动。科学家希望这种名为PIK3CA的基因能够为癌症诊断提供一种清晰"标志"，或成为研究癌症新药的方向。该基因是由一包括约翰霍普金斯大学癌症遗传学专家的研究小组所发现。在威尔克斯库（Victor Velculescu）博士的带领下，研究小组发现在234名结肠癌患者中有74人，即32%，出现了PIK3CA基因变异。而这种变异还发生在27%的脑部神经胶母细胞瘤（glioblastomas）患者中，以及25%的胃癌患者及8%的乳癌患者身上。研究报告发表在本周出版的《科学》（Science）杂志上。其中写到："单纯从我们所观察到的此种基因变异数量来看，它们的作用重大。"研究者称，这种变异一般似乎出现在肿瘤发育的晚期，即良性肿瘤向恶性（侵入性）转变的时期。
 
2. EGFR Mutations in Lung Cancer: Correlation with Clinical Response to Gefitinib Therapy. SCIENCE. 2004 Apr 29. PMID: 15118125
 
Paez JG, Janne PA, Lee JC, Tracy S, Greulich H, Gabriel S, Herman P, Kaye FJ, Lindeman N, Boggon TJ, Naoki K, Sasaki H, Fujii Y, Eck MJ, Sellers WR, Johnson BE, Meyerson M.
 
Receptor tyrosine kinase genes were sequenced in nonsmall cell lung cancer (NSCLC) and matched normal tissue. Somatic mutations of the epidermal growth factor receptor gene EGFR were found in 15 of 58 unselected tumors from Japan and 1 of 61 from the United States. Treatment with the EGFR kinase inhibitor gefitinib (Iressa) causes tumor regression in some patients with NSCLC, more frequently in Japan. EGFR mutations were found in additional lung cancer samples from U.S. patients who responded to gefitinib therapy and in a lung adenocarcinoma cell line that was hypersensitive to growth inhibition by gefitinib, but not in gefitinibinsensitive tumors or cell lines. These results suggest that EGFR mutations may predict sensitivity to gefitinib.
 
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肺癌的EGFR突变：跟gefitinib临床检测反应相关
 
在非小细胞肺癌和正常组织中对酪氨酸激酶受体基因进行了测序，表皮生长因子受体基因（EGFR）被发现在58个日本人的肿瘤组织中有15例发生突变，而在61例美国标本中，有1例突变。使用EGFR抑制剂gefitinib治疗非小细胞肺癌病人可抑制肿瘤生长，这个现象在日本人中更为常见。EGFR突变在另外的对gefitinib治疗有反应的美国肺癌病人中有发现，还在一个对gefitinib抑制生长超敏感的肺腺癌细胞系中发现，但是在对gefitinib不敏感的肿瘤或者细胞系中没有发现。这些结果暗示EGFR突变可用来预测对gefitinib的敏感性。
 
3. Mutational analysis of the tyrosine kinome in colorectal cancers. SCIENCE. 2003 May 9;300(5621):949. PMID: 12738854
 
Bardelli A, Parsons DW, Silliman N, Ptak J, Szabo S, Saha S, Markowitz S, Willson JK, Parmigiani G, Kinzler KW, Vogelstein B, Velculescu VE.
 
Tyrosine kinases (TKs) are central regulators of signaling pathways that control differentiation, transcription, cell cycle progression, apoptosis, motility, and invasion (1). Although a few TK genes have been shown to be mutationally altered in specific human cancers (1), it is not known how many or how often members of the TK gene family are altered in any particular cancer type. In this study, we have used high-throughput sequencing technologies and bioinformatics from the human genome project to address this question. A recent analysis organized the protein kinase complement of the human genome (the "kinome") into a dendrogram containing nine broad groups of genes (2). We selected one major branch of this dendrogram, containing three of the nine major groups, for mutational analysis. These included the 90 tyrosine kinase genes (TK group), the 43 tyrosine kinase-like genes (TKL group), and the 5 receptor guanylate cyclase genes (RGC group).
 
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直肠癌中酪氨酸激酶的突变分析
 
酪氨酸激酶（TK）是控制分化、转录、细胞循环，凋亡，运动和侵袭等信号通路的重要调节基因。尽管有少数TK基因被报道在特定的人类肿瘤中有突变，但对整个TK基因家族中有多少个基因多少次在某一特定肿瘤类型中有突变，还是个未知数。我们使用高通量测序技术及生物信息学来解决这个问题。近来的一次分析将蛋白质激酶基因组组织成一个系统发生树，包含9组基因群。我们从中选择了一大组进行突变分析，包括90个酪氨酸激酶（TK），43个类酪氨酸激酶（TKL），5个谷胱甘肽环化酶受体（RGC）。
 
4. Tumorigenesis: RAF/RAS oncogenes and mismatch-repair status. NATURE. 2002 Aug 29;418(6901):934. PMID: 12198537
 
Rajagopalan H, Bardelli A, Lengauer C, Kinzler KW, Vogelstein B, Velculescu VE.
 
Genes of the RAF family encode kinases that are regulated by Ras and mediate cellular responses to growth signals. Activating mutations in one RAF gene, BRAF, have been found in a high proportion of melanomas and in a small fraction of other cancers1. Here we show that BRAF mutations in colorectal cancers occur only in tumours that do not carry mutations in a RAS gene known as KRAS, and that BRAF mutation is linked to the proficiency of these tumours in repairing mismatched bases in DNA. Our results not only provide genetic support for the idea that mutations in BRAF and KRAS exert equivalent effects in tumorigenesis2, but also emphasize the role of repair processes in establishing the mutation spectra that underpin human cancer.
 
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肿瘤发生：RAF/FAS 原癌基因及错配修复状态
 
RAF基因家族编码被RAS调控并调节细胞对生长信号反应的激酶。在RAF基因中。BRAF被发现在高比例的黑素瘤中有活化突变，而在其它肿瘤中仅有一小部分。我们的研究表明，BRAF在结肠癌中的突变仅在RAS基因（就是KRAS）不发生突变的肿瘤中发生。BRAF突变跟这些肿瘤DNA的错配修复效率有关。我们的研究结果不仅证实BRAF突变和KRAS突变对肿瘤发生有相同的贡献，还突出了其通过影响DNA修复进程从而加强肿瘤发生的地位。
 
5. Inactivation of hCDC4 can cause chromosomal instability. Nature. 2004 Mar 4;428(6978):77-81. PMID: 14999283
 
Rajagopalan H, Jallepalli PV, Rago C, Velculescu VE, Kinzler KW, Vogelstein B, Lengauer C.
 
Aneuploidy, an abnormal chromosome number, has been recognized as a hallmark of human cancer for nearly a century; however, the mechanisms responsible for this abnormality have remained elusive. Here we report the identification of mutations in hCDC4 (also known as Fbw7 or Archipelago) in both human colorectal cancers and their precursor lesions. We show that genetic inactivation of hCDC4, by means of targeted disruption of the gene in karyotypically stable colorectal cancer cells, results in a striking phenotype associated with micronuclei and chromosomal instability. This phenotype can be traced to a defect in the execution of metaphase and subsequent transmission of chromosomes, and is dependent on cyclin E-a protein that is regulated by hCDC4 (refs 2-4). Our data suggest that chromosomal instability is caused by specific genetic alterations in a large fraction of human cancers and can occur before malignant conversion
 
译文
 
HCDC4的失活能导致染色体不稳定
 
染色体异常已经被认为是近一个世纪以来对人类肿瘤研究的里程碑。然而，染色体异常的机制仍然是个谜。我们在此报道了HCDC4（即FBW7或者archipelago）在人类结肠癌和癌前病变的突变情况。研究表明，在核型稳定的结肠癌细胞中，HCDC4的突变失活，表现为其靶点破坏，导致一个显著的与染色体不稳定相关的显型。该显型能通过检测细胞周期中期染色体位移得知，并依赖于周期蛋白E---HCDC4的下游调节基因。我们的数据显示染色体不稳定性在大部分人类肿瘤中由特定的遗传变化引发，而且可能在恶转以前发生。