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The Science/Nature articles in which Mutation Surveyor was applied to detect DNA mutations or SNPs
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.
　
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.
　
　
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).
　
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.
　
　
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