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1. 发明申请

WO2005113824A2 PROTEIN TYROSINE PHOSPHATASE MUTATIONS IN CANCERS 审中-公开
标题翻译：蛋白质酪氨酸磷酸酶突变体
公开(公告)号：WO2005113824A2
公开(公告)日：2005-12-01
申请号：PCT/US2005/017105
申请日：2005-05-16
申请人： WANG, Zhenghe , VELCULESCU, Victor , KINZLER, Kenneth, W. , VOGELSTEIN, Bert
发明人： WANG, Zhenghe , VELCULESCU, Victor , KINZLER, Kenneth, W. , VOGELSTEIN, Bert
IPC分类号： C12Q1/68
CPC分类号： C12Q1/6886 , C12N9/16 , C12Q2600/112 , C12Q2600/136 , C12Q2600/156 , C12Q2600/158 , C12Y301/03048 , G01N33/5011 , G01N2333/916
摘要： Tyrosine phosphorylation, regulated by protein tyrosine phosphatases (PTPs) and kinases (PTKs), is important in signaling pathways underlying tumorigenesis. A mutational analysis of the tyrosine phosphatase gene superfamily in human cancers identified 83 somatic mutations in six PTPs ( PTPRF, PTPRG, PTPRT, PTPN3, PTPN13, PTPN14 ) affecting 26 % of colorectal cancers and a smaller fraction of lung, breast and gastric cancers. Fifteen mutations were nonsense, frameshift or splice site alterations predicted to result in truncated proteins lacking phosphatase activity. Five missense mutations in the most commonly altered PTP ( PTPRP ) were biochemically examined and found to reduce phosphatase activity. Expression of wild-type but not a mutant PTPRT in human cancer cells inhibited cell growth. These observations suggest that the tyrosine phosphatase genes are tumor suppressor genes, regulating cellular pathways that may be amenable to therapeutic intervention.
摘要翻译：由蛋白酪氨酸磷酸酶（PTP）和激酶（PTK）调节的酪氨酸磷酸化在肿瘤发生的信号通路中是重要的。人类癌症中酪氨酸磷酸酶基因超家族的突变分析鉴定了影响26％结肠直肠癌和较小部分肺癌，乳腺癌和胃癌的6种PTPs（PTPRF，PTPRG，PTPRT，PTPN3，PTPN13，PTPN14）中的83个体细胞突变。十五个突变是无义，移位或剪接位点改变，预计会导致截短的蛋白质缺乏磷酸酶活性。在生物化学检查中发现最常改变的PTP（PTPRP）中的五个错义突变被发现可以降低磷酸酶活性。野生型但不是突变PTPRT在人类癌细胞中的表达抑制细胞生长。这些观察表明，酪氨酸磷酸酶基因是肿瘤抑制基因，调节可能适合于治疗性干预的细胞途径。

2. 发明申请

WO2004046370A3 DIGITAL KARYOTYPING 审中-公开
公开(公告)号：WO2004046370A3
公开(公告)日：2004-06-03
申请号：PCT/US2003/036502
申请日：2003-11-14
申请人： THE JOHNS HOPKINS UNIVERSITY , WANG, Tian-Li , VELCULESCU, Victor , KINZLER, Kenneth, W. , VOGELSTEIN, Bert
发明人： WANG, Tian-Li , VELCULESCU, Victor , KINZLER, Kenneth, W. , VOGELSTEIN, Bert
IPC分类号： C12Q1/68
摘要： Alterations in the genetic content of a cell underlie many human diseases, including cancers. A method called Digital Karyotyping provides quantitative analysis of DNA copy number at high resolution. This approach involves the isolation and enumeration of short sequence tags from specific genomic loci. Analysis of human cancer cells using this method identified gross chromosomal changes as well as amplifications and deletions, including regions not previously known to be altered. Foreign DNA sequences not present in the normal human genome could also be readily identified. Digital Karyotyping provides a broadly applicable means for systematic detection of DNA copy number changes on a genomic scale.

3. 发明申请

WO2002010438A3 SERIAL ANALYSIS OF TRANSCRIPT EXPRESSION USING LONG TAGS 审中-公开
公开(公告)号：WO2002010438A3
公开(公告)日：2002-02-07
申请号：PCT/US2001/023822
申请日：2001-07-27
申请人： THE JOHNS HOPKINS UNIVERSITY , VELCULESCU, Victor , SPARKS, Andrew, B. , VOGELSTEIN, Bert , KINZLER, Kenneth, W.
发明人： VELCULESCU, Victor , SPARKS, Andrew, B. , VOGELSTEIN, Bert , KINZLER, Kenneth, W.
IPC分类号： C12Q1/68
摘要： Serial analysis of gene expression, SAGE, a method for the rapid quantitative and qualitative analysis of transcripts, has been improved to provide more genetic information about each analyzed transcript. In SAGE, defined sequence tags corresponding to expressed genes are isolated and analyzed. Sequencing of over, 1,000 defined tags in a short period of time (e.g. hours) reveals a gene expression pattern characteristic of the function of a cell or tissue. Moreover, SAGE is useful as a gene discovery tool for the identification and isolation of novel squence tags corresponding to novel transcripts and genes.

4. 发明申请

WO2005076984A2 THYMIDYLATE SYNTHASE GENE AND METASTASIS 审中-公开
标题翻译：甲基合成酶基因和METASTASIS
公开(公告)号：WO2005076984A2
公开(公告)日：2005-08-25
申请号：PCT/US2005/003776
申请日：2005-02-07
申请人： THE JOHN HOPKINS UNIVERSITY , WANG, Tian-LI , DIAZ, Luis , LENGAUER, Christoph , VELCULESCU, Victor , KINZLER, Kenneth, W. , VOGELSTEIN, Bert
发明人： WANG, Tian-LI , DIAZ, Luis , LENGAUER, Christoph , VELCULESCU, Victor , KINZLER, Kenneth, W. , VOGELSTEIN, Bert
IPC分类号： C12Q1/68 , G01N33/48 , G01N33/50 , G06F19/00
CPC分类号： C12Q1/6886 , C12Q2600/106 , C12Q2600/136
摘要： Thymidylate synthase (TYMS) gene amplification was observed in 23% of 31 5-FU resistant liver metastases, while no amplification was observed in metastases of patients that had not been treated with 5-FU. Patients with metastases containing TYMS amplification had a substantially shorter median survival (329 days) than those without amplification (1021 days, p
摘要翻译：在31例5-FU耐药性肝转移患者中，23例患者观察到胸苷酸合成酶（TYMS）基因扩增，而未用5-FU治疗的患者转移灶未观察到扩增。含有TYMS扩增的转移患者的中位生存期（329天）比没有扩增的患者显着更短（1021天，p <0.01）。 TYMS的遗传扩增对复发性结肠直肠癌患者的治疗具有重要意义。

5. 发明申请

WO2004082458A3 TYROSINE KINOME 审中-公开
公开(公告)号：WO2004082458A3
公开(公告)日：2004-09-30
申请号：PCT/US2004/004452
申请日：2004-02-18
申请人： THE JOHNS HOPKINS UNIVERSITY , BARDELLI, Alberto , PARSONS, Will , VELCULESCU, Victor , KINZLER, Kenneth, W. , VOGELSTEIN, Bert
发明人： BARDELLI, Alberto , PARSONS, Will , VELCULESCU, Victor , KINZLER, Kenneth, W. , VOGELSTEIN, Bert
IPC分类号： C12Q1/68
摘要： Protein kinases are important signaling molecules involved in tumorigenesis. Mutational analysis of the human tyrosine kinase gene family (98 genes) identified somatic alterations in -20% of colorectal cancers, with the majority of mutations occurring in NTRK3, FES, GUCY2F and a previously uncharacterized tyrosine kinase gene called MCCK/MLK4. Most alterations were in conserved residues affecting key regions of the kinase domain. These data represent a paradigm for the unbiased analysis of signal transducing genes in cancer and provide useful targets for therapeutic intervention.

6. 发明申请

WO2006127607A2 PI3K PATHWAY MUTATIONS IN CANCER 审中-公开
标题翻译：癌症中PI3K路径突变
公开(公告)号：WO2006127607A2
公开(公告)日：2006-11-30
申请号：PCT/US2006/019748
申请日：2006-05-23
申请人： THE JOHNS HOPKINS UNIVERSITY , PARSONS, Donald, William , WANG, Tian-li. Ph.D. , SAMUELS, Yardena , BARDELLI, Alberto , LENGAUER, Christopher , VELCULESCU, Victor , KINZLER, Kenneth, W. , VOGELSTEIN, Bert
发明人： PARSONS, Donald, William , WANG, Tian-li. Ph.D. , SAMUELS, Yardena , BARDELLI, Alberto , LENGAUER, Christopher , VELCULESCU, Victor , KINZLER, Kenneth, W. , VOGELSTEIN, Bert
IPC分类号： C12Q1/68
CPC分类号： C12Q1/6883 , C12Q1/485 , C12Q2600/136 , C12Q2600/156 , G01N33/5044 , G01N33/57419
摘要： Given the important role of protein kinases in pathways affecting cellular growth and invasion, we have analyzed 340 serine/threonine kinases for genetic mutations in colorectal cancers. Mutations in eight genes were identified, including three members of the phosphatidylinositol-3- kinase (PI3K) pathway; the alterations in the latter genes each occurred in different tumors and did not overlap with mutations in PIK3CA or other non-serine-threonine kinase (STK) members of the PI3K pathway, suggesting that mutations in any of these genes had equivalent tumorigenic effects. These data demonstrate that the PI3K pathway is a major target for mutational activation in colorectal cancers and provide new opportunities for therapeutic intervention.
摘要翻译：鉴于蛋白激酶在影响细胞生长和侵袭的途径中的重要作用，我们已经分析了340个丝氨酸/苏氨酸激酶在结肠直肠癌中的遗传突变。鉴定出8个基因的突变，包括磷脂酰肌醇-3-激酶（PI3K）通路的3个成员; 后一种基因的改变各自发生在不同的肿瘤中，并且不与PIK3CA或PI3K途径的其他非丝氨酸 - 苏氨酸激酶（STK）成员的突变重叠，这表明任何这些基因中的突变具有相等的致瘤作用。这些数据表明，PI3K途径是结肠直肠癌突变激活的主要靶标，为治疗干预提供新的机会。

8. 发明申请

WO2010028098A2 PATHWAYS UNDERLYING PANCREATIC TUMORIGENESIS AND AN HEREDITARY PANCREATIC CANCER GENE 审中-公开
标题翻译：基于胰腺癌和胰腺癌基因的途径
公开(公告)号：WO2010028098A2
公开(公告)日：2010-03-11
申请号：PCT/US2009/055802
申请日：2009-09-03
申请人： THE JOHNS HOPKINS UNIVERSITY , VOGELSTEIN, Bert , KINZLER, Kenneth, W. , PARSONS, D., Williams , JONES, Sian , ZHANG, Xiaosong , LIN, Jimmy Chang-Ho , LEARY, Rebecca J. , ANGENENDT, Philipp , PAPADOPOULOS, Nickolas , VELCULESCU, Victor , PARMIGIANI, Giovanni , KARCHIN, Rachel , KERN, Scott , HRUBAN, Ralph , ESHLEMAN, James R. , GOGGINS, Michael , KLEIN, Alison
发明人： VOGELSTEIN, Bert , KINZLER, Kenneth, W. , PARSONS, D., Williams , JONES, Sian , ZHANG, Xiaosong , LIN, Jimmy Chang-Ho , LEARY, Rebecca J. , ANGENENDT, Philipp , PAPADOPOULOS, Nickolas , VELCULESCU, Victor , PARMIGIANI, Giovanni , KARCHIN, Rachel , KERN, Scott , HRUBAN, Ralph , ESHLEMAN, James R. , GOGGINS, Michael , KLEIN, Alison
IPC分类号： C12Q1/68
CPC分类号： G01N33/57438 , C12Q1/6886 , C12Q2600/156 , G01N2800/50
摘要： There are currently few therapeutic options for patients with pancreatic cancers and new insights into the pathogenesis of this lethal disease are urgently needed. To this end, we performed a comprehensive analysis of the genes altered in 24 pancreatic tumors. First, we determined the sequences of 23,781 transcripts, representing 20,583 protein-encoding genes, in DNA from these tumors. Second, we searched for homozygous deletions and amplifications using microarrays querying ~one million single nucleotide polymorphisms in each sample. Third, we analyzed the transcriptomes of the same samples using SAGE and next-generation sequencing-by-synthesis technologies. We found that pancreatic cancers contain an average of 63 genetic alterations, of which 49 are point mutations, 8 are homozygous deletions, and 6 are amplifications. Further analyses revealed a core set of 12 regulatory processes or pathways that were each genetically altered in 70 % to 100 % of the samples. The data suggest that dysregulation of this core set of pathways is responsible for the major features of pancreatic tumorigenesis.
摘要翻译：目前对胰腺癌患者几乎没有治疗方案，迫切需要对这种致死性疾病的发病机制的新见解。为此，我们对24个胰腺肿瘤中改变的基因进行了综合分析。首先，我们从这些肿瘤的DNA中确定了23,781个转录本，代表20,583个蛋白质编码基因的序列。其次，我们使用微阵列查询了每个样本中一百万个单核苷酸多态性的纯合缺失和扩增。第三，我们使用SAGE和下一代按序合成技术分析了相同样品的转录组。我们发现胰腺癌平均存在63个遗传改变，其中49个是点突变，8个是纯合缺失，6个是扩增。进一步的分析揭示了一组核心的12个调节过程或途径，在70％至100％的样品中进行了遗传改变。数据表明，这种核心途径的失调导致了胰腺肿瘤发生的主要特征。

9. 发明申请

WO2008103135A2 THE MICRORNAOME 审中-公开
标题翻译：微笑
公开(公告)号：WO2008103135A2
公开(公告)日：2008-08-28
申请号：PCT/US2007/004518
申请日：2007-02-16
申请人： THE JOHNS HOPKINS UNIVERSITY , CUMMINS, Jordan , VELCULESCU, Victor , KINZLER, Kenneth, W. , VOGELSTEIN, Bert
发明人： CUMMINS, Jordan , VELCULESCU, Victor , KINZLER, Kenneth, W. , VOGELSTEIN, Bert
IPC分类号： A61K48/00
CPC分类号： C12N15/113 , C12N2310/141 , C12N2320/11 , C12N2330/10 , C12N2510/00 , C12Q1/6886
摘要： MicroRNAs (miRNAs) are a class of small noncoding RNAs that have important regulatory roles in multicellular organisms. The public miRNA database contains 321 human miRNA sequences, 234 of which have been experimentally verified. To explore the possibility that additional miRNAs are present in the human genome, we have developed an experimental approach called miRNA serial analysis of gene expression (miRAGE) and used it to perform the largest experimental analysis of human miRNAs to date. Sequence analysis of 273,966 small RNA tags from human colorectal cells allowed us to identify 200 known mature miRNAs, 133 novel miRNA candidates, and 112 previously uncharacterized miRNA* forms. To aid in the evaluation of candidate miRNAs, we disrupted the Dicer locus in three human colorectal cancer cell lines and examined known and novel miRNAs in these cells. The miRNAs are useful to diagnose and treat cancers.
摘要翻译：微小RNA（miRNA）是一类具有重要调节作用的小型非编码RNA

10. 发明申请

WO2005091849A2 MUTATIONS OF THE PIK3CA GENE IN HUMAN CANCERS 审中-公开
标题翻译：人类癌症中PIK3CA基因的突变
公开(公告)号：WO2005091849A2
公开(公告)日：2005-10-06
申请号：PCT/US2005/005193
申请日：2005-02-18
申请人： THE JOHNS HOPKINS UNIVERSITY , SAMUELS, Yardena , VELCULESCU, Victor , KINZLER, Kenneth, W. , VOGELSTEIN, Bert
发明人： SAMUELS, Yardena , VELCULESCU, Victor , KINZLER, Kenneth, W. , VOGELSTEIN, Bert
CPC分类号： C12Q1/6886 , C12Q2600/156
摘要： Phosphatidylinositol 3-kinases (PI3Ks) are known to be important regulators of signaling pathways. To determine whether PI3Ks are genetically altered in cancers, we analyzed the sequences of the P13K gene family and discovered that one family member, PIK3CA, is frequently mutated in cancers of the colon and other organs. The majority of mutations clustered near two positions within the P13K helical or kinase domains. PIK3CA represents one of the most highly mutated oncogenes yet identified in human cancers and is useful as a diagnostic and therapeutic target.
摘要翻译：已知磷脂酰肌醇3-激酶（PI3K）是信号通路的重要调控因子。为了确定PI3K在癌症中的遗传改变，我们分析了P13K基因家族的序列，发现一个家族成员PIK3CA在结肠癌和其他器官的癌症中经常发生突变。大多数突变聚集在P13K螺旋或激酶结构域内的两个位置附近。 PIK3CA代表人类癌症中鉴定出来的最突变的癌基因之一，可用作诊断和治疗靶点。

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