公开(公告)号：US08026053B2

公开(公告)日：2011-09-27

申请号：US10591347

申请日：2005-02-18

申请人： Yardena Samuels ,  Victor Velculescu ,  Kenneth W. Kinzler ,  Bert Vogelstein

发明人： Yardena Samuels ,  Victor Velculescu ,  Kenneth W. Kinzler ,  Bert Vogelstein

IPC分类号： C12Q1/68

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代表人类癌症中尚未鉴定的最高突变型癌基因之一，可用作诊断和治疗靶点。

公开(公告)号：US20100137413A1

公开(公告)日：2010-06-03

申请号：US12521695

申请日：2007-02-16

申请人： Jordan Cummins ,  Victor Velculescu ,  Kenneth W. Kinzler ,  Bert Vogelstein

发明人： Jordan Cummins ,  Victor Velculescu ,  Kenneth W. Kinzler ,  Bert Vogelstein

IPC分类号： A61K31/711 ,  C07H21/02 ,  C12N5/071 ,  C12Q1/68 ,  G01N33/574 ,  C07H21/04 ,  A61K31/7105 ,  C12N5/09 ,  A61P35/00

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）是一类在多细胞生物体中具有重要调节作用的小型非编码RNA。 公共miRNA数据库包含321个人类miRNA序列，其中234个已经通过实验验证。 为了探讨其他miRNA存在于人类基因组中的可能性，我们开发了一种称为miRNA序列分析基因表达（miRAGE）的实验方法，并将其用于迄今为止对人类miRNA进行最大的实验分析。 来自人结肠直肠细胞的273,966个小RNA标签的序列分析允许我们鉴定200个已知的成熟miRNA，133个新型miRNA候选物和112个先前未表征的miRNA *形式。 为了帮助评估候选miRNA，我们破坏了三种人结肠直肠癌细胞系中Dicer基因座，并检测了这些细胞中已知和新型的miRNA。 这些miRNA可用于诊断和治疗癌症。

公开(公告)号：US20100184100A1

公开(公告)日：2010-07-22

申请号：US12705760

申请日：2010-02-15

申请人： Alberto Bardelli ,  Will Parsons ,  Victor Velculescu ,  Kenneth W. Kinzler ,  Bert Vogelstein

发明人： Alberto Bardelli ,  Will Parsons ,  Victor Velculescu ,  Kenneth W. Kinzler ,  Bert Vogelstein

IPC分类号： G01N33/574 ,  C07H21/00

CPC分类号： C12Q1/6886 ,  A61K31/506 ,  C12N9/1205 ,  C12Q1/025 ,  C12Q1/485 ,  C12Q1/6809 ,  C12Q1/6827 ,  C12Q2600/136 ,  C12Q2600/156 ,  G01N33/574

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.

摘要翻译： 蛋白激酶是参与肿瘤发生的重要信号分子。 人类酪氨酸激酶基因家族（98个基因）的突变分析鉴定了-20％的结肠直肠癌的体细胞变化，大部分突变发生在NTRK3，FES，GUCY2F和以前称为MCCK / MLK4的未表征的酪氨酸激酶基因。 大多数改变是保守的残基影响激酶结构域的关键区域。 这些数据代表了癌症中信号转导基因的无偏见分析的范例，并为治疗干预提供了有用的目标。

公开(公告)号：US09012145B2

公开(公告)日：2015-04-21

申请号：US13275958

申请日：2011-10-18

申请人： Zhenghe Wang ,  Victor Velculescu ,  Kenneth W. Kinzler ,  Bert Vogelstein

发明人： Zhenghe Wang ,  Victor Velculescu ,  Kenneth W. Kinzler ,  Bert Vogelstein

IPC分类号： C12Q1/68 ,  C12Q1/42

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 (PTPRT) 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六种PTP（PTPRF，PTPRG，PTPRT，PTPN3，PTPN13，PTPN14）中的83个体细胞突变，影响26％的结肠直肠癌和较小部分的肺癌，乳腺癌和胃癌 。 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（PTPRT）中的五个错义突变被发现可以减少磷酸酶活性。 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。 这些观察结果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干预的细胞途径。

公开(公告)号：US08586725B2

公开(公告)日：2013-11-19

申请号：US12521695

申请日：2007-02-16

申请人： Jordan Cummins ,  Victor Velculescu ,  Kenneth W. Kinzler ,  Bert Vogelstein

发明人： Jordan Cummins ,  Victor Velculescu ,  Kenneth W. Kinzler ,  Bert Vogelstein

IPC分类号： C07H21/02 ,  C07H21/04

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）是一类在多细胞生物体中具有重要调节作用的小型非编码RNA。 公共miRNA数据库包含321个人类miRNA序列，其中234个已经通过实验验证。 为了探讨其他miRNA存在于人类基因组中的可能性，我们开发了一种称为miRNA序列分析基因表达（miRAGE）的实验方法，并将其用于迄今为止对人类miRNA进行最大的实验分析。 来自人结肠直肠细胞的273,966个小RNA标签的序列分析允许我们鉴定200个已知的成熟miRNA，133个新型miRNA候选物和112个先前未表征的miRNA *形式。 为了帮助评估候选miRNA，我们破坏了三种人结肠直肠癌细胞系中Dicer基因座，并检测了这些细胞中已知和新型的miRNA。 这些miRNA可用于诊断和治疗癌症。

公开(公告)号：US20060166257A1

公开(公告)日：2006-07-27

申请号：US11389062

申请日：2006-03-27

申请人： Bert Vogelstein ,  Kenneth Kinzler ,  Nickolas Papadopoulos ,  Hai Yan

发明人： Bert Vogelstein ,  Kenneth Kinzler ,  Nickolas Papadopoulos ,  Hai Yan

IPC分类号： C12Q1/68 ,  C12N5/06 ,  C12N15/87

CPC分类号： C12N5/166 ,  C12Q1/6886 ,  C12Q2600/156

摘要： Detection of mutations associated with hereditary diseases is complicated by the diploid nature of mammalian cells. Mutations present in one allele are often masked by the wild-type sequence of the other allele. Individual alleles can be isolated from every chromosome within somatic cell hybrids generated from a single fusion. Nucleic acids from the hybrids can be analyzed for mutations in an unambiguous manner. This approach was used to detect two cancer-causing mutations that had previously defied genetic diagnosis. One of the families studied, Warthin Family G, was the first kindred with a hereditary colon cancer syndrome described in the biomedical literature.

公开(公告)号：US06399374B1

公开(公告)日：2002-06-04

申请号：US09461047

申请日：1999-12-15

申请人： Bert Vogelstein ,  Kenneth W. Kinzler ,  Hai Yan ,  Nicholas Papadopoulos

发明人： Bert Vogelstein ,  Kenneth W. Kinzler ,  Hai Yan ,  Nicholas Papadopoulos

IPC分类号： C12N512

CPC分类号： C12N5/166 ,  C12Q1/6886 ,  C12Q2600/156

摘要： Detection of mutations associated with hereditary diseases is complicated by the diploid nature of human cells. Mutations present in one allele are often masked by the wild-type sequence of the other allele. Individual alleles can be isolated from every chromosome within somatic cell hybrids generated from a single fusion. Nucleic acids from the hybrids can be analyzed for mutations in an unambiguous manner. This approach was used to detect two cancer-causing mutations that had previously defied genetic diagnosis. One of the families studied, Warthin Family G, was the first kindred with a hereditary colon cancer syndrome described in the biomedical literature.

摘要翻译： 与遗传性疾病相关的突变的检测由于人类细胞的二倍体性质而复杂化。 存在于一个等位基因中的突变通常被其他等位基因的野生型序列掩蔽。 可以从单次融合产生的体细胞杂交体内的每个染色体分离个体等位基因。 来自杂种的核酸可以以明确的方式分析突变。 这种方法被用于检测先前不符合遗传诊断的两种致癌突变。 研究的家庭之一，Warthin Family G，是生物医学文献中描述的第一个遗传性结肠癌综合症患者。

公开(公告)号：US09328343B2

公开(公告)日：2016-05-03

申请号：US13311120

申请日：2011-12-05

申请人： Devin Dressman ,  Hai Yan ,  Kenneth W Kinzler ,  Bert Vogelstein

发明人： Devin Dressman ,  Hai Yan ,  Kenneth W Kinzler ,  Bert Vogelstein

IPC分类号： C12Q1/68 ,  C12N15/10 ,  C07H21/04

CPC分类号： C12Q1/6858 ,  C07H21/04 ,  C12N15/1075 ,  C12Q1/686 ,  C12Q2565/537 ,  C12Q2563/149 ,  C12Q2563/143

摘要： Many areas of biomedical research depend on the analysis of uncommon variations in individual genes or transcripts. Here we describe a method that can quantify such variation at a scale and ease heretofore unattainable. Each DNA molecule in a collection of such molecules is converted into a single particle to which thousands of copies of DNA identical in sequence to the original are bound. This population of beads then corresponds to a one-to-one representation of the starting DNA molecules. Variation within the original population of DNA molecules can then be simply assessed by counting fluorescently-labeled particles via flow cytometry. Millions of individual DNA molecules can be assessed in this fashion with standard laboratory equipment. Moreover, specific variants can be isolated by flow sorting and employed for further experimentation. This approach can be used for the identification and quantification of rare mutations as well as to study variations in gene sequences or transcripts in specific populations or tissues.

摘要翻译： 生物医学研究的许多领域取决于对个别基因或转录本中不常见变异的分析。 在这里，我们描述一种可以量化这种变化的方法，其规模和容易度迄今为止是无法实现的。 将这样的分子的集合中的每个DNA分子转化成单个颗粒，其中与原始序列顺序相同的数千个拷贝的DNA被结合。 这种珠子群对应于起始DNA分子的一对一表示。 然后可以通过流式细胞术对荧光标记的颗粒进行计数，简单地评估原始DNA分子群体内的变异。 可以用标准实验室设备以这种方式评估数百万个单独的DNA分子。 此外，可以通过流动分选分离特定的变体并用于进一步的实验。 该方法可用于鉴定和定量稀有突变，并研究特定群体或组织中基因序列或转录本的变异。

公开(公告)号：US08048627B2

公开(公告)日：2011-11-01

申请号：US10562840

申请日：2004-06-09

申请人： Devin Dressman ,  Hai Yan ,  Kenneth W Kinzler ,  Bert Vogelstein

发明人： Devin Dressman ,  Hai Yan ,  Kenneth W Kinzler ,  Bert Vogelstein

IPC分类号： C12Q1/68 ,  C12P19/34 ,  C07H21/02

CPC分类号： C12Q1/6858 ,  C07H21/04 ,  C12N15/1075 ,  C12Q1/686 ,  C12Q2565/537 ,  C12Q2563/149 ,  C12Q2563/143

摘要： Many areas of biomedical research depend on the analysis of uncommon variations in individual genes or transcripts. Here we describe a method that can quantify such variation at a scale and ease heretofore unattainable. Each DNA molecule in a collection of such molecules is converted into a single particle to which thousands of copies of DNA identical in sequence to the original are bound. This population of beads then corresponds to a one-to-one representation of the starting DNA molecules. Variation within the original population of DNA molecules can then be simply assessed by counting fluorescently-labeled particles via flow cytometry. Millions of individual DNA molecules can be assessed in this fashion with standard laboratory equipment. Moreover, specific variants can be isolated by flow sorting and employed for further experimentation. This approach can be used for the identification and quantification of rare mutations as well as to study variations in gene sequences or transcripts in specific populations or tissues.

摘要翻译： 生物医学研究的许多领域取决于对个别基因或转录本中不常见变异的分析。 在这里，我们描述一种可以量化这种变化的方法，其规模和容易度迄今为止是无法实现的。 将这样的分子的集合中的每个DNA分子转化成单个颗粒，其中与原始序列顺序相同的数千个拷贝的DNA被结合。 这种珠子群对应于起始DNA分子的一对一表示。 然后可以通过流式细胞术对荧光标记的颗粒进行计数，简单地评估原始DNA分子群体内的变异。 可以用标准实验室设备以这种方式评估数百万个单独的DNA分子。 此外，可以通过流动分选分离特定的变体并用于进一步的实验。 该方法可用于鉴定和定量稀有突变，并研究特定群体或组织中基因序列或转录本的变异。

公开(公告)号：US5981725A

公开(公告)日：1999-11-09

申请号：US479808

申请日：1995-06-07

申请人： Bert Vogelstein ,  Darell Bigner

发明人： Bert Vogelstein ,  Darell Bigner

IPC分类号： A61K38/00 ,  A61K47/48 ,  A61K51/10 ,  C07K14/71 ,  C07K16/28 ,  C12P21/08 ,  C12Q1/68 ,  C12N15/11 ,  C12N5/10 ,  C12N15/12

CPC分类号： A61K47/48561 ,  A61K51/103 ,  C07K14/71 ,  C07K16/2863 ,  C12Q1/6886 ,  A61K2123/00 ,  A61K38/00 ,  C07K2317/34 ,  C12Q2600/156

摘要： Deletions in the EGF-R gene are found in many gliomas, breast tumors, and lung tumors. A particular truncated EGFR protein has been found in many tumors and provides diagnostic and therapeutic modalities.

摘要翻译： 在许多胶质瘤，乳腺肿瘤和肺肿瘤中发现EGF-R基因的缺失。 已经在许多肿瘤中发现特定的截短的EGFR蛋白质并提供诊断和治疗方式。