公开(公告)号：US10144971B2

公开(公告)日：2018-12-04

申请号：US13977810

申请日：2012-01-04

申请人： Bert Vogelstein ,  Kenneth W Kinzler ,  Victor Velculescu ,  Luis Diaz ,  Nikolas Papadopoulos ,  Yuchen Jiao ,  Ralph Hruban

发明人： Bert Vogelstein ,  Kenneth W Kinzler ,  Victor Velculescu ,  Luis Diaz ,  Nikolas Papadopoulos ,  Yuchen Jiao ,  Ralph Hruban

IPC分类号： C12Q1/68 ,  C12P19/34 ,  C12Q1/6886 ,  G01N33/574

摘要： Pancreatic Neuroendocrine Tumors (PanNETs) are a rare but clinically important form of pancreatic neoplasia. To explore the genetic basis of PanNETs, we determined the exomic sequences of ten non-familial PanNETs and then screened the most commonly mutated genes in 58 additional PanNETs. Remarkably, the most frequently mutated genes specify proteins implicated in chromatin remodeling: 44% of the tumors had somatic inactivating mutations in MEN-1, which encodes menin, a component of a histone methyltransferase complex; and 43% had mutations in genes encoding either of the two subunits of a transcription/chromatin remodeling complex consisting of DAXX (death-domain associated protein) and ATRX (alpha thalassemia/mental retardation syndrome X-linked). Clinically, mutations in the MEN1 and DAXX/ATRX genes were associated with better prognosis. We also found mutations in genes in the mTOR (mammalian target of rapamycin) pathway in 14% of the tumors, a finding that could potentially be used to stratify patients for treatment with mTOR inhibitors.

公开(公告)号：US20140045881A1

公开(公告)日：2014-02-13

申请号：US13977810

申请日：2012-01-04

申请人： Bert Vogelstein ,  Kenneth W. Kinzler ,  Victor Velculescu ,  Luis Diaz ,  Nikolas Papadopoulos ,  Yuchen Jiao ,  Ralph Hruban

发明人： Bert Vogelstein ,  Kenneth W. Kinzler ,  Victor Velculescu ,  Luis Diaz ,  Nikolas Papadopoulos ,  Yuchen Jiao ,  Ralph Hruban

IPC分类号： C12Q1/68

CPC分类号： C12Q1/6886 ,  C12Q2600/106 ,  C12Q2600/112 ,  C12Q2600/118 ,  C12Q2600/156 ,  G01N33/57438 ,  G01N2800/52

摘要： Pancreatic Neuroendocrine Tumors (PanNETs) are a rare but clinically important form of pancreatic neoplasia. To explore the genetic basis of PanNETs, we determined the exomic sequences of ten non-familial PanNETs and then screened the most commonly mutated genes in 58 additional PanNETs. Remarkably, the most frequently mutated genes specify proteins implicated in chromatin remodeling: 44% of the tumors had somatic inactivating mutations in MEN-1, which encodes menin, a component of a histone methyltransferase complex; and 43% had mutations in genes encoding either of the two subunits of a transcription/chromatin remodeling complex consisting of DAXX (death-domain associated protein) and ATRX (alpha thalassemia/mental retardation syndrome X-linked). Clinically, mutations in the MEN1 and DAXX/ATRX genes were associated with better prognosis. We also found mutations in genes in the mTOR (mammalian target of rapamycin) pathway in 14% of the tumors, a finding that could potentially be used to stratify patients for treatment with mTOR inhibitors.

摘要翻译： 胰腺神经内分泌肿瘤（Pannets）是一种罕见但临床上重要的胰腺肿瘤形式。 为了探索PanNETs的遗传基础，我们确定了十个非家族PanNETs的外显子序列，然后筛选了58个额外的PanNET中最常见的突变基因。 值得注意的是，最常突变的基因指定涉及染色质重塑的蛋白质：44％的肿瘤在MEN-1中具有体细胞失活突变，其编码menin，组蛋白甲基转移酶复合物的组分; 43％在编码由DAXX（死亡相关蛋白）和ATRX（α地中海贫血/智力迟钝综合征X连锁）组成的转录/染色质重塑复合物的两个亚基之一的基因中具有突变。 在临床上，MEN1和DAXX / ATRX基因的突变与更好的预后相关。 我们还发现在14％的肿瘤中mTOR（雷帕霉素的哺乳动物靶标）途径的基因突变，这种发现可能用于分层患者用mTOR抑制剂治疗。

公开(公告)号：US20120115735A1

公开(公告)日：2012-05-10

申请号：US13060453

申请日：2009-09-03

申请人： Bert Vogelstein ,  Kenneth W. Kinzler ,  D. Williams Parsons ,  Sian Jones ,  Xiaosong Zhang ,  Jimmy Cheng-Ho Lin ,  Rebecca J. Leary ,  Philipp Angenendt ,  Nickolas Papadopoulos ,  Victor Velculescu ,  Giovanni Parmigiani ,  Rachel Karchin ,  Scott Kern ,  Ralph Hruban ,  James R. Eshleman ,  Michael Goggins ,  Alison Klein

发明人： Bert Vogelstein ,  Kenneth W. Kinzler ,  D. Williams Parsons ,  Sian Jones ,  Xiaosong Zhang ,  Jimmy Cheng-Ho Lin ,  Rebecca J. Leary ,  Philipp Angenendt ,  Nickolas Papadopoulos ,  Victor Velculescu ,  Giovanni Parmigiani ,  Rachel Karchin ,  Scott Kern ,  Ralph Hruban ,  James R. Eshleman ,  Michael Goggins ,  Alison Klein

IPC分类号： C12Q1/68 ,  C40B20/00 ,  C07H21/04

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选择，迫切需要对这种致死性疾病的发病机理的新见解。 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。 第二，我们使用微阵列查询每个样本中的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。

公开(公告)号：US20130210900A1

公开(公告)日：2013-08-15

申请号：US13819933

申请日：2011-09-06

申请人： Bert Vogelstein ,  Kenneth W. Kinzler ,  Victor Velculescu ,  Nickolas Papadopoulos ,  Sian Jones

发明人： Bert Vogelstein ,  Kenneth W. Kinzler ,  Victor Velculescu ,  Nickolas Papadopoulos ,  Sian Jones

IPC分类号： C12Q1/68 ,  A61K31/711

CPC分类号： C12Q1/6886 ,  A61K31/7088 ,  A61K31/711 ,  C12Q2600/156 ,  G01N33/5011

摘要： Two genes, ARID1A (AT-rich interactive domain-containing protein 1A) and PPP2R1A (protein-phosphatase 2, regulatory subunit 1, alpha), can be used in methods which are useful for detecting cancer, diagnosing cancer, contributing to a diagnosis of cancer, confirming a diagnosis of cancer, identifying appropriate treatments for cancer, monitoring treatment of cancer, and evaluating treatment protocols for cancer, including ovarian clear cell carcinoma, breast cancer, colon cancer, gastric cancer, lung cancer, medulloblastoma, pancreatic cancer, and prostate cancer.

摘要翻译： 可用于检测癌症，诊断癌症，有助于诊断癌症的方法中使用两种基因ARID1A（含AT富含交互结构域的蛋白质1A）和PPP2R1A（蛋白质磷酸酶2，调节亚单位1，α） 确定癌症的诊断，确定癌症的适当治疗，监测癌症的治疗，以及评估癌症的治疗方案，包括卵巢透明细胞癌，乳腺癌，结肠癌，胃癌，肺癌，成神经管细胞瘤，胰腺癌和 前列腺癌。

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：US08685660B2

公开(公告)日：2014-04-01

申请号：US13060191

申请日：2009-09-03

申请人： Bert Vogelstein ,  Kenneth W. Kinzler ,  D. Williams Parsons ,  Xiaosong Zhang ,  Jimmy Cheng-Ho Lin ,  Rebecca J. Leary ,  Philipp Angenendt ,  Nickolas Papadopoulos ,  Victor Velculescu ,  Giovanni Parmigiani ,  Rachel Karchin ,  Sian Jones ,  Hai Yan ,  Darell Bigner ,  Chien-Tsun Kuan ,  Gregory J. Riggins

发明人： Bert Vogelstein ,  Kenneth W. Kinzler ,  D. Williams Parsons ,  Xiaosong Zhang ,  Jimmy Cheng-Ho Lin ,  Rebecca J. Leary ,  Philipp Angenendt ,  Nickolas Papadopoulos ,  Victor Velculescu ,  Giovanni Parmigiani ,  Rachel Karchin ,  Sian Jones ,  Hai Yan ,  Darell Bigner ,  Chien-Tsun Kuan ,  Gregory J. Riggins

IPC分类号： G01N33/574

CPC分类号： C12Q1/6886 ,  C12Q2600/112 ,  C12Q2600/118 ,  C12Q2600/136 ,  C12Q2600/156

摘要： We found mutations of the R132 residue of isocitrate dehydrogenase 1 (IDH1) in the majority of grade II and III astrocytomas and oligodendrogliomas as well as in glioblastomas that develop from these lower grade lesions. Those tumors without mutations in IDH1 often had mutations at the analogous R172 residue of the closely related IDH2 gene. These findings have important implications for the pathogenesis and diagnosis of malignant gliomas.

摘要翻译： 我们发现大多数II级和III级星形细胞瘤和少突胶质细胞瘤中异柠檬酸脱氢酶1（IDH1）的R132残基突变以及从这些较低级别病变发展的成胶质细胞瘤。 那些没有IDH1突变的肿瘤在紧密相关的IDH2基因的类似R172残基中经常具有突变。 这些发现对恶性胶质瘤的发病机制和诊断具有重要意义。

公开(公告)号：US08394598B2

公开(公告)日：2013-03-12

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： C12Q1/68 ,  G01N33/574

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：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：US20090123928A1

公开(公告)日：2009-05-14

申请号：US12247464

申请日：2008-10-08

申请人： Laura D. Wood ,  Williams D. Parsons ,  Sian Jones ,  Jimmy Lin ,  Tobias Sjoblom ,  Thomas Barber ,  Giovanni Parmigiani ,  Victor Velculescu ,  Kenneth W. Kinzler ,  Bert Vogelstein

发明人： Laura D. Wood ,  Williams D. Parsons ,  Sian Jones ,  Jimmy Lin ,  Tobias Sjoblom ,  Thomas Barber ,  Giovanni Parmigiani ,  Victor Velculescu ,  Kenneth W. Kinzler ,  Bert Vogelstein

IPC分类号： C12Q1/68 ,  C12Q1/02

CPC分类号： C12Q1/6886 ,  C12Q2600/112 ,  C12Q2600/156

摘要： Human cancer is caused by the accumulation of mutations in oncogenes and tumor suppressor genes. To catalogue the genetic changes that occur during tumorigenesis, we isolated DNA from 11 breast and 11 colorectal tumors and determined the sequences of the genes in the Reference Sequence database in these samples. Based on analysis of exons representing 20,857 transcripts from 18,191 genes, we conclude that the genomic landscapes of breast and colorectal cancers are composed of a handful of commonly mutated gene “mountains” and a much larger number of gene “hills” that are mutated at low frequency. We describe statistical and bioinformatic tools that may help identify mutations with a role in tumorigenesis. These results have implications for understanding the nature and heterogeneity of human cancers and for using personal genomics for tumor diagnosis and therapy.

摘要翻译： 人类癌症是由致癌基因和肿瘤抑制基因突变的积累引起的。 为了列出肿瘤发生过程中发生的遗传变化，我们从11个乳腺和11个结肠直肠肿瘤中分离出DNA，并在这些样品中确定了参考序列数据库中的基因序列。 根据对18,191个基因的20,857个转录本的外显子的分析，我们得出结论，乳腺癌和结肠直肠癌的基因组景观由少数常见的突变基因“山”组成，更多的基因“山”在低位突变 频率。 我们描述了统计和生物信息学工具，可以帮助识别在肿瘤发生中发挥作用的突变。 这些结果有助于了解人类癌症的性质和异质性以及使用个人基因组学进行肿瘤诊断和治疗。