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1. 发明申请

WO2005076984A3 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：WO2005076984A3
公开(公告)日：2009-04-02
申请号：PCT/US2005003776
申请日：2005-02-07
申请人： UNIV JOHNS HOPKINS , 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： C07H21/04 , 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。

2. 发明申请

WO2006127607A3 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：WO2006127607A3
公开(公告)日：2011-05-26
申请号：PCT/US2006019748
申请日：2006-05-23
申请人： UNIV JOHNS HOPKINS , 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： C40B30/06
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）途径的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通路是结直肠癌突变激活的主要靶标，为治疗干预提供新的机会。

3. 发明申请

WO2004046370A2 DIGITAL KARYOTYPING 审中-公开
公开(公告)号：WO2004046370A2
公开(公告)日：2004-06-03
申请号：PCT/US0336502
申请日：2003-11-14
申请人： UNIV JOHNS HOPKINS , 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： C12Q20060101 , C12Q1/68 , C12Q
CPC分类号： C12Q1/6841 , C12Q2565/102 , C12Q2537/157 , C12Q2521/313
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.
摘要翻译：细胞遗传内容的改变是许多人类疾病的基础，包括癌症。称为数字核型分析的方法以高分辨率提供DNA拷贝数的定量分析。这种方法涉及分离和列举来自特定基因组基因座的短序列标签。使用该方法分析人类癌细胞鉴定了总体染色体变化以及扩增和缺失，包括之前未知被改变的区域。不存在于正常人类基因组中的外来DNA序列也可以容易地鉴定。数字核型分析提供了一种广泛适用的手段，用于系统检测基因组规模上的DNA拷贝数变化。

4. 发明申请

WO2012094401A3 GENES FREQUENTLY ALTERED IN PANCREATIC NEUROENDOCRINE TUMORS 审中-公开
标题翻译：普遍存在于胰腺神经元肿瘤中的基因
公开(公告)号：WO2012094401A3
公开(公告)日：2012-10-18
申请号：PCT/US2012020199
申请日：2012-01-04
申请人： UNIV JOHNS HOPKINS , VOGELSTEIN BERT , KINZLER KENNETH W , VELCULESCU VICTOR , DIAZ LUIS , PAPADOPOULOS NIKOLAS , JIAO YUCHEN , HRUBAN RALPH
发明人： VOGELSTEIN BERT , KINZLER KENNETH W , VELCULESCU VICTOR , DIAZ LUIS , PAPADOPOULOS NIKOLAS , JIAO YUCHEN , HRUBAN RALPH
IPC分类号： C12Q1/68 , G01N33/574 , G01N33/58
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。

5. 发明申请

WO2011103236A3 PERSONALIZED TUMOR BIOMARKERS 审中-公开
标题翻译：个性化肿瘤生物标志物
公开(公告)号：WO2011103236A3
公开(公告)日：2012-02-09
申请号：PCT/US2011025152
申请日：2011-02-17
申请人： UNIV JOHNS HOPKINS , VOGELSTEIN BERT , KINZLER KENNETH W , VELCULESCU VICTOR , DIAZ LUIS , LEARY REBECCA J
发明人： VOGELSTEIN BERT , KINZLER KENNETH W , VELCULESCU VICTOR , DIAZ LUIS , LEARY REBECCA J
IPC分类号： C12Q1/68 , C12N15/11 , C40B40/06
CPC分类号： C12Q1/6886 , C12Q2600/156
摘要： Clinical management of human cancer is dependent on the accurate monitoring of residual and recurrent tumors. We have developed a method, called personalized analysis of rearranged ends (PARE), which can identify translocations in solid tumors. Analysis of four colorectal and two breast cancers revealed an average of nine rearranged sequences (range 4 to 15) per tumor. Polymerase chain reaction with primers spanning the breakpoints were able to detect mutant DNA molecules present at levels lower than 0.001% and readily identified mutated circulating DNA in patient plasma samples. This approach provides an exquisitely sensitive and broadly applicable approach for the development of personalized biomarkers to enhance the clinical management of cancer patients.
摘要翻译：人类癌症的临床管理取决于对残留和复发性肿瘤的准确监测。我们开发了一种称为重排末端（PARE）的个性化分析方法，可以识别实体瘤易位。对4例结直肠癌和2例乳腺癌的分析显示，每个肿瘤平均有9个重排序列（范围4至15）。与跨越断点的引物的聚合酶链反应能够检测出低于0.001％的突变型DNA分子，并且容易鉴定出患者血浆样品中突变的循环DNA。这种方法为个性化生物标志物的开发提供了一种非常灵敏和广泛适用的方法，以加强癌症患者的临床管理。

6. 发明申请

WO2005091849A3 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：WO2005091849A3
公开(公告)日：2009-04-16
申请号：PCT/US2005005193
申请日：2005-02-18
申请人： UNIV JOHNS HOPKINS , SAMUELS YARDENA , VELCULESCU VICTOR , KINZLER KENNETH W , VOGELSTEIN BERT
发明人： SAMUELS YARDENA , VELCULESCU VICTOR , KINZLER KENNETH W , VOGELSTEIN BERT
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）是信号传导途径的重要调控因子。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。

7. 发明申请

WO2010028098A3 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：WO2010028098A3
公开(公告)日：2010-06-10
申请号：PCT/US2009055802
申请日：2009-09-03
申请人： UNIV JOHNS HOPKINS , 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： This invention relates to new insights into the pathogenesis of pancreatic cancers by analyzing 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：本发明涉及通过分析24个胰腺肿瘤中改变的基因对胰腺癌发病机理的新见解。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和下一代合成技术分析相同样品的转录组我们发现胰腺癌平均含有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。

8. 发明申请

WO2009049166A2 GENOMIC LANDSCAPES OF HUMAN BREAST AND COLORECTAL CANCERS 审中-公开
标题翻译：人类乳腺癌和色素沉着病的基因组学观察
公开(公告)号：WO2009049166A2
公开(公告)日：2009-04-16
申请号：PCT/US2008079526
申请日：2008-10-10
申请人： UNIV JOHNS HOPKINS , WOOD LAURA D , PARSONS D WILLIAMS , JONES SIAN , LIN JIMMY , SJOEBLOM TOBIAS , BARBER THOMAS , PARMIGIANI GIOVANNI , VELCULESCU VICTOR , KINZLER KENNETH W , VOGELSTEIN BERT
发明人： WOOD LAURA D , PARSONS D WILLIAMS , JONES SIAN , LIN JIMMY , SJOEBLOM TOBIAS , BARBER THOMAS , PARMIGIANI GIOVANNI , VELCULESCU VICTOR , KINZLER KENNETH W , VOGELSTEIN BERT
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。

9. 发明申请

WO2012064721A2 MEDULLOBLASTOMA GENES AS TARGETS FOR DIAGNOSIS AND THERAPEUTICS 审中-公开
标题翻译：作为诊断和治疗目标的MEDLOBLASTOMA基因
公开(公告)号：WO2012064721A2
公开(公告)日：2012-05-18
申请号：PCT/US2011059751
申请日：2011-11-08
申请人： UNIV JOHNS HOPKINS , UNIV DUKE , VOGELSTEIN BERT , KINZLER KENNETH W , PAPADOPOULOS NICKOLAS , PARSONS DONALD WILLIAMS , LEARY REBECCA J , LI MENG , ZHANG XIAOSONG , JONES SIAN , RIGGINS GREGORY J , VELCULESCU VICTOR , BIGNER DARELL , YAN HAI
发明人： VOGELSTEIN BERT , KINZLER KENNETH W , PAPADOPOULOS NICKOLAS , PARSONS DONALD WILLIAMS , LEARY REBECCA J , LI MENG , ZHANG XIAOSONG , JONES SIAN , RIGGINS GREGORY J , VELCULESCU VICTOR , BIGNER DARELL , YAN HAI
IPC分类号： G01N33/574 , C12Q1/68 , G01N33/50
CPC分类号： C12Q1/6886 , C12Q2600/112 , C12Q2600/156 , G01N33/57407
摘要： Medulloblastoma (MB) is the most common malignant brain tumor of children. To identify the genetic alterations in this tumor type, we searched for copy number alterations using high density microarrays and sequenced all known protein-coding genes and miRNA genes using Sanger sequencing. We found that, on average, each tumor had 11 gene alterations, markedly fewer than in common adult cancers. In addition to alterations in the Hedgehog and Wnt pathways, our analysis led to the discovery of genes not previously known to be altered in MBs. Most notably, inactivating mutations of the histone H3K4 trimethylase genes MLL2 or MLL3 were identified in 16% of MB patients. These results demonstrate key differences between the genetic landscapes of adult and childhood cancers, highlight dysregulation of developmental pathways as an important mechanism underlying MBs, and identify a role for a specific type of histone methylation in human tumorigenesis.
摘要翻译：髓母细胞瘤（MB）是儿童最常见的恶性脑肿瘤。为了鉴定这种肿瘤类型的遗传改变，我们使用高密度微阵列搜索拷贝数改变，并使用Sanger测序对所有已知的蛋白质编码基因和miRNA基因进行测序。我们发现平均而言，每个肿瘤有11个基因改变，明显少于常见的成人癌症。除了Hedgehog和Wnt途径的改变之外，我们的分析还导致发现以前不知道在MB中改变的基因。最值得注意的是，在16％的MB患者中鉴定出组蛋白H3K4三甲基化酶基因MLL2或MLL3的失活突变。这些结果表明成人和儿童癌症的遗传景观之间的主要区别，突出发展途径的失调作为潜在的MB的重要机制，并确定在人类肿瘤特定类型的组蛋白甲基化的作用。

10. 发明申请

WO2008103135A3 THE MICRORNAOME 审中-公开
标题翻译：微笑
公开(公告)号：WO2008103135A3
公开(公告)日：2008-12-24
申请号：PCT/US2007004518
申请日：2007-02-16
申请人： UNIV JOHNS HOPKINS , 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： C07H21/02 , A01N43/04 , A61K31/70 , C07H21/04 , C12N15/113
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。

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