公开(公告)号：US09695479B2

公开(公告)日：2017-07-04

申请号：US13884154

申请日：2011-11-08

Applicant: Bert Vogelstein ,  Kenneth Kinzler ,  Nickolas Papadopoulos ,  Donald Williams Parsons ,  Rebecca J. Leary ,  Meng Li ,  Xiaosong Zhang ,  Sian Jones ,  Gregory J. Riggins ,  Victor Velculescu ,  Darell Bigner ,  Hai Yan

Inventor： Bert Vogelstein ,  Kenneth Kinzler ,  Nickolas Papadopoulos ,  Donald Williams Parsons ,  Rebecca J. Leary ,  Meng Li ,  Xiaosong Zhang ,  Sian Jones ,  Gregory J. Riggins ,  Victor Velculescu ,  Darell Bigner ,  Hai Yan

IPC: C12Q1/68 ,  G01N33/574

CPC classification number: C12Q1/6886 ,  C12Q2600/112 ,  C12Q2600/156 ,  G01N33/57407

Abstract: 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.

公开(公告)号：US20130210900A1

公开(公告)日：2013-08-15

申请号：US13819933

申请日：2011-09-06

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

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

IPC: C12Q1/68 ,  A61K31/711

CPC classification number: C12Q1/6886 ,  A61K31/7088 ,  A61K31/711 ,  C12Q2600/156 ,  G01N33/5011

Abstract: 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.

Abstract translation: 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：US20110319477A1

公开(公告)日：2011-12-29

申请号：US13210736

申请日：2011-08-16

Applicant: Yardena SAMUELS ,  Victor VELCULESCU ,  Kenneth W. KINZLER ,  Bert VOGELSTEIN

Inventor： Yardena SAMUELS ,  Victor VELCULESCU ,  Kenneth W. KINZLER ,  Bert VOGELSTEIN

IPC: A61K31/7088 ,  A61K31/713 ,  C07H21/04 ,  C12Q1/68 ,  C12N5/09 ,  C12Q1/48

Abstract: 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 PI3K 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 PI3K 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.

Abstract translation: 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PI3K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PI3K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：US20100184100A1

公开(公告)日：2010-07-22

申请号：US12705760

申请日：2010-02-15

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

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

IPC: G01N33/574 ,  C07H21/00

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

Abstract: 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.

Abstract translation: 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：US20070031851A1

公开(公告)日：2007-02-08

申请号：US10915727

申请日：2004-08-11

Applicant: Victor Velculescu ,  Bert Vogelstein ,  Kenneth Kinzler

Inventor： Victor Velculescu ,  Bert Vogelstein ,  Kenneth Kinzler

IPC: C12Q1/68 ,  C07H21/04 ,  C07K14/705

CPC classification number: C12Q1/6895 ,  C12Q1/6837 ,  C12Q2600/158

Abstract: Yeast genes which are differentially expressed during the cell cycle are described. They can be used to study, affect, and monitor the cell cycle of a eukaryotic cell. They can be used to obtain human homologs involved in cell cycle regulation. They can be used to identify antifungal agents and other classes of drugs. They can be formed into arrays on solid supports for interrogation of a cell's transcriptome under various conditions.

Abstract translation: 描述在细胞周期期间差异表达的酵母基因。 它们可用于研究，影响和监测真核细胞的细胞周期。 它们可用于获得涉及细胞周期调节的人类同源物。 它们可用于鉴定抗真菌剂和其他类别的药物。 它们可以在固体支持物上形成阵列，用于在各种条件下询问细胞的转录组。

公开(公告)号：US09637779B2

公开(公告)日：2017-05-02

申请号：US13131413

申请日：2009-12-02

Applicant: Bert Vogelstein ,  Kenneth W. Kinzler ,  Yiping He ,  Victor Velculescu ,  Nickolas Papadopoulos

Inventor： Bert Vogelstein ,  Kenneth W. Kinzler ,  Yiping He ,  Victor Velculescu ,  Nickolas Papadopoulos

IPC: C12Q1/68 ,  G06F19/22

CPC classification number: C12Q1/6844 ,  G06F19/22 ,  C12Q2539/113 ,  C12Q2523/125 ,  C12Q2521/107

Abstract: Transcription in mammalian cells can be assessed at a genome-wide level, but it has been difficult to reliably determine whether individual transcripts are derived from the Plus- or Minus-strands of chromosomes. This distinction can be critical for understanding the relationship between known transcripts (sense) and the complementary antisense transcripts that may regulate them. Here we describe a technique that can be used to (i) identify the DNA strand of origin for any particular RNA transcript and (ii) quantify the number of sense and antisense transcripts from expressed genes at a global level. We examined five different human cell types and in each case found evidence for antisense transcripts in 2900 to 6400 human genes. The distribution of antisense transcripts was distinct from that of sense transcripts, was non-random across the genome, and differed among cell types. Antisense transcripts thus appear to be a pervasive feature of human cells, suggesting that they are a fundamental component of gene regulation.

公开(公告)号：US09580750B2

公开(公告)日：2017-02-28

申请号：US11920860

申请日：2006-05-23

Applicant: Donald William Parsons ,  Tian-li Wang ,  Yardena Samuels ,  Alberto Bardelli ,  Christopher Lengauer ,  Victor Velculescu ,  Kenneth W. Kinzler ,  Bert Vogelstein

Inventor： Donald William Parsons ,  Tian-li Wang ,  Yardena Samuels ,  Alberto Bardelli ,  Christopher Lengauer ,  Victor Velculescu ,  Kenneth W. Kinzler ,  Bert Vogelstein

IPC: C12Q1/62 ,  G01N33/574 ,  C07K16/40 ,  C12Q1/68 ,  C12Q1/48 ,  G01N33/50

CPC classification number: C12Q1/6883 ,  C12Q1/485 ,  C12Q2600/136 ,  C12Q2600/156 ,  G01N33/5044 ,  G01N33/57419

Abstract: 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.

Abstract translation: 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。

公开(公告)号：US20130296408A1

公开(公告)日：2013-11-07

申请号：US13884154

申请日：2011-11-08

Applicant: Bert Vogelstein ,  Kenneth Kinzler ,  Nickolas Papadopoulos ,  Donald Williams Parsons ,  Rebecca J. Leary ,  Meng Li ,  Xiaosong Zhang ,  Sian Jones ,  Gregory J. Riggins ,  Victor Velculescu

Inventor： Bert Vogelstein ,  Kenneth Kinzler ,  Nickolas Papadopoulos ,  Donald Williams Parsons ,  Rebecca J. Leary ,  Meng Li ,  Xiaosong Zhang ,  Sian Jones ,  Gregory J. Riggins ,  Victor Velculescu

IPC: C12Q1/68

CPC classification number: C12Q1/6886 ,  C12Q2600/112 ,  C12Q2600/156 ,  G01N33/57407

Abstract: 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.

Abstract translation: 成神经管细胞瘤（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变化，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。 我们发现平均每个肿瘤有11个基因改变，明显少于普通成年癌症。 除了Hedgehog和Wnt途径的改变之外，我们的分析导致了以前未知在MB中被改变的基因的发现。 最明显的是，在16％的MB患者中鉴定了组蛋白H3K4三甲基酶基因MLL2或MLL3的失活突变。 这些结果显示了成年和儿童期癌症遗传景观之间的关键差异，突出了发育途径的失调作为MBs的重要机制，并确定了特定类型的组蛋白甲基化在人类肿瘤发生中的作用。

公开(公告)号：US20120009573A1

公开(公告)日：2012-01-12

申请号：US13131413

申请日：2009-12-02

Applicant: Bert Vogelstein ,  Kenneth W. Kinzler ,  Yiping He ,  Victor Velculescu ,  Nickolas Papadopoulos

Inventor： Bert Vogelstein ,  Kenneth W. Kinzler ,  Yiping He ,  Victor Velculescu ,  Nickolas Papadopoulos

IPC: C12Q1/68

CPC classification number: C12Q1/6844 ,  G06F19/22 ,  C12Q2539/113 ,  C12Q2523/125 ,  C12Q2521/107

Abstract: Transcription in mammalian cells can be assessed at a genome-wide level, but it has been difficult to reliably determine whether individual transcripts are derived from the Plus- or Minus-strands of chromosomes. This distinction can be critical for understanding the relationship between known transcripts (sense) and the complementary antisense transcripts that may regulate them. Here we describe a technique that can be used to (i) identify the DNA strand of origin for any particular RNA transcript and (ii) quantify the number of sense and antisense transcripts from expressed genes at a global level. We examined five different human cell types and in each case found evidence for antisense transcripts in 2900 to 6400 human genes. The distribution of antisense transcripts was distinct from that of sense transcripts, was non-random across the genome, and differed among cell types. Anti-sense transcripts thus appear to be a pervasive feature of human cells, suggesting that they are a fundamental component of gene regulation.

Abstract translation: 哺乳动物细胞中的转录可以在全基因组范围内进行评估，但是难以可靠地确定个体转录本是否衍生自染色体的加号或阴影链。 这种区别对于了解已知转录物（有义）和可能调节它们的互补反义转录物之间的关系可能是至关重要的。 在这里，我们描述了一种可用于（i）识别任何特定RNA转录物的DNA链起源的技术，（ii）在全球范围内量化来自表达基因的正义和反义转录本的数量。 我们检查了五种不同的人类细胞类型，并且在每种情况下都发现2900至6400个人类基因中的反义转录物的证据。 反义转录物的分布与有义转录物的分布不同，在基因组中是非随机的，并且在细胞类型之间不同。 因此，反义转录物似乎是人类细胞的普遍特征，表明它们是基因调控的基本组成部分。

公开(公告)号：US08039210B2

公开(公告)日：2011-10-18

申请号：US11596349

申请日：2005-05-16

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

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

IPC: C12Q1/68

CPC classification number: C12Q1/6886 ,  C12N9/16 ,  C12Q2600/112 ,  C12Q2600/136 ,  C12Q2600/156 ,  C12Q2600/158 ,  C12Y301/03048 ,  G01N33/5011 ,  G01N2333/916

Abstract: 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.

Abstract translation: 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。