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    MUTANT PROTEINS AS CANCER-SPECIFIC BIOMARKERS
    2.
    发明申请
    MUTANT PROTEINS AS CANCER-SPECIFIC BIOMARKERS 审中-公开
    突变蛋白作为癌症特异性生物标志物

    公开(公告)号：WO2012099881A2

    公开(公告)日：2012-07-26

    申请号：PCT/US2012021553

    申请日：2012-01-17

    Applicant: UNIV JOHNS HOPKINS ,  VOGELSTEIN BERT ,  WANG QING ,  PANDEY AKHILESH ,  KINZLER KENNETH W ,  PAPADOPOULOS NICKOLAS

    Inventor： VOGELSTEIN BERT ,  WANG QING ,  PANDEY AKHILESH ,  KINZLER KENNETH W ,  PAPADOPOULOS NICKOLAS

    IPC: G01N33/68 ,  G01N33/551 ,  G01N33/574

    CPC classification number: G01N33/6893 ,  G01N33/574 ,  G01N33/6848

    Abstract: Altered protein products resulting from somatic mutations are directly identified and quantified by mass spectrometry. The peptides expressed from normal and mutant alleles are detected by Selected Reaction Monitoring (SRM) of their product ions using a triple quadrupole mass spectrometer. As a prototypical example of this approach, we quantify the number and fraction of mutant Ras protein present in cancer cell lines. There were an average of 1.3 million molecules of Ras protein per cell and the ratio of mutant to normal Ras proteins ranged from 0.49 to 5.6. Similarly, we detected and quantified mutant Ras proteins in clinical specimens such as colorectal and pancreatic tumor tissues as well as in pre-malignant pancreatic cyst fluids. These methods are useful for diagnostic applications.

    Abstract translation: 通过质谱法直接鉴定和定量由体细胞突变产生的改变的蛋白质产物。 使用三重四极质谱仪通过其产物离子的选择性反应监测（SRM）来检测从正常和突变等位基因表达的肽。 作为这种方法的原型实例，我们量化了存在于癌细胞系中的突变型Ras蛋白的数量和分数。 每个细胞平均有130万个Ras蛋白分子，突变体与正常Ras蛋白的比例范围为0.49至5.6。 同样，我们在临床标本如结直肠癌和胰腺肿瘤组织以及恶变前胰腺囊液中检测并定量了突变型Ras蛋白。 这些方法对诊断应用程序很有用。

    GENES FREQUENTLY ALTERED IN PANCREATIC NEUROENDOCRINE TUMORS
    3.
    发明申请
    GENES FREQUENTLY ALTERED IN PANCREATIC NEUROENDOCRINE TUMORS 审中-公开
    在胰腺神经内分泌肿瘤中常见改变的基因

    公开(公告)号：WO2012094401A2

    公开(公告)日：2012-07-12

    申请号：PCT/US2012/020199

    申请日：2012-01-04

    Applicant: THE JOHNS HOPKINS UNIVERSITY ,  VOGELSTEIN, Bert ,  KINZLER, Kenneth W. ,  VELCULESCU, Victor ,  DIAZ, Luis ,  PAPADOPOULOS, Nikolas ,  JIAO, Yuchen ,  HRUBAN, Ralph

    Inventor： VOGELSTEIN, Bert ,  KINZLER, Kenneth W. ,  VELCULESCU, Victor ,  DIAZ, Luis ,  PAPADOPOULOS, Nikolas ,  JIAO, Yuchen ,  HRUBAN, Ralph

    IPC: C12Q1/68 ,  G01N33/574 ,  G01N33/58

    CPC classification number: C12Q1/6886 ,  C12Q2600/106 ,  C12Q2600/112 ,  C12Q2600/118 ,  C12Q2600/156 ,  G01N33/57438 ,  G01N2800/52

    Abstract: 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.

    Abstract translation: 胰腺神经内分泌肿瘤（PanNETs）是罕见但临床上重要的胰腺瘤形成形式。 为了探索PanNET的遗传基础，我们确定了10个非家族性PanNET的外显子序列，然后筛选58个额外PanNET中最常见的突变基因。 值得注意的是，最经常突变的基因指定涉及染色质重塑的蛋白质：MEN-1中44％的肿瘤具有体细胞失活突变，MEN-1编码组蛋白甲基转移酶复合物的组分; 和43％在编码由DAXX（死亡域相关蛋白）和ATRX（α地中海贫血/智力低下综合征X连锁）组成的转录/染色质重塑复合体的两个亚基中的任一个的基因中具有突变。 临床上，MEN1和DAXX / ATRX基因的突变与更好的预后相关。 我们还在14％的肿瘤中发现了mTOR（哺乳动物雷帕霉素靶标）途径中的基因突变，这一发现可能潜在地用于将患者分层以用mTOR抑制剂治疗。

    DIGITAL QUANTIFICATION OF DNA METHYLATION
    6.
    发明申请
    DIGITAL QUANTIFICATION OF DNA METHYLATION 审中-公开
    DNA甲基化的数字量化

    公开(公告)号：WO2010118016A2

    公开(公告)日：2010-10-14

    申请号：PCT/US2010/030084

    申请日：2010-04-06

    Applicant: THE JOHNS HOPKINS UNIVERSITY ,  CASE WESTERN RESERVE UNIVERSITY ,  VOGELSTEIN, Bert ,  KINZLER, Kenneth, W. ,  LI, Meng ,  DIAZ, Luis ,  PAPADOPOULOS, Nickolas ,  MARKOWITZ, Sanford

    Inventor： VOGELSTEIN, Bert ,  KINZLER, Kenneth, W. ,  LI, Meng ,  DIAZ, Luis ,  PAPADOPOULOS, Nickolas ,  MARKOWITZ, Sanford

    IPC: C12Q1/68 ,  C12N15/11 ,  G01N33/52

    CPC classification number: C12Q1/6816 ,  C12Q1/6886 ,  C12Q2600/154 ,  C12Q2565/501 ,  C12Q2527/125 ,  C12Q2523/125

    Abstract: Abnormal DNA methylation can be used as a biomarker in cancer patients. For such purposes, it is important to determine precisely the fraction of methylated molecules in an analyzed sample. A technology we term Methyl-BEAMing achieves this goal. Individual bisulfite-treated DNA molecules can be PCR-amplified within aqueous nanocompartments containing beads, resulting in a population of beads each containing thousands of copies of the template molecule. After hybridization with probes specific for methylated sequences, the beads can be analyzed by flow cytometry. This approach enables detection and enumeration of one methylated molecule in a population of ~5000 unmethylated molecules. Methyl-BEAMing provides digital quantification of rare methylation events and is generally applicable to the assessment of methylated genes in clinical samples.

    Abstract translation: DNA甲基化异常可用作癌症患者的生物标志物。 为此目的，重要的是精确测定分析样品中甲基化分子的分数。 我们称之为甲基BEAMing的技术实现了这一目标。 单独的亚硫酸氢盐处理的DNA分子可以在含有珠粒的含水纳米间隔内进行PCR扩增，导致每个珠粒群含有数千份拷贝的模板分子。 与特异于甲基化序列的探针杂交后，可以通过流式细胞术分析珠粒。 这种方法能够检测和计数一个约5000个非甲基化分子的一个甲基化分子。 甲基BEAMing提供罕见甲基化事件的数字量化，通常适用于临床样品中甲基化基因的评估。

    THE ANTISENSE TRANSCRIPTOMES OF CELLS
    7.
    发明申请
    THE ANTISENSE TRANSCRIPTOMES OF CELLS 审中-公开

    公开(公告)号：WO2010065576A3

    公开(公告)日：2010-06-10

    申请号：PCT/US2009/066313

    申请日：2009-12-02

    Applicant: THE JOHNS HOPKINS UNIVERSITY ,  VOGELSTEIN, Bert ,  KINZLER, Kenneth W. ,  HE, Yiping ,  VELCULESCU, Victor ,  PAPADOPOULOS, Nickolas

    Inventor： VOGELSTEIN, Bert ,  KINZLER, Kenneth W. ,  HE, Yiping ,  VELCULESCU, Victor ,  PAPADOPOULOS, Nickolas

    IPC: C12N15/11 ,  C12Q1/68 ,  G06F19/00

    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.

    THE MICRORNAOME
    9.
    发明申请
    THE MICRORNAOME 审中-公开
    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

    Applicant: UNIV JOHNS HOPKINS ,  CUMMINS JORDAN ,  VELCULESCU VICTOR ,  KINZLER KENNETH W ,  VOGELSTEIN BERT

    Inventor： CUMMINS JORDAN ,  VELCULESCU VICTOR ,  KINZLER KENNETH W ,  VOGELSTEIN BERT

    IPC: C07H21/02 ,  A01N43/04 ,  A61K31/70 ,  C07H21/04 ,  C12N15/113

    CPC classification number: C12N15/113 ,  C12N2310/141 ,  C12N2320/11 ,  C12N2330/10 ,  C12N2510/00 ,  C12Q1/6886

    Abstract: 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.

    Abstract translation: 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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