公开(公告)号：US09873917B2

公开(公告)日：2018-01-23

申请号：US14233296

申请日：2012-07-18

申请人： Bert Vogelstein ,  Kenneth W. Kinzler ,  Chetan Bettegowda ,  Nishant Agrawal ,  Nickolas Papadopoulos ,  Darell Bigner ,  Hai Yan ,  Roger McLendon

发明人： Bert Vogelstein ,  Kenneth W. Kinzler ,  Chetan Bettegowda ,  Nishant Agrawal ,  Nickolas Papadopoulos ,  Darell Bigner ,  Hai Yan ,  Roger McLendon

IPC分类号： C12Q1/68

CPC分类号： C12Q1/6886 ,  C12Q2600/106 ,  C12Q2600/112 ,  C12Q2600/118 ,  C12Q2600/156 ,  C12Q2600/158

摘要： Oligodendrogliomas are the second most common malignant brain tumor in adults. These tumors often contain a chromosomal abnormality involving a pericentromeric fusion of chromosomes 1 and 19, resulting in losses of the entire short arm of the former and the long arm of the latter. To identify the molecular genetic basis for this alteration, we performed exomic sequencing of seven anaplastic oligodendrogliomas with chromosome 1p and 19q losses. Among other changes, we found that that CIC (homolog of the Drosophila gene capicua) on chromosome 19q was somatically mutated in six of the seven cases and that FUBP1 (far upstream element (FUSE) binding protein) on chromosome 1p was somatically mutated in two of the seven cases. Examination of 27 additional oligodendrogliomas revealed 12 and 3 more tumors with mutations of CIC and FUBP1, respectively, 58% of which were predicted to result in truncations of the encoded proteins. These results suggest a critical role for these genes in the biology and pathology of oligodendrocytes.

公开(公告)号：US20140221219A1

公开(公告)日：2014-08-07

申请号：US14233296

申请日：2012-07-18

申请人： Bert Vogelstein ,  Kenneth W. Kinzler ,  Chetan Bettegowda ,  Nishant Agrawal ,  Nickolas Papadopoulos ,  Darell Bigner ,  Hai Yan ,  Roger Mclendon

发明人： Bert Vogelstein ,  Kenneth W. Kinzler ,  Chetan Bettegowda ,  Nishant Agrawal ,  Nickolas Papadopoulos ,  Darell Bigner ,  Hai Yan ,  Roger Mclendon

IPC分类号： C12Q1/68

CPC分类号： C12Q1/6886 ,  C12Q2600/106 ,  C12Q2600/112 ,  C12Q2600/118 ,  C12Q2600/156 ,  C12Q2600/158

摘要： Oligodendrogliomas are the second most common malignant brain tumor in adults. These tumors often contain a chromosomal abnormality involving a pericentromeric fusion of chromosomes 1 and 19, resulting in losses of the entire short arm of the former and the long arm of the latter. To identify the molecular genetic basis for this alteration, we performed exomic sequencing of seven anaplastic oligodendrogliomas with chromosome 1p and 19q losses. Among other changes, we found that that CIC (homolog of the Drosophila gene capicua) on chromosome 19q was somatically mutated in six of the seven cases and that FUBP1 (far upstream element (FUSE) binding protein) on chromosome 1p was somatically mutated in two of the seven cases. Examination of 27 additional oligodendrogliomas revealed 12 and 3 more tumors with mutations of CIC and FUBP1, respectively, 58% of which were predicted to result in truncations of the encoded proteins. These results suggest a critical role for these genes in the biology and pathology of oligodendrocytes.

摘要翻译： 少突神经胶质瘤是成人中第二常见的恶性脑肿瘤。 这些肿瘤通常包含染色体异常，涉及染色体1和染色体1的致晕体融合，导致前者的整个短臂和后者的长臂的损失。 为了确定这种改变的分子遗传基础，我们对染色体1p和19q损失进行了7个分离性少突胶质细胞瘤的外切测序。 在其他变化中，我们发现在七种病例中的六种中，染色体19q上的CIC（果蝇基因capicua的同系物）被体细胞突变，并且染色体1p上的FUBP1（远上游元件（FUSE）结合蛋白）在两个体内被突变 的七例。 另外27例少突胶质细胞瘤的检查显示有12例和3例分别具有CIC和FUBP1突变的肿瘤，其中58％预计会导致编码蛋白的截短。 这些结果表明这些基因在少突胶质细胞的生物学和病理学中的关键作用。

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：US09982306B2

公开(公告)日：2018-05-29

申请号：US14129850

申请日：2012-06-28

申请人： Hai Yan ,  Darell Bigner ,  Bert Vogelstein ,  Kenneth W. Kinzler ,  Alan Meeker ,  Ralph Hruban ,  Nickolas Papadopoulos ,  Luis Diaz ,  Yuchen Jiao

发明人： Hai Yan ,  Darell Bigner ,  Bert Vogelstein ,  Kenneth W. Kinzler ,  Alan Meeker ,  Ralph Hruban ,  Nickolas Papadopoulos ,  Luis Diaz ,  Yuchen Jiao

IPC分类号： G01N33/68 ,  C12Q1/68 ,  G01N33/574 ,  C07K16/40 ,  C12N15/113

CPC分类号： C12Q1/6886 ,  C07K16/40 ,  C12N15/1137 ,  C12Q2600/118 ,  C12Q2600/156 ,  G01N33/57407

摘要： We determined the sequence of ATRX and DAXX in 447 cancers from various sites. We found mutations most commonly in pediatric glioblastoma multiformae (GBM) (11.1%), adult GBM (6.5%), oligodendrogliomas (7.7%) and medulloblastomas (1.5%); and showed that Alternative Lengthening of Telomeres (ALT), a telomerase-independent telomere maintenance mechanism found in cancers that have not activated telomerase, perfectly correlated with somatic mutations of either gene. In contrast, neuroblastomas, and adenocarcinomas of the ovary, breast, and pancreas were negative for mutations in ATRX and DAXX. Alterations in ATRX or DAXX define a specific molecular pathway that is closely associated with an alternative telomere maintenance function in human cancers.

公开(公告)号：US20140227271A1

公开(公告)日：2014-08-14

申请号：US14129850

申请日：2012-06-28

申请人： Hai Yan ,  Darell Bigner ,  Bert Vogelstein ,  Kenneth W. Kinzler ,  Alan Meeker ,  Ralph Hruban ,  Nickolas Papadopoulos ,  Luis Diaz ,  Yuchen Jiao

发明人： Hai Yan ,  Darell Bigner ,  Bert Vogelstein ,  Kenneth W. Kinzler ,  Alan Meeker ,  Ralph Hruban ,  Nickolas Papadopoulos ,  Luis Diaz ,  Yuchen Jiao

IPC分类号： C12Q1/68 ,  C07K16/40 ,  C12N15/113 ,  G01N33/574

CPC分类号： C12Q1/6886 ,  C07K16/40 ,  C12N15/1137 ,  C12Q2600/118 ,  C12Q2600/156 ,  G01N33/57407

摘要： We determined the sequence of ATRX and DAXX in 447 cancers from various sites. We found mutations most commonly in pediatric glioblastoma multiformae (GBM) (11.1%), adult GBM (6.5%), oligodendrogliomas (7.7%) and medulloblastomas (1.5%); and showed that Alternative Lengthening of Telomeres (ALT), a telomerase-independent telomere maintenance mechanism found in cancers that have not activated telomerase, perfectly correlated with somatic mutations of either gene. In contrast, neuroblastomas, and adenocarcinomas of the ovary, breast, and pancreas were negative for mutations in ATRX and DAXX. Alterations in ATRX or DAXX define a specific molecular pathway that is closely associated with an alternative telomere maintenance function in human cancers.

摘要翻译： 我们确定了来自各个位点的447例癌症中ATRX和DAXX的序列。 我们发现多形性小儿多形性成胶质细胞瘤（GBM）（11.1％），成人GBM（6.5％），少突胶质细胞瘤（7.7％）和成神经管细胞瘤（1.5％）中最常见的突变; 并且表明，在未激活端粒酶的癌症中发现端粒酶不依赖端粒维持机制的替代延长端粒（ALT）与任一基因的体细胞突变完全相关。 相比之下，成骨细胞瘤和卵巢，乳腺和胰腺腺癌对于ATRX和DAXX中的突变是阴性的。 ATRX或DAXX中的改变定义了与人类癌症中替代端粒维持功能密切相关的特定分子途径。

公开(公告)号：US20110229479A1

公开(公告)日：2011-09-22

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

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

IPC分类号： A61K39/395 ,  C12Q1/68 ,  G01N33/574 ,  C07K16/32 ,  A61K39/00 ,  C12N9/04 ,  C07H21/04 ,  C12Q1/32 ,  A61P37/04 ,  A61P35/00

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：US09695479B2

公开(公告)日：2017-07-04

申请号：US13884154

申请日：2011-11-08

申请人： 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

发明人： 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分类号： C12Q1/68 ,  G01N33/574

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.

公开(公告)号：US07045352B2

公开(公告)日：2006-05-16

申请号：US10210066

申请日：2002-08-02

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

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

IPC分类号： C12N5/12 ,  C12Q1/00 ,  C12N15/06 ,  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：US06475794B1

公开(公告)日：2002-11-05

申请号：US09504860

申请日：2000-02-16

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

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

IPC分类号： C12N1502

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.

摘要翻译： 与遗传性疾病相关的突变的检测由于哺乳动物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：US08613917B2

公开(公告)日：2013-12-24

申请号：US13198850

申请日：2011-08-05

申请人： Long Dang ,  Chetan Bettegowda ,  Kenneth W. Kinzler ,  Bert Vogelstein

发明人： Long Dang ,  Chetan Bettegowda ,  Kenneth W. Kinzler ,  Bert Vogelstein

IPC分类号： A61K35/00 ,  A01N63/00 ,  A01N63/02 ,  C12N1/20 ,  C12N3/00

CPC分类号： A61K35/742 ,  A61K31/337 ,  A61K31/427 ,  A61K45/06 ,  Y10S435/842 ,  A61K2300/00

摘要： Current approaches for treating cancer are limited, in part, by the inability of drugs to affect the poorly vascularized regions of tumors. We have found that spores of anaerobic bacteria in combination with agents which interact with microtubules can cause the destruction of both the vascular and avascular compartments of tumors. Two classes of microtubule inhibitors were found to exert markedly different effects. Some agents that inhibited microtubule synthesis, such as vinorelbine, caused rapid, massive hemorrhagic necrosis when used in combination with spores. In contrast, agents that stabilized microtubules, such as the taxane, docetaxel, resulted in slow tumor regressions that killed most neoplastic cells. Remaining cells in the poorly perfused regions of tumors could be eradicated by sporulated bacteria. Mechanistic studies showed that the microtubule destabilizers, but not the microtubule stabilizers, radically reduced blood flow to tumors, thereby enlarging the hypoxic niche in which spores could germinate. A single intravenous injection of spores plus selected microtubule-interacting agents was able to cause regressions of several tumors in the absence of excessive toxicity.

摘要翻译： 目前用于治疗癌症的方法在一定程度上受到药物不能影响肿瘤血管不足的区域的限制。 我们已经发现，厌氧细菌的孢子与与微管相互作用的药物组合可能导致肿瘤的血管和非血管性腔室的破坏。 发现两类微管抑制剂发挥显着不同的作用。 抑制微管合成的一些药物，如长春瑞滨，当与孢子结合使用时，引起快速，大规模的出血性坏死。 相比之下，稳定微管（如紫杉烷，多西紫杉醇）的药物导致肿瘤消退缓慢，导致大多数肿瘤细胞死亡。 肿瘤不良灌注区域的剩余细胞可以被孢子细菌消灭。 机理研究表明，微管不稳定剂，而不是微管稳定剂，从根本上减少了流向肿瘤的血液，从而扩大了孢子可以发芽的缺氧生态位。 在没有过量毒性的情况下，单次静脉注射孢子加选择的微管相互作用剂能够引起几种肿瘤的回归。