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：US20130296408A1

公开(公告)日：2013-11-07

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

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

IPC分类号： C12Q1/68

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： 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：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：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：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：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：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：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：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。