公开(公告)号：EP3266879B1

公开(公告)日：2019-07-03

申请号：EP17168866.6

申请日：2009-09-03

申请人： The Johns Hopkins University ,  Duke University

发明人： VOGELSTEIN, Bert ,  KINZLER, Kenneth ,  PAPADOPOULOS, Nickolas ,  VELCULESCU, Victor ,  PARMIGIANI, Giovanni ,  KARCHIN, Rachel ,  JONES, Sian ,  YAN, Hai ,  BIGNER, Darell ,  KUAN, Chien-Tsun ,  RIGGINS, Gregory ,  PARSONS, Williams ,  ZHANG, Xiaosong ,  LIN, Jimmy Cheng-Ho ,  LEARY, Rebecca ,  ANGENENDT, Philipp

IPC分类号： C12Q1/68

公开(公告)号：EP2326735B1

公开(公告)日：2016-11-16

申请号：EP09792198.5

申请日：2009-09-03

申请人： The Johns Hopkins University ,  Duke University

发明人： VOGELSTEIN, Bert ,  KINZLER, Kenneth W. ,  PARSONS, D. Williams ,  ZHANG, Xiaosong ,  LIN, Jimmy Cheng-Ho ,  LEARY, Rebecca J. ,  ANGENENDT, Philipp ,  PAPADOPOULOS, Nickolas ,  VELCULESCU, Victor ,  PARMIGIANI, Giovanni ,  KARCHIN, Rachel ,  JONES, Sian ,  YAN, Hai ,  BIGNER, Darell ,  KUAN, Chien-Tsun ,  RIGGINS, Gregory J.

IPC分类号： C12Q1/68

CPC分类号： C12Q1/6886 ,  C12Q2600/112 ,  C12Q2600/118 ,  C12Q2600/136 ,  C12Q2600/156

公开(公告)号：EP2956556B1

公开(公告)日：2019-04-10

申请号：EP14751900.3

申请日：2014-02-18

申请人： Duke University ,  The Johns Hopkins University

发明人： YAN, Hai ,  VOGELSTEIN, Bert ,  PAPADOPOULOS, Nickolas ,  KINZLER, Kenneth W. ,  JIAO, Yuchen ,  BETTEGOWDA, Chetan ,  BIGNER, Darell D.

IPC分类号： C12Q1/6886

公开(公告)号：EP3266879A1

公开(公告)日：2018-01-10

申请号：EP17168866.6

申请日：2009-09-03

申请人： The Johns Hopkins University ,  Duke University

发明人： VOGELSTEIN, Bert ,  KINZLER, Kenneth ,  PAPADOPOULOS, Nickolas ,  VELCULESCU, Victor ,  PARMIGIANI, Giovanni ,  KARCHIN, Rachel ,  JONES, Sian ,  YAN, Hai ,  BIGNER, Darell ,  KUAN, Chien-Tsun ,  RIGGINS, Gregory ,  PARSONS, Williams ,  ZHANG, Xiaosong ,  LIN, Jimmy Cheng-Ho ,  LEARY, Rebecca ,  ANGENENDT, Philipp

IPC分类号： C12Q1/68

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： 我们在大多数II级和III级星形细胞瘤以及少突胶质细胞瘤以及从这些低级病变发展而来的胶质母细胞瘤中发现异柠檬酸脱氢酶1（IDH1）的R132残基突变。 没有IDH1突变的那些肿瘤通常在密切相关的IDH2基因的类似R172残基处具有突变。 这些发现对于恶性神经胶质瘤的发病机制和诊断具有重要意义。

公开(公告)号：EP2726869B1

公开(公告)日：2017-08-09

申请号：EP12804757.8

申请日：2012-06-28

申请人： Duke University ,  The Johns Hopkins University

发明人： YAN, Hai ,  BIGNER, Darell ,  VOGELSTEIN, Bert ,  KINZLER, Kenneth W. ,  MEEKER, Alan ,  HRUBAN, Ralph ,  PAPADAPOULOS, Nickolas ,  DIAZ, Luis ,  JIAO, Yuchen

IPC分类号： G01N33/53 ,  C12Q1/68 ,  A61K39/00 ,  A61K31/7105

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： 我们在来自不同地点的447种癌症中确定了ATRX和DAXX的序列。 我们发现小儿胶质母细胞瘤多形性（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％）中最常见突变; 并表明端粒替代延长（ALT）是一种端粒酶非依赖性端粒维持机制，在未激活端粒酶的癌症中发现，与任一基因的体细胞突变完全相关。 相反，神经母细胞瘤和卵巢癌，乳腺癌和胰腺腺癌的ATRX和DAXX突变均为阴性。 ATRX或DAXX的改变定义了与人类癌症中替代的端粒维持功能密切相关的特定分子途径。

公开(公告)号：EP2734644B1

公开(公告)日：2016-12-21

申请号：EP12814956.4

申请日：2012-07-18

申请人： The Johns Hopkins University ,  Duke University

发明人： VOGELSTEIN, Bert ,  KINZLER, Kenneth W. ,  BETTEGOWDA, Chetan ,  AGRAWAL, Nishant ,  PAPADOPOULOS, Nickolas ,  BIGNER, Darell ,  YAN, Hai ,  MCLENDON, Roger

IPC分类号： C12Q1/68 ,  A61K39/00

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： 少突胶质瘤是成人中第二常见的恶性脑肿瘤。 这些肿瘤通常含有染色体异常，涉及染色体1和染色体1的周期性融合，导致前者的整个短臂和后者的长臂的损失。 为了鉴定这一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）在两个体系中被体细胞突变 的七例。 另外27例少突胶质细胞瘤的检查显示，分别有12例和3例具有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：EP2734644A2

公开(公告)日：2014-05-28

申请号：EP12814956.4

申请日：2012-07-18

申请人： The Johns Hopkins University ,  Duke University

发明人： VOGELSTEIN, Bert ,  KINZLER, Kenneth W. ,  BETTEGOWDA, Chetan ,  AGRAWAL, Nishant ,  BIGNER, Darell ,  YAN, Hai ,  MCLENDON, Roger , 

IPC分类号： C12Q1/68 ,  C12N15/11

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：EP2726869A2

公开(公告)日：2014-05-07

申请号：EP12804757.8

申请日：2012-06-28

申请人： Duke University ,  The Johns Hopkins University

发明人： YAN, Hai ,  BIGNER, Darell ,  VOGELSTEIN, Bert ,  KINZLER, Kenneth W. ,  MEEKER, Alan ,  HRUBAN, Ralph ,  PAPADAPOULOS, Nickolas ,  DIAZ, Luis ,  JIAO, Yuchen

IPC分类号： G01N33/53 ,  C12Q1/68 ,  A61K39/00 ,  A61K31/7105

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成釉细胞瘤（GBM）（11.1％），成人GBM（6.5％），少突神经胶质瘤（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，ATRX和DAXX中的突变，母细胞瘤和卵巢癌，乳腺癌和胰腺癌的腺癌阴性。 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：EP0491007B1

公开(公告)日：1996-03-13

申请号：EP90915375.1

申请日：1990-08-15

申请人： THE JOHNS HOPKINS UNIVERSITY ,  DUKE UNIVERSITY

发明人： VOGELSTEIN, Bert ,  BIGNER, Darell

IPC分类号： C07K14/71 ,  C12N15/12 ,  C12Q1/68 ,  C12P21/08 ,  G01N33/53 ,  A61K39/395

CPC分类号： C07K14/71 ,  A61K38/00 ,  A61K47/6849 ,  A61K51/103 ,  A61K2123/00 ,  C07K16/2863 ,  C07K2317/34 ,  C12Q1/6886 ,  C12Q2600/156 ,  Y10S435/96 ,  Y10S436/804 ,  Y10S436/813 ,  Y10S530/81 ,  Y10S530/812

摘要： The epidermal growth factor receptor (EGFR) gene is amplified in 40 % of malignant gliomas and the amplified genes are frequently rearranged. The genetic alterations associated with these rearrangements are characterized in five malignant gliomas. In one tumor, the rearrangement resulted in the deletion of most of the extracytoplasmic domain of the receptor, resulting in a hybrid mRNA between new sequences and the truncated EGFR. The predicted amino acid sequence of the protein from this tumor was remarkably similar to that described for several viral erb-B oncogenes. Four other tumors were noted to have internal deletions of the EGF receptor gene. These rearrangements brought about in-frame deletions affecting either of two cysteine-rich domains in the extracytoplasmic portion of the molecule. The clonal nature of these alterations, and the fact that identical alterations were seen in more than one tumor, suggests a role for these mutant receptor proteins in tumorigenesis. Furthermore, these studies document the existence of tumor specific cell molecules resulting from somatic mutation.

公开(公告)号：EP0491007A1

公开(公告)日：1992-06-24

申请号：EP90915375.0

申请日：1990-08-15

申请人： THE JOHNS HOPKINS UNIVERSITY ,  DUKE UNIVERSITY

发明人： VOGELSTEIN, Bert ,  BIGNER, Darell

IPC分类号： A61K39 ,  A61K45 ,  A61K47 ,  A61K49 ,  A61K51 ,  A61P35 ,  C07K7 ,  C07K14 ,  C07K16 ,  C12N1 ,  C12N5 ,  C12N15 ,  C12P21 ,  C12Q1 ,  G01N33 ,  A61K38

CPC分类号： C07K14/71 ,  A61K38/00 ,  A61K47/6849 ,  A61K51/103 ,  A61K2123/00 ,  C07K16/2863 ,  C07K2317/34 ,  C12Q1/6886 ,  C12Q2600/156 ,  Y10S435/96 ,  Y10S436/804 ,  Y10S436/813 ,  Y10S530/81 ,  Y10S530/812

摘要： Le gène récepteur du facteur de croissance épidermique (RFCE) est renforcé de 40 % chez les gliômes malins et les gènes renforcés sont fréquemment réarrangés. Les modifications génétiques associées à ces réarrangements se caractérisent par cinq gliômes malins. Dans une tumeur, le réarrangement a eu pour résultat la délétion de la majorité du domaine extracytoplasmique du récepteur, donnant un ARNm hybride situé entre de nouvelles séquences et le RFCE tronqué. La séquence prédite d'acides aminés de la protéine provenant de cette tumeur était étonnamment similaire à celle décrite pour plusieurs encogènes erb-B viraux. Quatre autres tumeurs ont été repérées pour avoir des délétions internes du gène récepteur FCE. Ces réarrangements entraînent des délétions réalisées dans le cadre de lecture affectant l'un ou l'autre des deux domaines riches en cystéine de la partie extracytoplasmique de la molécule. La nature clonale de ces modifications et le fait que des modifications identiques ont été repérées dans plus d'une autre tumeur, font penser que ces protéines mutantes du récepteur jouent un rôle dans la génèse de la tumeur. De plus, ces études rendent compte de l'existence de molécules de cellules spécifiques à la tumeur, résultant de la mutation somatique.