公开(公告)号：WO2013063519A1

公开(公告)日：2013-05-02

申请号：PCT/US2012/062295

申请日：2012-10-26

Applicant: ASURAGEN, INC. ,  JOHNS HOPKINS UNIVERSITY

Inventor： ADAI, Alex, T. ,  SZAFRANSKA-SCHWARZBACH, Anna, E. ,  ANDRUSS, Bernard, F. ,  MAITRA, Anirban ,  MATTHAEI, Hanno ,  WYLIE, Dennis ,  HRUBAN, Ralph

IPC: C12Q1/68

CPC classification number: C12Q1/6837 ,  C12Q1/6886 ,  C12Q2600/158 ,  C12Q2600/178 ,  G16H50/30

Abstract: Embodiments concern methods and compositions for evaluating a pancreatic cyst in a patient based on the expression levels of one or more miRNAs to determine whether the pancreatic cyst is a low or high risk lesion and in further need of treatment such as resection.

Abstract translation: 实施方案涉及基于一种或多种miRNA的表达水平来评估患者胰腺囊肿的方法和组合物，以确定胰腺囊肿是低风险或高风险病变，还需要进一步治疗如切除。

公开(公告)号：WO2013074438A1

公开(公告)日：2013-05-23

申请号：PCT/US2012/064629

申请日：2012-11-12

Applicant: THE JOHNS HOPKINS UNIVERSITY

Inventor： VOGELSTEIN, Bert ,  KINZLER, Kenneth W. ,  PAPADOPOULOS, Nickolas ,  WU, Jian ,  HRUBAN, Ralph ,  MAITRA, Anirban ,  DAL MOLIN, Marco

IPC: C12Q1/68 ,  C12N15/11

CPC classification number: C12Q1/6886 ,  C12Q1/6883 ,  C12Q2600/156

Abstract: More than 2% of adults harbor a pancreatic cyst, a subset of which progress to invasive lesions with lethal consequences. To assess the genomic landscapes of neoplastic cysts of the pancreas, we determined the exomic sequences of DNA from the neoplastic epithelium of eight surgically resected cysts of each of the major neoplastic cyst types: serous cystadenomas (SCAs), intraductal papillary mucinous neoplasms (IPMNs), mucinous cystic neoplasms (MCNs) and solid pseudo-papillary neoplasms (SPNs). SPNs are low-grade malignancies, and IPMNs and MCNs, but not SCAs, have the capacity to progress to cancer. We found that SCAs, IPMNs, MCNs, and SPNs contained 10 = 4.6, 27 = 12, 16 = 7.6, and 2.9 = 2.1 somatic mutations per tumor, respectively. Among the mutations identified, E3 ubiquitin ligase components were of particular note. Four of the eight SCAs contained mutations of VHL, a key component of the VHL ubiquitin ligase complex that has previously been assoCiated both with renal cell carcinomas, SCAs, and other neoplasms. Six of the eight IPMNs and three of the eight MCNs harbored mutations of RNF43, a gene coding for a protein with intrinsic E3 ubiquitin ligase activity that has not previously been found to be genetically altered in any human cancer. The preponderance of inactivating mutations in RNF43 unequivoCally establish it as a suppressor of both IPMNs and MCNs. SPNs contained remarkably few genetic alterations, but always contained mutations of CTNNB1, previously demonstrated to inhibit degradation of the encoded protein (ß-catenin) by E3 ubiquitin ligases. These results highlight the essential role of ubiquitin ligases in these neoplasms and have important implications for the diagnosis and treatment of patients with cystic tumors.

Abstract translation: 超过2％的成年人患有胰腺囊肿，其中一部分进展到具有致命后果的侵入性损伤。 为了评估胰腺肿瘤囊肿的基因组景观，我们确定了每个主要肿瘤性囊肿类型的八个手术切除的囊肿的肿瘤上皮的DNA的外显子序列：浆液性囊腺瘤（SCA），管内乳头状粘液性肿瘤（IPMN） ，粘液性囊性肿瘤（MCN）和固体假乳头状肿瘤（SPN）。 SPN是低度恶性肿瘤，IPMNs和MCNs而不是SCA具有进展为癌症的能力。 我们发现SCA，IPMNs，MCNs和SPN分别包含10 = 4.6,27 = 12,16 = 7.6和2.9 = 2.1肿瘤体细胞突变。 在确定的突变中，E3泛素连接酶组分特别值得注意。 八个SCA中的四个包含VHL的突变，VHL是VHL泛素连接酶复合物的关键组分，其先前与肾细胞癌，SCA和其他肿瘤相关。 八个IPMN中的六个和八个MCN中的三个携带RNF43的突变，RNF43是编码具有内在E3泛素连接酶活性的蛋白质的基因，其在以前没有发现在任何人类癌症中被遗传改变。 RNF43中失活突变的优势不平凡地将其建立为IPMNs和MCNs的抑制因子。 SPNs具有极少的遗传改变，但总是包含CTNNB1的突变，其先前证明可以通过E3泛素连接酶抑制编码的蛋白质（β-catenin）的降解。 这些结果突出了泛素连接酶在这些肿瘤中的重要作用，对囊性肿瘤患者的诊断和治疗具有重要意义。

公开(公告)号：WO2015041788A1

公开(公告)日：2015-03-26

申请号：PCT/US2014/051808

申请日：2014-08-20

Applicant: THE JOHNS HOPKINS UNIVERSITY

Inventor： VOGELSTEIN, Bert ,  KINZLER, Kenneth W. ,  DIAZ, Luis ,  PAPADOPOULOS, Nickolas ,  NETTO, George J. ,  HRUBAN, Ralph ,  KINDE, Isaac A.

IPC: C12Q1/68

CPC classification number: C12Q1/6886 ,  C12Q2600/156

Abstract: TERT promoter mutations occur in both papillary and flat lesion bladder cancers, are the most frequent genetic alterations identified to date in noninvasive precursor lesions of the bladder, are detectable in urine, and appear to be strongly associated with bladder cancer recurrence. The TERT promoter mutations are useful urinary biomarker for both the early detection and monitoring of bladder neoplasia.

Abstract translation: TERT启动子突变发生在乳头状和扁平病变膀胱癌中，是迄今为止在膀胱非侵入性前体病变中鉴定的最常见的遗传改变，在尿液中是可检测的，并且似乎与膀胱癌复发密切相关。 TERT启动子突变是膀胱肿瘤早期检测和监测的有用的尿生物标志物。

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。

公开(公告)号：WO2022272014A1

公开(公告)日：2022-12-29

申请号：PCT/US2022/034827

申请日：2022-06-24

Applicant: THE JOHNS HOPKINS UNIVERSITY

Inventor： KIEMEN, Ashley ,  WU, Pei-Hsun ,  WOOD, Laura D. ,  WIRTZ, Denis Gaston ,  HRUBAN, Ralph ,  SNEIDER, Alexandra ,  GU, Luo ,  HABIBI, Mehran ,  KIM, Joo Ho

IPC: G06T15/08 ,  G06T7/11 ,  G06T19/20

Abstract: This document generally describes methods and systems for generating digital reconstructions of tissue from humans or other species. The method can, for example, include receiving, at a computing system, image data of a tissue sample, where one or more sections of the tissue sample are stained with hematoxylin and eosin (H&E), registering the image data to generate registered image data, identifying tissue subtypes based on application of a machine learning model to the registered image data, annotating the identified tissue subtypes to generate annotated image data, and determining a digital volume of the tissue sample in three dimensional (3D) space based on the annotated image data. The disclosed technology can provide for single-cell analysis and other analysis of tissue samples, such as early detection of cancer in human tissue samples.

公开(公告)号：WO2004006837A3

公开(公告)日：2004-01-22

申请号：PCT/US2003/021643

申请日：2003-07-14

Applicant: THE JOHNS HOPKINS UNIVERSITY ,  JAFFEE, Elizabeth ,  WU, Tzyy-Choou ,  HUNG, Chien-Fu ,  HRUBAN, Ralph

Inventor： JAFFEE, Elizabeth ,  WU, Tzyy-Choou ,  HUNG, Chien-Fu ,  HRUBAN, Ralph

IPC: A01N63/00 ,  A01K67/00 ,  A01K67/027 ,  A01K67/033 ,  A61K35/12 ,  A61K38/00 ,  A61K39/00 ,  A61K39/38 ,  A61K39/385 ,  C07K5/00 ,  C07K7/00 ,  C07K16/00 ,  C07K17/00 ,  C12N1/20 ,  C12N5/00 ,  C12N5/02 ,  C12N5/06 ,  C12N5/08 ,  G01N33/00

Abstract: Mesothelin can be used as an immunotherapeutic target. It induces a cytolytic T cell response. Portions of mesothelin which induce such responses are identified. Vaccines can be either polynucleotide- or polypeptide-based. Carriers for raising a cytolytic T cell response include bacteria and viruses. A mouse model for testing vaccines and other anti-tumor therapeutics and prophylactics comprises a strongly mesothelin-expressing, transformed peritoneal cell line.

公开(公告)号：WO2013003583A2

公开(公告)日：2013-01-03

申请号：PCT/US2012/044631

申请日：2012-06-28

Applicant: DUKE UNIVERSITY ,  THE JOHNS HOPKINS UNIVERSITY ,  YAN, Hai ,  BIGNER, Darell ,  VOGELSTEIN, Bert ,  KINZLER, Kenneth W. ,  MEEKER, Alan ,  HRUBAN, Ralph ,  PAPADAPOULOS, Nickolas ,  DIAZ, Luis ,  JIAO, Yuchen

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

CPC classification number: C12Q1/6886 ,  C07K16/40 ,  C12N15/1137 ,  C12Q2600/118 ,  C12Q2600/156 ,  G01N33/57407

Abstract: 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.

Abstract translation: 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非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：WO2012178034A3

公开(公告)日：2012-12-27

申请号：PCT/US2012/043783

申请日：2012-06-22

Applicant: THE JOHNS HOPKINS UNIVERSITY ,  VOGELSTEIN, Bert ,  KINZLER, Kenneth W. ,  WU, Jian ,  DIAZ, Luis ,  PAPADOPOULOS, Nickolas ,  MATTHAEI, Hanno ,  HRUBAN, Ralph ,  MAITRA, Anirban

Inventor： VOGELSTEIN, Bert ,  KINZLER, Kenneth W. ,  WU, Jian ,  DIAZ, Luis ,  PAPADOPOULOS, Nickolas ,  MATTHAEI, Hanno ,  HRUBAN, Ralph ,  MAITRA, Anirban

IPC: C12Q1/68 ,  C12N15/11

Abstract: To help reveal the pathogenesis of these lesions, we purified the DNA from Intraductal Papillary Mucinous Neoplasm (IPMN) cyst fluids from 19 patients and searched for mutations in 169 genes commonly altered in human cancers. We identified recurrent mutations at codon 201 of GNAS. We found that GNAS mutations were present in 66% of IPMNs and that either KRAS or GNAS mutations could be identified in 96%. In eight cases, we could investigate invasive adenocarcinomas that developed in association with IPMNs containing GNAS mutations. In seven of these eight cases, the GNAS mutations present in the IPMNs were also found in the invasive lesion. GNAS mutations were not found in other types of cystic neoplasms of the pancreas or in invasive adenocarcinomas not associated with IPMNs. These data suggest that GNAS mutations can inform the diagnosis and management of patients with cystic pancreatic lesions.

公开(公告)号：WO2010102160A2

公开(公告)日：2010-09-10

申请号：PCT/US2010/026290

申请日：2010-03-05

Applicant: THE JOHNS HOPKINS UNIVERSITY ,  VOGELSTEIN, Bert ,  KINZLER, Kenneth W. ,  PARSONS, D. Williams ,  JONES, Sian ,  KERN, Scott ,  HRUBAN, Ralph ,  ESHLEMAN, James R. ,  GOGGINS, Michael ,  KLEIN, Alison ,  HIDALGO, Manuel ,  VELCULESCU, Victor E.

Inventor： VOGELSTEIN, Bert ,  KINZLER, Kenneth W. ,  PARSONS, D. Williams ,  JONES, Sian ,  KERN, Scott ,  HRUBAN, Ralph ,  ESHLEMAN, James R. ,  GOGGINS, Michael ,  KLEIN, Alison ,  HIDALGO, Manuel ,  VELCULESCU, Victor E.

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

CPC classification number: C12Q1/6886 ,  A61K31/407 ,  C12Q2600/106 ,  C12Q2600/156 ,  C12Q2600/158 ,  G01N33/57438 ,  G01N2333/47

Abstract: The present invention provides a method for detecting mutations in the PALB2 gene in pancreatic cancer patients and in individuals having a family history of pancreatic cancer. Methods are also provided for diagnosing a predisposition to pancreatic cancer, for predicting a patient's response to pancreatic cancer therapies, and for treating pancreatic cancer, based on presence of a PALB2 mutation or abberant PALB2 gene expression in a patient.

Abstract translation: 本发明提供了一种检测胰腺癌患者和具有胰腺癌家族史的个体中PALB2基因突变的方法。 还提供了用于诊断患有胰腺癌的倾向，用于预测患者对胰腺癌治疗的反应以及用于治疗患者胰腺癌的方法，其基于在患者体内PALB2突变或异常PALB2基因表达的存在。

公开(公告)号：WO2010028098A2

公开(公告)日：2010-03-11

申请号：PCT/US2009/055802

申请日：2009-09-03

Applicant: THE JOHNS HOPKINS UNIVERSITY ,  VOGELSTEIN, Bert ,  KINZLER, Kenneth, W. ,  PARSONS, D., Williams ,  JONES, Sian ,  ZHANG, Xiaosong ,  LIN, Jimmy Chang-Ho ,  LEARY, Rebecca J. ,  ANGENENDT, Philipp ,  PAPADOPOULOS, Nickolas ,  VELCULESCU, Victor ,  PARMIGIANI, Giovanni ,  KARCHIN, Rachel ,  KERN, Scott ,  HRUBAN, Ralph ,  ESHLEMAN, James R. ,  GOGGINS, Michael ,  KLEIN, Alison

Inventor： VOGELSTEIN, Bert ,  KINZLER, Kenneth, W. ,  PARSONS, D., Williams ,  JONES, Sian ,  ZHANG, Xiaosong ,  LIN, Jimmy Chang-Ho ,  LEARY, Rebecca J. ,  ANGENENDT, Philipp ,  PAPADOPOULOS, Nickolas ,  VELCULESCU, Victor ,  PARMIGIANI, Giovanni ,  KARCHIN, Rachel ,  KERN, Scott ,  HRUBAN, Ralph ,  ESHLEMAN, James R. ,  GOGGINS, Michael ,  KLEIN, Alison

IPC: C12Q1/68

CPC classification number: G01N33/57438 ,  C12Q1/6886 ,  C12Q2600/156 ,  G01N2800/50

Abstract: 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.

Abstract translation: 目前对胰腺癌患者几乎没有治疗方案，迫切需要对这种致死性疾病的发病机制的新见解。 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。 其次，我们使用微阵列查询了每个样本中一百万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。