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21. 发明申请

WO2016209703A1 HEAD AND NECK SQUAMOUS CELL CARCINOMA ASSAYS 审中-公开
公开(公告)号：WO2016209703A1
公开(公告)日：2016-12-29
申请号：PCT/US2016/037793
申请日：2016-06-16
申请人： THE JOHNS HOPKINS UNIVERSITY
发明人： VOGELSTEIN, Bert , KINZLER, Kenneth W. , DIAZ, Luis , PAPADOPOULOS, Nickolas , AGRAWAL, Nishant , WANG, Yuxuan , SPRINGER, Simeon
IPC分类号： C12Q1/68
CPC分类号： C12Q1/6886 , C12Q2600/112 , C12Q2600/118 , C12Q2600/156 , C12Q2600/158
摘要： We queried DNA from saliva or plasma of 93 HNSCC patients, searching for somatic mutations or human papillomavirus genes, collectively referred to as tumor DNA. When both plasma and saliva were tested, tumor DNA was detected in 96% (95% CI, 84% to 99%) of 47 patients. The fractions of patients with detectable tumor DNA in early- and late-stage disease were 100% (n=10) and 95% (n=37), respectively. Saliva is preferentially enriched for tumor DNA from the oral cavity, whereas plasma is preferentially enriched for tumor DNA from the other sites. Tumor DNA in the saliva and plasma is a valuable biomarker for detection of HNSCC.
摘要翻译：我们从93名HNSCC患者的唾液或血浆中查询DNA，寻找体细胞突变或人乳头瘤病毒基因，统称为肿瘤DNA。当测试血浆和唾液时，检测到47例患者的96％（95％CI，84％至99％）的肿瘤DNA。早期和晚期疾病中可检测肿瘤DNA的患者分数分别为100％（n = 10）和95％（n = 37）。唾液优先从口腔富集肿瘤DNA，而血浆优先从其他部位富集肿瘤DNA。唾液和血浆中的肿瘤DNA是检测HNSCC的有价值的生物标志物。

22. 发明申请

WO2016154246A1 HLA-RESTRICTED EPITOPES ENCODED BY SOMATICALLY MUTATED GENES 审中-公开
标题翻译： HLA受限制的外周血单核细胞由人造血清基因编码
公开(公告)号：WO2016154246A1
公开(公告)日：2016-09-29
申请号：PCT/US2016/023673
申请日：2016-03-23
申请人： THE JOHNS HOPKINS UNIVERSITY
发明人： VOGELSTEIN, Bert , KINZLER, Kenneth W. , ZHOU, Shibin , DIAZ, Luis , PAPADOPOULOS, Nickolas , SKORA, Andrew , DOUGLASS, Jackie , HWANG, Michael S.
IPC分类号： C07K16/28 , C07K16/32 , C07K14/74 , C07K19/00 , G01N33/532 , A61K47/48 , C40B30/04
CPC分类号： C07K16/2833 , C07K7/00 , C07K14/47 , C07K14/4746 , C07K14/71 , C07K14/82 , C07K16/005 , C07K16/18 , C07K16/2863 , C07K16/32 , C07K16/40 , C07K19/00 , C07K2317/24 , C07K2317/32 , C07K2317/34 , C07K2317/55 , C07K2317/56 , C07K2317/565 , C07K2317/622 , C07K2317/734 , C07K2317/92 , C07K2319/00 , C07K2319/03 , C07K2319/41 , C07K2319/50 , G01N33/574 , G01N33/6854 , G01N2333/7051 , G01N2333/70539
摘要： Mutant epitopes encoded by cancer genes are virtually always located in the interior of cells, making them invisible to conventional antibodies. We generated single chain variable fragments (scFvs) specific for mutant peptides presented on the cell surface by human leukocyte antigen (HLA) molecules. These scFvs can be converted to full-length antibodies, termed MANAbodies, targeting "Mutation Associated Neo-Antigens" bound to HLA. A phage display library representing a highly diverse array of single-chain variable fragment sequences was first designed and constructed. A competitive selection protocol was then used to identify clones specific for peptides bound to pre-defined HLA types. In this way, we obtained scFvs, including one specific for a peptide encoded by a common KRAS mutant and another by a common EGFR mutant. Molecules targeting MANA can be developed that specifically react with mutant peptide-HLA complexes even when these peptides differ by only one amino acid from the normal, wild-type form.
摘要翻译：由癌基因编码的突变表位实际上总是位于细胞内部，使得它们对常规抗体不可见。我们产生了特异于人白细胞抗原（HLA）分子在细胞表面上呈现的突变肽的单链可变片段（scFv）。这些scFv可以转化为与HLA结合的靶向“突变相关新抗原”的全长抗体，称为MANA体。首先设计并构建了代表高度多样化的单链可变片段序列阵列的噬菌体展示文库。然后使用竞争性选择方案来鉴定与预定义HLA类型结合的肽特异性的克隆。以这种方式，我们获得了scFv，包括一个特定于由普通KRAS突变体编码的肽，另一个由常见EGFR突变体编码的肽。可以开发靶向MANA的分子，其特异性与突变型肽-HLA复合物反应，即使这些肽仅与正常野生型形式仅一个氨基酸不同。

23. 发明申请

WO2014127359A1 TERT PROMOTER MUTATIONS IN GLIOMAS AND A SUBSET OF TUMORS 审中-公开
标题翻译：睾丸激素在GLIOMAS和肿瘤的一个SUBSET
公开(公告)号：WO2014127359A1
公开(公告)日：2014-08-21
申请号：PCT/US2014/016906
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： C12Q1/68 , C12N15/12
CPC分类号： C12Q1/6886 , C12Q2600/112 , C12Q2600/156
摘要： We surveyed 1,230 tumors of 60 different types and found that tumors could be divided into types with low ( TERT promoter mutations. The nine TERT-high tumor types almost always originated in tissues with relatively low rates of self renewal, including melanomas, liposarcomas, hepatocellular carcinomas, urothelial carcinomas, squamous cell carcinomas of the tongue, medulloblastomas, and subtypes of gliomas (including 83% of primary glioblastoma, the most common brain tumor type). TERT and ATRX mutations were mutually exclusive, suggesting that these two genetic mechanisms confer equivalent selective growth advantages. In addition to their implications for understanding the relationship between telomeres and tumorigenesis, TERT mutations provide a biomarker for the early detection of urinary tract and liver tumors and aid in the classification and prognostication of brain tumors.
摘要翻译：我们对60种不同类型的1,230例肿瘤进行了调查，发现肿瘤可分为低（15％）和高（≥15％）TERT启动子突变频率的类型。九种TERT高肿瘤类型几乎始终起源于自我更新率较低的组织，包括黑素瘤，脂肪肉瘤，肝细胞癌，尿路上皮癌，舌鳞状细胞癌，成神经管细胞瘤和神经胶质瘤亚型（包括83％的原发性胶质母细胞瘤，最常见的脑瘤型）。 TERT和ATRX突变是相互排斥的，表明这两种遗传机制赋予等效的选择性生长优势。除了它们对于了解端粒与肿瘤发生之间的关系的影响外，TERT突变提供了用于早期检测尿路和肝肿瘤的生物标志物，有助于脑肿瘤的分类和预后。

24. 发明申请

WO2013148496A1 RAPID ANEUPLOIDY DETECTION 审中-公开
标题翻译：快速异常检测
公开(公告)号：WO2013148496A1
公开(公告)日：2013-10-03
申请号：PCT/US2013/033451
申请日：2013-03-22
申请人： THE JOHNS HOPKINS UNIVERSITY
发明人： VOGELSTEIN, Bert , KINZLER, Kenneth W. , PAPADOPOULOS, Nickolas , KINDE, Isaac G.
IPC分类号： C12Q1/68 , C12N15/11 , G01N33/53 , G01N33/48
CPC分类号： C12Q1/6869 , C12Q1/6811 , C12Q1/6827 , C12Q1/6883 , C12Q2600/112 , C12Q2600/156 , C12Q2600/16 , C12Q2535/122 , C12Q2537/16 , C12Q2537/165 , C12Q2545/114
摘要： Massively parallel sequencing of cell-free, maternal plasma DNA was recently demonstrated to be a safe and effective screening method for fetal chromosomal aneuploidies. Here, we report an improved sequencing method achieving significantly increased throughput and decreased cost by replacing laborious sequencing library preparation steps with PCR employing a single primer pair. Using this approach, samples containing as little as 4% trisomy 21 DNA could be readily distinguished from euploid samples.
摘要翻译：最近证明无细胞母体血浆DNA的大规模平行测序是胎儿染色体非整倍体的安全有效的筛选方法。在这里，我们报告一种改进的测序方法，通过使用单引物对的PCR替代费力的测序文库制备步骤，实现显着增加的产量和降低成本。使用这种方法，含有少至4％21型21 DNA的样品可以容易地与整倍体样品区分开来。

25. 发明申请

WO2013074438A1 DIFFERENTIAL IDENTIFICATION OF PANCREATIC CYSTS 审中-公开
标题翻译：胰蛋白酶的差异鉴定
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
申请人： THE JOHNS HOPKINS UNIVERSITY
发明人： VOGELSTEIN, Bert , KINZLER, Kenneth W. , PAPADOPOULOS, Nickolas , WU, Jian , HRUBAN, Ralph , MAITRA, Anirban , DAL MOLIN, Marco
IPC分类号： C12Q1/68 , C12N15/11
CPC分类号： C12Q1/6886 , C12Q1/6883 , C12Q2600/156
摘要： 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.
摘要翻译：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。

26. 发明申请

WO2013012927A2 OLIGODENDROGLIOMA DRIVER GENES 审中-公开
标题翻译： OLIGODENDROGLIOMA驱动器基因
公开(公告)号：WO2013012927A2
公开(公告)日：2013-01-24
申请号：PCT/US2012/047211
申请日：2012-07-18
申请人： THE JOHNS HOPKINS UNIVERSITY , DUKE UNIVERSITY , VOGELSTEIN, Bert , KINZLER, Kenneth W. , BETTEGOWDA, Chetan , AGRAWAL, Nishant , PAPADOPOULOS, Nickolas , BIGNER, Darell , YAN, Hai , MCLENDON, Roger
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 , 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.
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。

27. 发明申请

WO2013003585A2 ENRICHMENT OF NUCLEIC ACIDS BY COMPLIMENTARY CAPTURE 审中-公开
标题翻译：通过缉拿获得核酸
公开(公告)号：WO2013003585A2
公开(公告)日：2013-01-03
申请号：PCT/US2012/044634
申请日：2012-06-28
申请人： THE JOHNS HOPKINS UNIVERSITY , VOGELSTEIN, Bert , KINZLER, Kenneth W. , PAPADOPOULOS, Nickolas , WU, Jian
发明人： VOGELSTEIN, Bert , KINZLER, Kenneth W. , PAPADOPOULOS, Nickolas , WU, Jian
CPC分类号： C12Q1/6806 , C12Q2535/122 , C12Q2563/131 , C12Q2563/149 , C12Q2565/518
摘要： Assays can be used to detect mutations found in neoplasms of the pancreas, as well as for other neoplasms and other uses. Nucleic acids can be captured from body fluids such as cyst fluids. Thousands of oligonucleotides can be synthesized in parallel, amplified and ligated together. The ligated products can be further amplified. The amplified, ligated products are used to capture complementary DNA sequences, which can be analyzed, for example by massively parallel sequencing.
摘要翻译：检测可用于检测胰腺肿瘤中发现的突变，以及其他肿瘤和其他用途。核酸可以从体液如囊液中捕获。数千个寡核苷酸可以并行合成，扩增并连接在一起。连接的产物可以进一步扩增。扩增的连接产物用于捕获互补DNA序列，其可以例如通过大规模并行测序来分析。

28. 发明申请

WO2011103236A2 PERSONALIZED TUMOR BIOMARKERS 审中-公开
标题翻译：个性化肿瘤生物标志物
公开(公告)号：WO2011103236A2
公开(公告)日：2011-08-25
申请号：PCT/US2011/025152
申请日：2011-02-17
申请人： THE JOHNS HOPKINS UNIVERSITY , VOGELSTEIN, Bert , KINZLER, Kenneth W. , VELCULESCU, Victor , DIAZ, Luis , LEARY, Rebecca J.
发明人： VOGELSTEIN, Bert , KINZLER, Kenneth W. , VELCULESCU, Victor , DIAZ, Luis , LEARY, Rebecca J.
IPC分类号： C12Q1/68 , C12N15/11 , C40B40/06
CPC分类号： C12Q1/6886 , C12Q2600/156
摘要： Clinical management of human cancer is dependent on the accurate monitoring of residual and recurrent tumors. We have developed a method, called personalized analysis of rearranged ends (PARE), which can identify translocations in solid tumors. Analysis of four colorectal and two breast cancers revealed an average of nine rearranged sequences (range 4 to 15) per tumor. Polymerase chain reaction with primers spanning the breakpoints were able to detect mutant DNA molecules present at levels lower than 0.001% and readily identified mutated circulating DNA in patient plasma samples. This approach provides an exquisitely sensitive and broadly applicable approach for the development of personalized biomarkers to enhance the clinical management of cancer patients.
摘要翻译：人类癌症的临床管理取决于对残留和复发性肿瘤的准确监测。我们开发了一种称为重排末端（PARE）的个性化分析方法，可以识别实体瘤易位。对4例结直肠癌和2例乳腺癌的分析显示，每个肿瘤平均有9个重排序列（范围4至15）。与跨越断点的引物的聚合酶链反应能够检测出低于0.001％的突变型DNA分子，并且容易鉴定出患者血浆样品中突变的循环DNA。这种方法为个性化生物标志物的开发提供了一种非常灵敏和广泛适用的方法，以加强癌症患者的临床管理。

29. 发明申请

WO2010014920A1 CIRCULATING MUTANT DNA TO ASSESS TUMOR DYNAMICS 审中-公开
标题翻译：循环突变DNA评估肿瘤动力学
公开(公告)号：WO2010014920A1
公开(公告)日：2010-02-04
申请号：PCT/US2009/052436
申请日：2009-07-31
申请人： THE JOHNS HOPKINS UNIVERSITY , DIEHL, Frank , DIAZ, Luis , KINZLER, Kenneth, W. , VOGELSTEIN, Bert , SCHMIDT, Kerstin
发明人： DIEHL, Frank , DIAZ, Luis , KINZLER, Kenneth, W. , VOGELSTEIN, Bert , SCHMIDT, Kerstin
IPC分类号： C12Q1/68
CPC分类号： C12Q1/6886 , C12Q2525/197 , C12Q2535/131 , C12Q2549/119 , C12Q2600/112 , C12Q2600/118 , C12Q2600/136
摘要： DNA containing somatic mutations is highly tumor specific and thus, in theory, can provide optimum markers. However, the number of circulating mutant gene fragments is small compared to the number of normal circulating DNA fragments, making it difficult to detect and quantify them with the sensitivity required for meaningful clinical use. We apply a highly sensitive approach to quantify circulating tumor DNA (ctDNA) in body samples of patients. Measurements of ctDNA can be used to reliably monitor tumor dynamics in subjects with cancer, especially those who are undergoing surgery or chemotherapy. This personalized genetic approach can be generally applied.
摘要翻译：含有体细胞突变的DNA具有高度的肿瘤特异性，因此在理论上可以提供最佳的标记。然而，循环突变基因片段的数量与正常循环DNA片段的数量相比较小，使得难以用有意义的临床使用所需的灵敏度来检测和量化它们。我们应用高度敏感的方法来量化患者身体样本中的循环肿瘤DNA（ctDNA）。 ctDNA的测量可用于可靠地监测癌症患者的肿瘤动态，特别是正在接受手术或化疗的患者。这种个性化的遗传方法一般可以应用。

30. 发明申请

WO2009049166A3 GENOMIC LANDSCAPES OF HUMAN BREAST AND COLORECTAL CANCERS 审中-公开
公开(公告)号：WO2009049166A3
公开(公告)日：2009-04-16
申请号：PCT/US2008/079526
申请日：2008-10-10
申请人： THE JOHNS HOPKINS UNIVERSITY , WOOD, Laura D. , PARSONS, D. Williams , JONES, Sian , LIN, Jimmy , SJÖBLOM, Tobias , BARBER, Thomas , PARMIGIANI, Giovanni , VELCULESCU, Victor , KINZLER, Kenneth W. , VOGELSTEIN, Bert
发明人： WOOD, Laura D. , PARSONS, D. Williams , JONES, Sian , LIN, Jimmy , SJÖBLOM, Tobias , BARBER, Thomas , PARMIGIANI, Giovanni , VELCULESCU, Victor , KINZLER, Kenneth W. , VOGELSTEIN, Bert
IPC分类号： G01N33/53
摘要： Human cancer is caused by the accumulation of mutations in oncogenes and tumor suppressor genes. To catalogue the genetic changes that occur during tumorigenesis, we isolated DNA from 11 breast and 11 colorectal tumors and determined the sequences of the genes in the Reference Sequence database in these samples. Based on analysis of exons representing 20,857 transcripts from 18,191 genes, we conclude that the genomic landscapes of breast and colorectal cancers are composed of a handful of commonly mutated gene 'mountains' and a much larger number of gene 'hills' that are mutated at low frequency. We describe statistical and bioinformatic tools that may help identify mutations with a role in tumorigenesis. These results have implications for understanding the nature and heterogeneity of human cancers and for using personal genomics for tumor diagnosis and therapy.

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