Patents by Inventor Kenneth W. Kinzler

Kenneth W. Kinzler has filed for patents to protect the following inventions. This listing includes patent applications that are pending as well as patents that have already been granted by the United States Patent and Trademark Office (USPTO).

  • Patent number: 8859206
    Abstract: The identification of pre-defined mutations expected to be present in a minor fraction of a cell population is important for a variety of basic research and clinical applications. The exponential, analog nature of the polymerase chain reaction is transformed into a linear, digital signal suitable for this purpose. Single molecules can be isolated by dilution and individually amplified; each product is then separately analyzed for the presence of pre-defined mutations. The process provides a reliable and quantitative measure of the proportion of variant sequences within a DNA sample.
    Type: Grant
    Filed: March 24, 2011
    Date of Patent: October 14, 2014
    Assignee: The Johns Hopkins University
    Inventors: Bert Vogelstein, Kenneth W. Kinzler
  • Publication number: 20140227705
    Abstract: The identification of mutations that are present in a small fraction of DNA templates is essential for progress in several areas of biomedical research. Though massively parallel sequencing instruments are in principle well-suited to this task, the error rates in such instruments are generally too high to allow confident identification of rare variants. We here describe an approach that can substantially increase the sensitivity of massively parallel sequencing instruments for this purpose. One example of this approach, called “Safe-SeqS” for (Safe-Sequencing System) includes (i) assignment of a unique identifier (UID) to each template molecule; (ii) amplification of each uniquely tagged template molecule to create UID-families; and (iii) redundant sequencing of the amplification products. PCR fragments with the same UID are truly mutant (“super-mutants”) if ?95% of them contain the identical mutation.
    Type: Application
    Filed: April 12, 2012
    Publication date: August 14, 2014
    Applicant: THE JOHNS HOPKINS UNIVERSITY
    Inventors: Bert Vogelstein, Kenneth W. Kinzler, Nickolas Papadopoulos, Isaac Kinde
  • Publication number: 20140227271
    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.
    Type: Application
    Filed: June 28, 2012
    Publication date: August 14, 2014
    Applicants: DUKE UNIVERSITY, THE JOHNS HOPKINS UNIVERSITY
    Inventors: Hai Yan, Darell Bigner, Bert Vogelstein, Kenneth W. Kinzler, Alan Meeker, Ralph Hruban, Nickolas Papadopoulos, Luis Diaz, Yuchen Jiao
  • Publication number: 20140221219
    Abstract: 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.
    Type: Application
    Filed: July 18, 2012
    Publication date: August 7, 2014
    Applicants: DUKE UNIVERSITY, THE JOHNS HOPKINS UNIVERSITY
    Inventors: Bert Vogelstein, Kenneth W. Kinzler, Chetan Bettegowda, Nishant Agrawal, Nickolas Papadopoulos, Darell Bigner, Hai Yan, Roger Mclendon
  • Publication number: 20140187764
    Abstract: 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.
    Type: Application
    Filed: December 11, 2013
    Publication date: July 3, 2014
    Applicants: Duke University, The Johns Hopkins University
    Inventors: 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
  • Publication number: 20140179538
    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.
    Type: Application
    Filed: June 22, 2012
    Publication date: June 26, 2014
    Applicant: THE JOHNS HOPKINS UNIVERSITY
    Inventors: Bert Vogelstein, Kenneth W. Kinzler, Jian Wu, Luis Diaz, Nickolas Papadopoulos, Hanno Matthaei, Ralph Hruban, Anirban Maitra
  • Publication number: 20140155275
    Abstract: Assays for detecting mutant sequences at particular locations, especially against a background of non-mutant sequences, employ thermocycling ligase reactions. Differentially labeled or sized probes can be used to distinguish wild-type and mutant sequences. Physico-chemical properties of the probes can be critical to successful detection. Mutation detection can be used for diagnosis, monitoring, or prognosticating diseases such as cancers.
    Type: Application
    Filed: July 6, 2012
    Publication date: June 5, 2014
    Applicant: THE JOHNS HOPKINS UNIVERSITY
    Inventors: Bert Vogelstein, Kenneth W. Kinzler
  • Publication number: 20140154683
    Abstract: 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.
    Type: Application
    Filed: June 28, 2012
    Publication date: June 5, 2014
    Applicant: The Johns Hopkins University
    Inventors: Bert Vogelstein, Kenneth W. Kinzler, Nickolas Papadopoulos, Jian WU
  • Patent number: 8741573
    Abstract: Analysis of 13,023 genes in 11 breast and 11 colorectal cancers revealed that individual tumors accumulate an average of ˜90 mutant genes but that only a subset of these contribute to the neoplastic process. Using stringent criteria to delineate this subset, we identified 189 genes (average of 11 per tumor) that were mutated at significant frequency. The vast majority of these genes were not known to be genetically altered in tumors and are predicted to affect a wide range of cellular functions, including transcription, adhesion, and invasion. These data define the genetic landscape of two human cancer types, provide new targets for diagnostic and therapeutic intervention and monitoring.
    Type: Grant
    Filed: August 13, 2007
    Date of Patent: June 3, 2014
    Assignee: The Johns Hopkins University
    Inventors: Tobias Sjoblom, Sian Jones, D. Williams Parsons, Laura D. Wood, Jimmy Lin, Thomas Barber, Diana Mandelker, Bert Vogelstein, Kenneth W. Kinzler, Victor E. Velculesu
  • Patent number: 8715934
    Abstract: Modulation of the viscosity of the oil phase of a microemulsion used for amplification of DNA on a bead increases the homogeneity of product beads and the amount of amplified DNA per bead. Moreover the number of separate microemulsion populations that can be formed in parallel is increased using multi-well plates and mixer mill disruptor machines designed to lyse biological samples.
    Type: Grant
    Filed: June 19, 2007
    Date of Patent: May 6, 2014
    Assignee: The Johns Hopkins University
    Inventors: Frank Diehl, Kenneth W. Kinzler, Bert Vogelstein
  • Patent number: 8709723
    Abstract: Genome-wide analysis of copy number changes in breast and colorectal tumors used approaches that can reliably detect homozygous deletions and amplifications. The number of genes altered by major copy number changes—deletion of all copies or amplification of at least twelve copies per cell—averaged thirteen per tumor. These data were integrated with previous mutation analysis of the Reference Sequence genes in these same tumor types to identify genes and cellular pathways affected by both copy number changes and point alterations. Pathways enriched for genetic alterations include those controlling cell adhesion, intracellular signaling, DNA topological change, and cell cycle control. These analysis provide an integrated view of copy number and sequencing alterations on a genome-wide scale and identify genes and pathways that are useful for cancer diagnosis and therapy.
    Type: Grant
    Filed: May 1, 2012
    Date of Patent: April 29, 2014
    Assignee: The Johns Hopkins University
    Inventors: Bert Vogelstein, Kenneth W. Kinzler, Rebecca J. Leary, Victor E. Velculescu
  • Publication number: 20140113954
    Abstract: MicroRNAs (miR-NAs) are a class of small noncoding RNAs that have important regulatory roles in multicellular organisms. The public miRNA database contains 321 human miRNA sequences, 234 of which have been experimentally verified. To explore the possibility that additional miRNAs are present in the human genome, we have developed an experimental approach called miRNA serial analysis of gene expression (miRAGE) and used it to perform the largest experimental analysis of human miRNAs to date. Sequence analysis of 273,966 small RNA tags from human colorectal cells allowed us to identify 200 known mature miRNAs, 133 novel miRNA candidates, and 112 previously uncharacterized miRNA* forms. To aid in the evaluation of candidate miRNAs, we disrupted the Dicer locus in three human colorectal cancer cell lines and examined known and novel miRNAs in these cells. The miRNAs are useful to diagnose and treat cancers.
    Type: Application
    Filed: November 19, 2013
    Publication date: April 24, 2014
    Applicant: The Johns Hopkins University
    Inventors: Jordan CUMMINS, Victor VELCULESCU, Kenneth W. KINZLER, Bert VOGELSTEIN
  • Patent number: 8685660
    Abstract: 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.
    Type: Grant
    Filed: September 3, 2009
    Date of Patent: April 1, 2014
    Assignees: The Johns Hopkins University, Duke University
    Inventors: 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
  • Patent number: 8669062
    Abstract: Genetic diseases can be diagnosed by detection of mutations in causative genes. Protein truncation assays can be used to detect gene products of truncation-type mutations. However, the sensitivity of the assays is often insufficient to detect mutations present in a sample of DNA at a low frequency. Sensitivity can be increased by dividing samples so that the signal generated by a mutant allele comprises a larger fraction of the total alleles than prior to dividing. Thus a previously undetectable signal generated by the mutant allele can become detectable in the assay. Such increased sensitivity permits detection at early stages and in samples having high levels of other alleles.
    Type: Grant
    Filed: March 16, 2011
    Date of Patent: March 11, 2014
    Assignee: The Johns Hopkins University
    Inventors: C. Giovanni Traverso, Kenneth W. Kinzler, Bert Vogelstein
  • Publication number: 20140051105
    Abstract: Altered protein products resulting from somatic mutations are directly identified and quantified by mass spectrometry. The peptides expressed from normal and mutant alleles are detected by Selected Reaction Monitoring (SRM) of their productions using a triple quadrupole mass spectrometer. As a prototypical example of this approach, we quantify the number and fraction of mutant Ras protein present in cancer cell lines. There were an average of 1.3 million molecules of Ras protein per cell and the ratio of mutant to normal Ras proteins ranged from 0.49 to 5.6. Similarly, we detected and quantified mutant Ras proteins in clinical specimens such as colorectal and pancreatic tumor tissues as well as in pre-malignant pancreatic cyst fluids. These methods are useful for diagnostic applications.
    Type: Application
    Filed: January 17, 2012
    Publication date: February 20, 2014
    Applicant: THE JOHNS HOPKINS UNIVERSITY
    Inventors: Bert Vogelstein, Qing Wang, Akhilesh Pandey, Kenneth W. Kinzler, Nickolas Papadopoulos
  • Publication number: 20140045881
    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.
    Type: Application
    Filed: January 4, 2012
    Publication date: February 13, 2014
    Applicant: The Johns Hopkins University
    Inventors: Bert Vogelstein, Kenneth W. Kinzler, Victor Velculescu, Luis Diaz, Nikolas Papadopoulos, Yuchen Jiao, Ralph Hruban
  • Patent number: 8613917
    Abstract: 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.
    Type: Grant
    Filed: August 5, 2011
    Date of Patent: December 24, 2013
    Assignee: The Johns Hopkins University
    Inventors: Long Dang, Chetan Bettegowda, Kenneth W. Kinzler, Bert Vogelstein
  • Publication number: 20130315986
    Abstract: Clostridium novyi is an obligate anaerobe that can infect hypoxic regions within experimental tumors. We found that mice bearing large, established tumors were often cured when treated with C. novyi plus a single dose of liposomal doxorubicin. The secreted factor responsible for this phenomenon was identified and, surprisingly, proved to be a member of the lipase family. The gene encoding this protein, called liposomase, has the potential to be incorporated into diverse therapeutic methods to deliver specifically a variety of chemotherapeutic agents to tumors.
    Type: Application
    Filed: August 9, 2013
    Publication date: November 28, 2013
    Applicant: Johns Hopkins University
    Inventors: Ian CHEONG, Shibin ZHOU, Kenneth W. KINZLER, Bert VOGELSTEIN
  • Patent number: 8586725
    Abstract: MicroRNAs (miRNAs) are a class of small noncoding RNAs that have important regulatory roles in multicellular organisms. The public miRNA database contains 321 human miRNA sequences, 234 of which have been experimentally verified. To explore the possibility that additional miRNAs are present in the human genome, we have developed an experimental approach called miRNA serial analysis of gene expression (miRAGE) and used it to perform the largest experimental analysis of human miRNAs to date. Sequence analysis of 273,966 small RNA tags from human colorectal cells allowed us to identify 200 known mature miRNAs, 133 novel miRNA candidates, and 112 previously uncharacterized miRNA* forms. To aid in the evaluation of candidate miRNAs, we disrupted the Dicer locus in three human colorectal cancer cell lines and examined known and novel miRNAs in these cells. The miRNAs are useful to diagnose and treat cancers.
    Type: Grant
    Filed: February 16, 2007
    Date of Patent: November 19, 2013
    Assignee: The Johns Hopkins University
    Inventors: Jordan Cummins, Victor Velculescu, Kenneth W. Kinzler, Bert Vogelstein
  • Patent number: 8568708
    Abstract: Clostridium novyi is an obligate anaerobe that can infect hypoxic regions within experimental tumors. We found that mice bearing large, established tumors were often cured when treated with C. novyi plus a single dose of liposomal doxorubicin. The secreted factor responsible for this phenomenon was identified and, surprisingly, proved to be a member of the lipase family. The gene encoding this protein, called liposomase, has the potential to be incorporated into diverse therapeutic methods to deliver specifically a variety of chemotherapeutic agents to tumors.
    Type: Grant
    Filed: December 3, 2012
    Date of Patent: October 29, 2013
    Assignee: The John Hopkins University
    Inventors: Ian Cheong, Shibin Zhou, Kenneth W. Kinzler, Bert Vogelstein