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  • 1
    Publication Date: 2015-10-08
    Description: Activation of oncogenes by mechanisms other than genetic aberrations such as mutations, translocations, or amplifications is largely undefined. Here we report a novel isoform of the anaplastic lymphoma kinase (ALK) that is expressed in approximately 11% of melanomas and sporadically in other human cancer types, but not in normal tissues. The novel ALK transcript initiates from a de novo alternative transcription initiation (ATI) site in ALK intron 19, and was termed ALK(ATI). In ALK(ATI)-expressing tumours, the ATI site is enriched for H3K4me3 and RNA polymerase II, chromatin marks characteristic of active transcription initiation sites. ALK(ATI) is expressed from both ALK alleles, and no recurrent genetic aberrations are found at the ALK locus, indicating that the transcriptional activation is independent of genetic aberrations at the ALK locus. The ALK(ATI) transcript encodes three proteins with molecular weights of 61.1, 60.8 and 58.7 kilodaltons, consisting primarily of the intracellular tyrosine kinase domain. ALK(ATI) stimulates multiple oncogenic signalling pathways, drives growth-factor-independent cell proliferation in vitro, and promotes tumorigenesis in vivo in mouse models. ALK inhibitors can suppress the kinase activity of ALK(ATI), suggesting that patients with ALK(ATI)-expressing tumours may benefit from ALK inhibitors. Our findings suggest a novel mechanism of oncogene activation in cancer through de novo alternative transcription initiation.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Wiesner, Thomas -- Lee, William -- Obenauf, Anna C -- Ran, Leili -- Murali, Rajmohan -- Zhang, Qi Fan -- Wong, Elissa W P -- Hu, Wenhuo -- Scott, Sasinya N -- Shah, Ronak H -- Landa, Inigo -- Button, Julia -- Lailler, Nathalie -- Sboner, Andrea -- Gao, Dong -- Murphy, Devan A -- Cao, Zhen -- Shukla, Shipra -- Hollmann, Travis J -- Wang, Lu -- Borsu, Laetitia -- Merghoub, Taha -- Schwartz, Gary K -- Postow, Michael A -- Ariyan, Charlotte E -- Fagin, James A -- Zheng, Deyou -- Ladanyi, Marc -- Busam, Klaus J -- Berger, Michael F -- Chen, Yu -- Chi, Ping -- DP2 CA174499/CA/NCI NIH HHS/ -- DP2CA174499/CA/NCI NIH HHS/ -- K08 CA151660/CA/NCI NIH HHS/ -- K08CA140946/CA/NCI NIH HHS/ -- K08CA151660/CA/NCI NIH HHS/ -- P01 CA129243/CA/NCI NIH HHS/ -- P01CA12943/CA/NCI NIH HHS/ -- P30 CA008748/CA/NCI NIH HHS/ -- P50 CA172012/CA/NCI NIH HHS/ -- P50CA172012/CA/NCI NIH HHS/ -- England -- Nature. 2015 Oct 15;526(7573):453-7. doi: 10.1038/nature15258. Epub 2015 Oct 7.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York 10065, USA. ; Department of Dermatology, Medical University of Graz, 8010 Graz, Austria. ; Computational Biology Program, Memorial Sloan Kettering Cancer Center, New York 10065, USA. ; Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York 10065, USA. ; Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York 10065, USA. ; Department of Pathology, Memorial Sloan Kettering Cancer Center, New York 10065, USA. ; Marie-Josee and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York 10065, USA. ; Department of Pathology and Laboratory Medicine, Weill Cornell Medical College/New York Presbyterian Hospital, New York 10065, USA. ; Institute for Computational Biomedicine, Weill Cornell Medical College/New York Presbyterian Hospital, New York 10065, USA. ; Institute for Precision Medicine, Weill Cornell Medical College/New York Presbyterian Hospital, New York, USA. ; Immunology Program, Memorial Sloan Kettering Cancer Center 10065, New York, USA. ; Herbert Irving Comprehensive Cancer Center, Columbia University Cancer Center, New York 10032, USA. ; Department of Medicine, Memorial Sloan Kettering Cancer Center, New York 10065, USA. ; Department of Medicine, Weill Cornell Medical College, New York 10065, USA. ; Department of Surgery, Memorial Sloan Kettering Cancer Center, New York 10065, USA. ; Department of Neurology, Albert Einstein College of Medicine, New York 10461, USA. ; Department of Genetics, Albert Einstein College of Medicine, New York 10461, USA. ; Department of Neuroscience, Albert Einstein College of Medicine, New York 10461, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26444240" target="_blank"〉PubMed〈/a〉
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 2
    Publication Date: 2011-07-30
    Description: Head and neck squamous cell carcinoma (HNSCC) is a common, morbid, and frequently lethal malignancy. To uncover its mutational spectrum, we analyzed whole-exome sequencing data from 74 tumor-normal pairs. The majority exhibited a mutational profile consistent with tobacco exposure; human papillomavirus was detectable by sequencing DNA from infected tumors. In addition to identifying previously known HNSCC genes (TP53, CDKN2A, PTEN, PIK3CA, and HRAS), our analysis revealed many genes not previously implicated in this malignancy. At least 30% of cases harbored mutations in genes that regulate squamous differentiation (for example, NOTCH1, IRF6, and TP63), implicating its dysregulation as a major driver of HNSCC carcinogenesis. More generally, the results indicate the ability of large-scale sequencing to reveal fundamental tumorigenic mechanisms.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3415217/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3415217/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Stransky, Nicolas -- Egloff, Ann Marie -- Tward, Aaron D -- Kostic, Aleksandar D -- Cibulskis, Kristian -- Sivachenko, Andrey -- Kryukov, Gregory V -- Lawrence, Michael S -- Sougnez, Carrie -- McKenna, Aaron -- Shefler, Erica -- Ramos, Alex H -- Stojanov, Petar -- Carter, Scott L -- Voet, Douglas -- Cortes, Maria L -- Auclair, Daniel -- Berger, Michael F -- Saksena, Gordon -- Guiducci, Candace -- Onofrio, Robert C -- Parkin, Melissa -- Romkes, Marjorie -- Weissfeld, Joel L -- Seethala, Raja R -- Wang, Lin -- Rangel-Escareno, Claudia -- Fernandez-Lopez, Juan Carlos -- Hidalgo-Miranda, Alfredo -- Melendez-Zajgla, Jorge -- Winckler, Wendy -- Ardlie, Kristin -- Gabriel, Stacey B -- Meyerson, Matthew -- Lander, Eric S -- Getz, Gad -- Golub, Todd R -- Garraway, Levi A -- Grandis, Jennifer R -- P50 CA097190/CA/NCI NIH HHS/ -- R01 CA077308/CA/NCI NIH HHS/ -- R01 CA098372/CA/NCI NIH HHS/ -- UL1 TR000005/TR/NCATS NIH HHS/ -- Howard Hughes Medical Institute/ -- New York, N.Y. -- Science. 2011 Aug 26;333(6046):1157-60. doi: 10.1126/science.1208130. Epub 2011 Jul 28.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21798893" target="_blank"〉PubMed〈/a〉
    Keywords: Algorithms ; Apoptosis ; Carcinoma/*genetics/metabolism/virology ; Carcinoma, Squamous Cell ; Cell Differentiation ; Exons ; Head and Neck Neoplasms/*genetics/metabolism/virology ; Humans ; *Mutation ; Neoplasms, Squamous Cell/*genetics/metabolism/virology ; Papillomaviridae/isolation & purification ; Papillomavirus Infections/virology ; Point Mutation ; Receptor, Notch1/*genetics/metabolism ; *Sequence Analysis, DNA ; Sequence Deletion ; Signal Transduction ; Smoking ; Tobacco
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 3
    Publication Date: 2012-05-25
    Description: Melanoma is notable for its metastatic propensity, lethality in the advanced setting and association with ultraviolet exposure early in life. To obtain a comprehensive genomic view of melanoma in humans, we sequenced the genomes of 25 metastatic melanomas and matched germline DNA. A wide range of point mutation rates was observed: lowest in melanomas whose primaries arose on non-ultraviolet-exposed hairless skin of the extremities (3 and 14 per megabase (Mb) of genome), intermediate in those originating from hair-bearing skin of the trunk (5-55 per Mb), and highest in a patient with a documented history of chronic sun exposure (111 per Mb). Analysis of whole-genome sequence data identified PREX2 (phosphatidylinositol-3,4,5-trisphosphate-dependent Rac exchange factor 2)--a PTEN-interacting protein and negative regulator of PTEN in breast cancer--as a significantly mutated gene with a mutation frequency of approximately 14% in an independent extension cohort of 107 human melanomas. PREX2 mutations are biologically relevant, as ectopic expression of mutant PREX2 accelerated tumour formation of immortalized human melanocytes in vivo. Thus, whole-genome sequencing of human melanoma tumours revealed genomic evidence of ultraviolet pathogenesis and discovered a new recurrently mutated gene in melanoma.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3367798/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3367798/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Berger, Michael F -- Hodis, Eran -- Heffernan, Timothy P -- Deribe, Yonathan Lissanu -- Lawrence, Michael S -- Protopopov, Alexei -- Ivanova, Elena -- Watson, Ian R -- Nickerson, Elizabeth -- Ghosh, Papia -- Zhang, Hailei -- Zeid, Rhamy -- Ren, Xiaojia -- Cibulskis, Kristian -- Sivachenko, Andrey Y -- Wagle, Nikhil -- Sucker, Antje -- Sougnez, Carrie -- Onofrio, Robert -- Ambrogio, Lauren -- Auclair, Daniel -- Fennell, Timothy -- Carter, Scott L -- Drier, Yotam -- Stojanov, Petar -- Singer, Meredith A -- Voet, Douglas -- Jing, Rui -- Saksena, Gordon -- Barretina, Jordi -- Ramos, Alex H -- Pugh, Trevor J -- Stransky, Nicolas -- Parkin, Melissa -- Winckler, Wendy -- Mahan, Scott -- Ardlie, Kristin -- Baldwin, Jennifer -- Wargo, Jennifer -- Schadendorf, Dirk -- Meyerson, Matthew -- Gabriel, Stacey B -- Golub, Todd R -- Wagner, Stephan N -- Lander, Eric S -- Getz, Gad -- Chin, Lynda -- Garraway, Levi A -- DP2 OD002750/OD/NIH HHS/ -- DP2 OD002750-01/OD/NIH HHS/ -- R33 CA126674/CA/NCI NIH HHS/ -- R33 CA126674-03/CA/NCI NIH HHS/ -- R33 CA126674-04/CA/NCI NIH HHS/ -- R33 CA155554/CA/NCI NIH HHS/ -- R33 CA155554-01/CA/NCI NIH HHS/ -- T32 CA009172/CA/NCI NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2012 May 9;485(7399):502-6. doi: 10.1038/nature11071.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉The Broad Institute of Harvard and MIT, Cambridge, Massachusetts 02142, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22622578" target="_blank"〉PubMed〈/a〉
    Keywords: Chromosome Breakpoints/radiation effects ; DNA Damage ; DNA Mutational Analysis ; Gene Expression Regulation, Neoplastic ; Genome, Human/*genetics ; Guanine Nucleotide Exchange Factors/*genetics/metabolism ; Humans ; Melanocytes/metabolism/pathology ; Melanoma/*genetics/pathology ; Mutagenesis/radiation effects ; Mutation/*genetics/radiation effects ; Oncogenes/genetics ; Sunlight/*adverse effects ; Ultraviolet Rays/adverse effects
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 4
    Publication Date: 2011-02-11
    Description: Prostate cancer is the second most common cause of male cancer deaths in the United States. However, the full range of prostate cancer genomic alterations is incompletely characterized. Here we present the complete sequence of seven primary human prostate cancers and their paired normal counterparts. Several tumours contained complex chains of balanced (that is, 'copy-neutral') rearrangements that occurred within or adjacent to known cancer genes. Rearrangement breakpoints were enriched near open chromatin, androgen receptor and ERG DNA binding sites in the setting of the ETS gene fusion TMPRSS2-ERG, but inversely correlated with these regions in tumours lacking ETS fusions. This observation suggests a link between chromatin or transcriptional regulation and the genesis of genomic aberrations. Three tumours contained rearrangements that disrupted CADM2, and four harboured events disrupting either PTEN (unbalanced events), a prostate tumour suppressor, or MAGI2 (balanced events), a PTEN interacting protein not previously implicated in prostate tumorigenesis. Thus, genomic rearrangements may arise from transcriptional or chromatin aberrancies and engage prostate tumorigenic mechanisms.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3075885/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3075885/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Berger, Michael F -- Lawrence, Michael S -- Demichelis, Francesca -- Drier, Yotam -- Cibulskis, Kristian -- Sivachenko, Andrey Y -- Sboner, Andrea -- Esgueva, Raquel -- Pflueger, Dorothee -- Sougnez, Carrie -- Onofrio, Robert -- Carter, Scott L -- Park, Kyung -- Habegger, Lukas -- Ambrogio, Lauren -- Fennell, Timothy -- Parkin, Melissa -- Saksena, Gordon -- Voet, Douglas -- Ramos, Alex H -- Pugh, Trevor J -- Wilkinson, Jane -- Fisher, Sheila -- Winckler, Wendy -- Mahan, Scott -- Ardlie, Kristin -- Baldwin, Jennifer -- Simons, Jonathan W -- Kitabayashi, Naoki -- MacDonald, Theresa Y -- Kantoff, Philip W -- Chin, Lynda -- Gabriel, Stacey B -- Gerstein, Mark B -- Golub, Todd R -- Meyerson, Matthew -- Tewari, Ashutosh -- Lander, Eric S -- Getz, Gad -- Rubin, Mark A -- Garraway, Levi A -- 2 P50 CA090381-11/CA/NCI NIH HHS/ -- DP2 OD002750/OD/NIH HHS/ -- DP2 OD002750-01/OD/NIH HHS/ -- R33 CA126674/CA/NCI NIH HHS/ -- R33 CA126674-03/CA/NCI NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2011 Feb 10;470(7333):214-20. doi: 10.1038/nature09744.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉The Broad Institute of Harvard and MIT, Cambridge, Massachusetts 02142, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21307934" target="_blank"〉PubMed〈/a〉
    Keywords: Carrier Proteins/genetics ; Case-Control Studies ; Cell Adhesion Molecules/genetics ; Chromatin/genetics/metabolism ; Chromosome Aberrations ; Chromosome Breakpoints ; Epigenesis, Genetic/genetics ; Gene Expression Regulation, Neoplastic ; Genome, Human/*genetics ; Humans ; Male ; PTEN Phosphohydrolase/genetics/metabolism ; Prostatic Neoplasms/*genetics ; Recombination, Genetic/genetics ; Signal Transduction/genetics ; Transcription, Genetic
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 5
    Publication Date: 2012-03-31
    Description: The systematic translation of cancer genomic data into knowledge of tumour biology and therapeutic possibilities remains challenging. Such efforts should be greatly aided by robust preclinical model systems that reflect the genomic diversity of human cancers and for which detailed genetic and pharmacological annotation is available. Here we describe the Cancer Cell Line Encyclopedia (CCLE): a compilation of gene expression, chromosomal copy number and massively parallel sequencing data from 947 human cancer cell lines. When coupled with pharmacological profiles for 24 anticancer drugs across 479 of the cell lines, this collection allowed identification of genetic, lineage, and gene-expression-based predictors of drug sensitivity. In addition to known predictors, we found that plasma cell lineage correlated with sensitivity to IGF1 receptor inhibitors; AHR expression was associated with MEK inhibitor efficacy in NRAS-mutant lines; and SLFN11 expression predicted sensitivity to topoisomerase inhibitors. Together, our results indicate that large, annotated cell-line collections may help to enable preclinical stratification schemata for anticancer agents. The generation of genetic predictions of drug response in the preclinical setting and their incorporation into cancer clinical trial design could speed the emergence of 'personalized' therapeutic regimens.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3320027/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3320027/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Barretina, Jordi -- Caponigro, Giordano -- Stransky, Nicolas -- Venkatesan, Kavitha -- Margolin, Adam A -- Kim, Sungjoon -- Wilson, Christopher J -- Lehar, Joseph -- Kryukov, Gregory V -- Sonkin, Dmitriy -- Reddy, Anupama -- Liu, Manway -- Murray, Lauren -- Berger, Michael F -- Monahan, John E -- Morais, Paula -- Meltzer, Jodi -- Korejwa, Adam -- Jane-Valbuena, Judit -- Mapa, Felipa A -- Thibault, Joseph -- Bric-Furlong, Eva -- Raman, Pichai -- Shipway, Aaron -- Engels, Ingo H -- Cheng, Jill -- Yu, Guoying K -- Yu, Jianjun -- Aspesi, Peter Jr -- de Silva, Melanie -- Jagtap, Kalpana -- Jones, Michael D -- Wang, Li -- Hatton, Charles -- Palescandolo, Emanuele -- Gupta, Supriya -- Mahan, Scott -- Sougnez, Carrie -- Onofrio, Robert C -- Liefeld, Ted -- MacConaill, Laura -- Winckler, Wendy -- Reich, Michael -- Li, Nanxin -- Mesirov, Jill P -- Gabriel, Stacey B -- Getz, Gad -- Ardlie, Kristin -- Chan, Vivien -- Myer, Vic E -- Weber, Barbara L -- Porter, Jeff -- Warmuth, Markus -- Finan, Peter -- Harris, Jennifer L -- Meyerson, Matthew -- Golub, Todd R -- Morrissey, Michael P -- Sellers, William R -- Schlegel, Robert -- Garraway, Levi A -- DP2 OD002750/OD/NIH HHS/ -- DP2 OD002750-01/OD/NIH HHS/ -- R33 CA126674/CA/NCI NIH HHS/ -- R33 CA126674-04/CA/NCI NIH HHS/ -- R33 CA155554/CA/NCI NIH HHS/ -- R33 CA155554-02/CA/NCI NIH HHS/ -- England -- Nature. 2012 Mar 28;483(7391):603-7. doi: 10.1038/nature11003.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉The Broad Institute of Harvard and MIT, Cambridge, Massachusetts 02142, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22460905" target="_blank"〉PubMed〈/a〉
    Keywords: Antineoplastic Agents/pharmacology ; Cell Line, Tumor ; Cell Lineage ; Chromosomes, Human/genetics ; Clinical Trials as Topic/methods ; *Databases, Factual ; Drug Screening Assays, Antitumor/*methods ; *Encyclopedias as Topic ; Gene Expression Profiling ; Gene Expression Regulation, Neoplastic ; Genes, ras/genetics ; Genome, Human/genetics ; Genomics ; Humans ; Mitogen-Activated Protein Kinase Kinases/antagonists & inhibitors/metabolism ; *Models, Biological ; Neoplasms/*drug therapy/genetics/metabolism/*pathology ; Pharmacogenetics ; Plasma Cells/cytology/drug effects/metabolism ; Precision Medicine/methods ; Receptor, IGF Type 1/antagonists & inhibitors/metabolism ; Receptors, Aryl Hydrocarbon/genetics/metabolism ; Sequence Analysis, DNA ; Topoisomerase Inhibitors/pharmacology
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 6
    Publication Date: 2014-11-20
    Description: Broad and deep tumour genome sequencing has shed new light on tumour heterogeneity and provided important insights into the evolution of metastases arising from different clones. There is an additional layer of complexity, in that tumour evolution may be influenced by selective pressure provided by therapy, in a similar fashion to that occurring in infectious diseases. Here we studied tumour genomic evolution in a patient (index patient) with metastatic breast cancer bearing an activating PIK3CA (phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha, PI(3)Kalpha) mutation. The patient was treated with the PI(3)Kalpha inhibitor BYL719, which achieved a lasting clinical response, but the patient eventually became resistant to this drug (emergence of lung metastases) and died shortly thereafter. A rapid autopsy was performed and material from a total of 14 metastatic sites was collected and sequenced. All metastatic lesions, when compared to the pre-treatment tumour, had a copy loss of PTEN (phosphatase and tensin homolog) and those lesions that became refractory to BYL719 had additional and different PTEN genetic alterations, resulting in the loss of PTEN expression. To put these results in context, we examined six other patients also treated with BYL719. Acquired bi-allelic loss of PTEN was found in one of these patients, whereas in two others PIK3CA mutations present in the primary tumour were no longer detected at the time of progression. To characterize our findings functionally, we examined the effects of PTEN knockdown in several preclinical models (both in cell lines intrinsically sensitive to BYL719 and in PTEN-null xenografts derived from our index patient), which we found resulted in resistance to BYL719, whereas simultaneous PI(3)K p110beta blockade reverted this resistance phenotype. We conclude that parallel genetic evolution of separate metastatic sites with different PTEN genomic alterations leads to a convergent PTEN-null phenotype resistant to PI(3)Kalpha inhibition.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4326538/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4326538/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Juric, Dejan -- Castel, Pau -- Griffith, Malachi -- Griffith, Obi L -- Won, Helen H -- Ellis, Haley -- Ebbesen, Saya H -- Ainscough, Benjamin J -- Ramu, Avinash -- Iyer, Gopa -- Shah, Ronak H -- Huynh, Tiffany -- Mino-Kenudson, Mari -- Sgroi, Dennis -- Isakoff, Steven -- Thabet, Ashraf -- Elamine, Leila -- Solit, David B -- Lowe, Scott W -- Quadt, Cornelia -- Peters, Malte -- Derti, Adnan -- Schegel, Robert -- Huang, Alan -- Mardis, Elaine R -- Berger, Michael F -- Baselga, Jose -- Scaltriti, Maurizio -- CA105388/CA/NCI NIH HHS/ -- P30 CA008748/CA/NCI NIH HHS/ -- T32 CA-71345-15/CA/NCI NIH HHS/ -- T32 CA071345/CA/NCI NIH HHS/ -- T32 GM065094/GM/NIGMS NIH HHS/ -- U01 CA168409/CA/NCI NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2015 Feb 12;518(7538):240-4. doi: 10.1038/nature13948. Epub 2014 Nov 17.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Massachusetts General Hospital Cancer Center, 55 Fruit Street, Boston, Massachusetts 02114, USA. ; Human Oncology and Pathogenesis Program (HOPP), Memorial Sloan Kettering Cancer Center, 1275 York Avenue, Box 20, New York, New York 10065, USA. ; 1] Department of Genetics, Washington University School of Medicine, 4566 Scott Avenue, St Louis, Missouri 63110, USA [2] Siteman Cancer Center, Washington University School of Medicine, 660 South Euclid Avenue, St Louis, Missouri 63110, USA [3] The Genome Institute, Washington University School of Medicine, 4444 Forest Park Avenue, St Louis, Missouri 63108, USA. ; 1] Siteman Cancer Center, Washington University School of Medicine, 660 South Euclid Avenue, St Louis, Missouri 63110, USA [2] The Genome Institute, Washington University School of Medicine, 4444 Forest Park Avenue, St Louis, Missouri 63108, USA [3] Department of Medicine, Washington University School of Medicine, 660 South Euclid Avenue, St Louis, Missouri 63110, USA. ; 1] Human Oncology and Pathogenesis Program (HOPP), Memorial Sloan Kettering Cancer Center, 1275 York Avenue, Box 20, New York, New York 10065, USA [2] Department of Pathology, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, Box 20, New York, New York 10065, USA. ; Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, Box 20, New York, New York 10065, USA. ; The Genome Institute, Washington University School of Medicine, 4444 Forest Park Avenue, St Louis, Missouri 63108, USA. ; 1] Human Oncology and Pathogenesis Program (HOPP), Memorial Sloan Kettering Cancer Center, 1275 York Avenue, Box 20, New York, New York 10065, USA [2] Division of Genitourinary Oncology, Department of Medicine, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, Box 20, New York, New York 10065, USA. ; 1] Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, Box 20, New York, New York 10065, USA [2] Howard Hughes Medical Institute, Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, Box 20, New York, New York 10065, USA. ; Novartis Pharma AG, Forum 1, Novartis Campus, CH-4056 Basel, Switzerland. ; Oncology Translational Medicine, Novartis Institutes for BioMedical Research, Cambridge, Massachusetts 02139, USA. ; 1] Department of Genetics, Washington University School of Medicine, 4566 Scott Avenue, St Louis, Missouri 63110, USA [2] Siteman Cancer Center, Washington University School of Medicine, 660 South Euclid Avenue, St Louis, Missouri 63110, USA [3] The Genome Institute, Washington University School of Medicine, 4444 Forest Park Avenue, St Louis, Missouri 63108, USA [4] Department of Medicine, Washington University School of Medicine, 660 South Euclid Avenue, St Louis, Missouri 63110, USA. ; 1] Human Oncology and Pathogenesis Program (HOPP), Memorial Sloan Kettering Cancer Center, 1275 York Avenue, Box 20, New York, New York 10065, USA [2] Breast Medicine Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, Box 20, New York, New York 10065, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25409150" target="_blank"〉PubMed〈/a〉
    Keywords: Alleles ; Animals ; Breast Neoplasms/*drug therapy/*genetics/metabolism/pathology ; Drug Resistance, Neoplasm/drug effects/*genetics ; Female ; Humans ; Loss of Heterozygosity/drug effects/genetics ; Mice ; Mice, Nude ; PTEN Phosphohydrolase/*deficiency/*genetics/metabolism ; Phosphatidylinositol 3-Kinases/*antagonists & inhibitors ; Thiazoles/*pharmacology/therapeutic use ; Xenograft Model Antitumor Assays
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 7
    Publication Date: 2012-08-28
    Description: Cancer drugs often induce dramatic responses in a small minority of patients. We used whole-genome sequencing to investigate the genetic basis of a durable remission of metastatic bladder cancer in a patient treated with everolimus, a drug that inhibits the mTOR (mammalian target of rapamycin) signaling pathway. Among the somatic mutations was a loss-of-function mutation in TSC1 (tuberous sclerosis complex 1), a regulator of mTOR pathway activation. Targeted sequencing revealed TSC1 mutations in about 8% of 109 additional bladder cancers examined, and TSC1 mutation correlated with everolimus sensitivity. These results demonstrate the feasibility of using whole-genome sequencing in the clinical setting to identify previously occult biomarkers of drug sensitivity that can aid in the identification of patients most likely to respond to targeted anticancer drugs.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3633467/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3633467/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Iyer, Gopa -- Hanrahan, Aphrothiti J -- Milowsky, Matthew I -- Al-Ahmadie, Hikmat -- Scott, Sasinya N -- Janakiraman, Manickam -- Pirun, Mono -- Sander, Chris -- Socci, Nicholas D -- Ostrovnaya, Irina -- Viale, Agnes -- Heguy, Adriana -- Peng, Luke -- Chan, Timothy A -- Bochner, Bernard -- Bajorin, Dean F -- Berger, Michael F -- Taylor, Barry S -- Solit, David B -- T32 CA009207/CA/NCI NIH HHS/ -- New York, N.Y. -- Science. 2012 Oct 12;338(6104):221. doi: 10.1126/science.1226344. Epub 2012 Aug 23.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22923433" target="_blank"〉PubMed〈/a〉
    Keywords: Antineoplastic Agents/*therapeutic use ; Clinical Trials, Phase II as Topic ; Codon, Nonsense ; Disease-Free Survival ; Drug Resistance, Neoplasm/*genetics ; Everolimus ; Genome, Human ; Genome-Wide Association Study ; Humans ; Molecular Targeted Therapy ; Multiprotein Complexes ; Neoplasm Metastasis ; Neurofibromin 2/genetics ; Proteins/antagonists & inhibitors ; Sequence Deletion ; Sirolimus/*analogs & derivatives/therapeutic use ; TOR Serine-Threonine Kinases ; Tumor Suppressor Proteins/*genetics ; Urinary Bladder Neoplasms/*drug therapy/genetics/pathology
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 8
    Electronic Resource
    Electronic Resource
    Springer
    Journal of scientific computing 7 (1992), S. 197-228 
    ISSN: 1573-7691
    Keywords: Optimization ; gradient methods ; global convergence
    Source: Springer Online Journal Archives 1860-2000
    Topics: Computer Science
    Notes: Abstract The idea of hierarchical gradient methods for optimization is considered. It is shown that the proposed approach provides powerful means to cope with some global convergence problems characteristic of the classical gradient methods. Concerning global convergence problems, four topics are addressed: The “detour” effect, the problem of multiscale models, the problem of highly ill-conditioned objective functions, and the problem of local-minima traps related to ambiguous regions of attractions. The great potential of hierarchical gradient algorithms is revealed through a hierarchical Gauss-Newton algorithm for unconstrained nonlinear least-squares problems. The algorithm, while maintaining a superlinear convergence rate like the common conjugate gradient or quasi-Newton methods, requires the evaluation of partial derivatives with respect to only one variable on each iteration. This property enables economized consumption of CPU time in case the computer codes for the derivatives are intensive CPU consumers, e.g., when the gradient evaluations of ODE or PDE models are produced by numerical differentiation. The hierarchical Gauss-Newton algorithm is extended to handle interval constraints on the variables and its effectiveness demonstrated by computational results.
    Type of Medium: Electronic Resource
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  • 9
    Publication Date: 2018-07-03
    Description: Purpose: To identify molecular factors that determine duration of response to EGFR tyrosine kinase inhibitors and to identify novel mechanisms of drug resistance, we molecularly profiled EGFR -mutant tumors prior to treatment and after progression on EGFR TKI using targeted next-generation sequencing. Experimental Design: Targeted next-generation sequencing was performed on 374 consecutive patients with metastatic EGFR -mutant lung cancer. Clinical data were collected and correlated with somatic mutation data. Erlotinib resistance due to acquired MTOR mutation was functionally evaluated by in vivo and in vitro studies. Results: In 200 EGFR -mutant pretreatment samples, the most frequent concurrent alterations were mutations in TP53, PIK3CA, CTNNB1 , and RB1 and focal amplifications in EGFR, TTF1, MDM2, CDK4 , and FOXA1 . Shorter time to progression on EGFR TKI was associated with amplification of ERBB2 (HR = 2.4, P = 0.015) or MET (HR = 3.7, P = 0.019), or mutation in TP53 (HR = 1.7, P = 0.006). In the 136 posttreatment samples, we identified known mechanisms of acquired resistance: EGFR T790M (51%), MET (7%), and ERBB2 amplifications (5%). In the 38 paired samples, novel acquired alterations representing putative resistance mechanisms included BRAF fusion, FGFR3 fusion, YES1 amplification, KEAP1 loss, and an MTOR E2419K mutation. Functional studies confirmed the contribution of the latter to reduced sensitivity to EGFR TKI in vitro and in vivo . Conclusions: EGFR -mutant lung cancers harbor a spectrum of concurrent alterations that have prognostic and predictive significance. By utilizing paired samples, we identified several novel acquired alterations that may be relevant in mediating resistance, including an activating mutation in MTOR further validated functionally. Clin Cancer Res; 24(13); 3108–18. ©2018 AACR .
    Print ISSN: 1078-0432
    Electronic ISSN: 1557-3265
    Topics: Medicine
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  • 10
    Publication Date: 2018-12-04
    Description: Purpose: Advanced-stage endometrial cancers have limited treatment options and poor prognosis, highlighting the need to understand genetic drivers of therapeutic vulnerabilities and/or prognostic predictors. We examined whether prospective molecular characterization of recurrent and metastatic disease can reveal grade and histology-specific differences, facilitating enrollment onto clinical trials. Experimental Design: We integrated prospective clinical sequencing and IHC data with detailed clinical and treatment histories for 197 tumors, profiled by MSK-IMPACT from 189 patients treated at Memorial Sloan Kettering Cancer Center. Results: Patients had advanced disease and high-grade histologies, with poor progression-free survival on first-line therapy (PFS 1 ). When matched for histology and grade, the genomic landscape was similar to that of primary untreated disease profiled by TCGA. Using multiple complementary genomic and mutational signature-based methods, we identified patients with microsatellite instability (MSI), even when standard MMR protein IHC staining failed. Tumor and matched normal DNA sequencing identified rare pathogenic germline mutations in BRCA2 and MLH1 . Clustering the pattern of DNA copy-number alterations revealed a novel subset characterized by heterozygous losses across the genome and significantly worse outcomes compared with other clusters (median PFS 1 9.6 months vs. 17.0 and 17.4 months; P = 0.006). Of the 68% of patients harboring potentially actionable mutations, 27% were enrolled to matched clinical trials, of which 47% of these achieved clinical benefit. Conclusions: Prospective clinical sequencing of advanced endometrial cancer can help refine prognosis and aid treatment decision making by simultaneously detecting microsatellite status, germline predisposition syndromes, and potentially actionable mutations. A small overall proportion of all patients tested received investigational, genomically matched therapy as part of clinical trials.
    Print ISSN: 1078-0432
    Electronic ISSN: 1557-3265
    Topics: Medicine
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