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The SLC16A11 risk haplotype is associated with decreased insulin action, higher transaminases and large-size adipocytes

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EUROPEAN JOURNAL OF ENDOCRINOLOGY 2019年第2期180卷 99-107页

作者： Almeda-Valdes, Paloma Gomez Velascol, Donaji V. Arellano Campos, Olimpia Yaxmehen Bello-Chavolla, Omar del Rocio Sevilla-Gonzalez, Magdalena Viveros Ruiz, Tannia Martagon Rosado, Alexandro J. Bautista, Claudia J. Munoz Hernandez, Liliana Cruz-Bautista, Ivette Moreno-Maciass, Hortensia Huerta-Chagoya, Alicia Guadalupe Rodriguez-Alvarez, Karen Watford, Geoffrey A. Jacobs, Suzanne B. R. Guillen Pineda, Luz E. Luisa Ordonez-Sanchez, Ma Roldan-Valadez, Ernesto Azpiroz, Joaquin Furuzawa-Carballeda, Jannette Clark, Patricia Herrera-Hernandez, Miguel F. Zambrano, Elena Florez, Jose C. Tusie Luna, Maria Teresa Aguilar-Salinas, Carlos A. Inst Nacl Ciencias Med & Nutr Salvador Zubiran Unidad Invest Enfermedades Metab Mexico City DF Mexico Tecnol Monterrey Escuela Med & Ciencias Salud Monterrey NL Mexico Inst Nacl Ciencias Med & Nutr Salvador Zubiran Dept Endocrinol & Metab Mexico City DF Mexico Univ Nacl Autonoma Mexico Fac Med MD PhD PECEM Program Mexico City DF Mexico Inst Nacl Ciencias Med & Nutr Salvador Zubiran Dept Biol Reprod Mexico City DF Mexico Univ Nacl Autonoma Mexico Inst Invest Biomed Inst Nacl Ciencias Med & Nutr Salvador Zubiran Unidad Biol Mol & Med Genom Mexico City DF Mexico Univ Autonoma Metropolitana Div Ciencias Sociales & Humanidades Mexico City DF Mexico Broad Inst Harvard & MIT Programs Metab & Med & Populat Genet Cambridge MA USA Hosp Gen Mexico Dr Eduardo Liceaga Directorate Res Dr Balmis 148 Mexico City 06726 DF Mexico Univ Autonoma Metropolitana Ctr Nacl Invest Imagenol & Instrumentat Med Mexico City DF Mexico Inst Nadonal Ciencias Med & Nutr Salvador Zubiran Dept Inmunol & Reumatol Mexico City DF Mexico Univ Nacl Autonoma Mexico Fac Med Hosp Infantil Mexico Federico Gomez Unidad Epidemiol Clin Mexico City DF Mexico Inst Nacl Ciencias Med & Nutr Salvador Zubiran Dept Cirugia Mexico City DF Mexico Massachusetts Gen Hosp Ctr Genom Med Boston MA 02114 USA Massachusetts Gen Hosp Diabet Res Ctr Diabet Unit Boston MA 02114 USA Harvard Med Sch Dept Med Boston MA USA IM Sechenov First Moscow State Med Univ Sechenov Univ Dept Radiol Trubetskaya Str 8B-2 Moscow 119992 Russia

Objective: A haplotype at chromosome 17p13 that reduces expression and function of the solute carrier transporter SLC16A11 is associated with increased risk for type 2 diabetes in Mexicans. We aim to investigate the detailed metabolic profile of SLC16A11 risk haplotype carriers to identify potential physiological mechanisms explaining the increased type 2 diabetes risk. Design: Cross-sectional study. Methods: We evaluated carriers (n = 72) and non-carriers (n = 75) of the SLC16A11 risk haplotype, with or without type 2 diabetes. An independent sample of 1069 subjects was used to replicate biochemical findings. The evaluation included euglycemic-hyperinsulinemic clamp, frequently sampled intravenous glucose tolerance test (FSIVGTT), dual-energy X-ray absorptiometry (DXA), MRI and spectroscopy and subcutaneous abdominal adipose tissue biopsies. Results: Fat-free mass (FFM)-adjusted M value was lower in carriers of the SLC16A11 risk haplotype after adjusting for age and type 2 diabetes status (beta = -0.164, P = 0.04). Subjects with type 2 diabetes and the risk haplotype demonstrated an increase of 8.76 U/L in alanine aminotransferase (ALT) (P = 0.02) and of 7.34 U/L in gammaglutamyltransferase (GGT) (P = 0.05) compared with non-carriers and after adjusting for gender, age and ancestry. Among women with the risk haplotype and normal BMI, the adipocyte size was higher (P < 0.001). Conclusions: Individuals carrying the SLC16A11 risk haplotype exhibited decreased insulin action. Higher serum ALT and GGT levels were found in carriers with type 2 diabetes, and larger adipocytes in subcutaneous fat in the size distribution in carrier women with normal weight.

关键词： large sizes Mexicans 17p13 Adipocytes Transaminases Haplotypes Type 2 Diabetes Mellitus

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Disruption of chromatin folding domains by somatic genomic rearrangements in human cancer

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NATURE GENETICS 2020年第3期52卷 294-+页

作者： Akdemir, Kadir C. Le, Victoria T. Chandran, Sahaana Li, Yilong Verhaak, Roel G. Beroukhim, Rameen Campbell, Peter J. Chin, Lynda Dixon, Jesse R. Futreal, P. Andrew Alvarez, Eva G. Baez-Ortega, Adrian Beroukhim, Rameen Boutros, Paul C. Bowtell, David D. L. Brors, Benedikt Burns, Kathleen H. Chan, Kin Chen, Ken Cortes-Ciriano, Isidro Dueso-Barroso, Ana Dunford, Andrew J. Edwards, Paul A. Estivill, Xavier Etemadmoghadam, Dariush Feuerbach, Lars Fink, J. Lynn Frenkel-Morgenstern, Milana Garsed, Dale W. Gerstein, Mark Gordenin, Dmitry A. Haan, David Haber, James E. Hess, Julian M. Hutter, Barbara Imielinski, Marcin Jones, David T. W. Ju, Young Seok Kazanov, Marat D. Klimczak, Leszek J. Koh, Youngil Korbel, Jan O. Kumar, Kiran Lee, Eunjung Alice Lee, Jake June-Koo Lynch, Andy G. Macintyre, Geoff Markowetz, Florian Martincorena, Inigo Martinez-Fundichely, Alexander Meyerson, Matthew Miyano, Satoru Nakagawa, Hidewaki Navarro, Fabio C. P. Ossowski, Stephan Park, Peter J. Pearson, John V. Puiggros, Montserrat Rippe, Karsten Roberts, Nicola D. Roberts, Steven A. Rodriguez-Martin, Bernardo Schumacher, Steven E. Scully, Ralph Shackleton, Mark Sidiropoulos, Nikos Sieverling, Lina Stewart, Chip Torrents, David Tubio, Jose M. C. Villasante, Izar Waddell, Nicola Wala, Jeremiah A. Weischenfeldt, Joachim Yang, Lixing Yao, Xiaotong Yoon, Sung-Soo Zamora, Jorge Zhang, Cheng-Zhong Univ Texas MD Anderson Canc Ctr Dept Genom Med Houston TX 77030 USA Salk Inst Biol Studies 10010 N Torrey Pines Rd La Jolla CA 92037 USA Wellcome Trust Sanger Inst Cambridge England Jackson Lab Genom Med Div Computat Biol Farmington CT USA Dana Farber Canc Inst Dept Med Oncol Boston MA 02115 USA Dana Farber Canc Inst Dept Canc Biol Cambridge MA USA Broad Inst MIT & Harvard Cambridge MA 02142 USA Harvard Med Sch Boston MA 02115 USA Univ Cambridge Dept Haematol Cambridge England Univ Texas Houston Inst Hlth Transformat Houston TX USA Univ Santiago de Compostela Dept Zool Genet & Phys Anthropol Santiago De Compostela Spain Univ Santiago de Compostela Ctr Res Mol Med & Chron Dis CIMUS Santiago De Compostela Spain Univ Vigo Biomed Res Ctr CINBIO Vigo Spain Univ Cambridge Dept Vet Med Transmissible Canc Grp Cambridge England Ontario Inst Canc Res Computat Biol Program Toronto ON Canada Univ Toronto Dept Med Biophys Toronto ON Canada Univ Toronto Dept Pharmacol Toronto ON Canada Univ Calif Los Angeles Los Angeles CA USA Peter MacCallum Canc Ctr Melbourne Vic Australia Univ Melbourne Sir Peter MacCallum Dept Oncol Melbourne Vic Australia German Canc Res Ctr Div Appl Bioinformat Heidelberg Germany German Canc Res Ctr German Canc Consortium DKTK Heidelberg Germany Natl Ctr Tumor Dis NCT Heidelberg Heidelberg Germany Johns Hopkins Sch Med Baltimore MD USA Univ Ottawa Fac Med Dept Biochem Microbiol & Immunol Ottawa ON Canada Univ Texas MD Anderson Canc Ctr Houston TX 77030 USA Univ Cambridge Dept Chem Ctr Mol Sci Informat Cambridge England Harvard Med Sch Dept Biomed Informat Boston MA 02115 USA Harvard Med Sch Ludwig Ctr Boston MA 02115 USA BSC Barcelona Spain Univ Cambridge Canc Res UK Cambridge Inst Cambridge England Univ Cambridge Cambridge England Sidra Med Doha Qatar Univ Melbourne Sir Peter MacCallum Dept Oncol Melbourne Vic Australia Univ Queensland Inst Mol Biosci Queensland Ctr Med Genom St Lucia Qld Australia

Chromatin is folded into successive layers to organize linear DNA. Genes within the same topologically associating domains (TADs) demonstrate similar expression and histone-modification profiles, and boundaries separating different domains have important roles in reinforcing the stability of these features. Indeed, domain disruptions in human cancers can lead to misregulation of gene expression. However, the frequency of domain disruptions in human cancers remains unclear. Here, as part of the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA), which aggregated whole-genome sequencing data from 2,658 cancers across 38 tumor types, we analyzed 288,457 somatic structural variations (SVs) to understand the distributions and effects of SVs across TADs. Notably, SVs can lead to the fusion of discrete TADs, and complex rearrangements markedly change chromatin folding maps in the cancer genomes. Notably, only 14% of the boundary deletions resulted in a change in expression in nearby genes of more than twofold. A pan-cancer genomic analysis reports the effects of structural variations on chromatin domains (TADs). Most TAD disruptions do not result in appreciable changes in expression of nearby genes.

关键词： Cancer Data mining Gene expression

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mTORC1 Activator SLC38A9 Is Required to Efflux Essential Amino Acids from Lysosomes and Use Protein as a Nutrient

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CELL 2017年第3期171卷 642-+页

作者： Wyant, Gregory A. Abu-Remaileh, Monther Wolfson, Rachel L. Chen, Walter W. Freinkman, Elizaveta Danai, Laura V. Heiden, Matthew G. Vander Sabatini, David M. Whitehead Inst Biomed Res Cambridge MA 02142 USA MIT Dept Biol 9 Cambridge Ctr Cambridge MA 02142 USA Howard Hughes Med Inst Cambridge MA 02139 USA Koch Inst Integrat Canc Res 77 Massachusetts Ave Cambridge MA 02139 USA Broad Inst MIT & Harvard 7 Cambridge Ctr Cambridge MA 02142 USA Harvard Med Sch MD PhD Program Daniel C Tosteson Med Educ Ctr 260 Longwood Ave Boston MA 02115 USA Dana Farber Canc Inst Boston MA 02115 USA Metabolon Inc Res Triangle Pk NC 27709 USA

The mTORC1 kinase is a master growth regulator that senses many environmental cues, including amino acids. Activation of mTORC1 by arginine requires SLC38A9, a poorly understood lysosomal membrane protein with homology to amino acid transporters. Here, we validate that SLC38A9 is an arginine sensor for the mTORC1 pathway, and we uncover an unexpectedly central role for SLC38A9 in amino acid homeostasis. SLC38A9 mediates the transport, in an arginine- regulated fashion, of many essential amino acids out of lysosomes, including leucine, which mTORC1 senses through the cytosolic Sestrin proteins. SLC38A9 is necessary for leucine generated via lysosomal proteolysis to exit lysosomes and activate mTORC1. Pancreatic cancer cells, which use macropinocytosed protein as a nutrient source, require SLC38A9 to form tumors. Thus, through SLC38A9, arginine serves as a lysosomal messenger that couples mTORC1 activation to the release from lysosomes of the essential amino acids needed to drive cell growth.

关键词： amino acid sensing nutrient sensing mTOR lysosome micropinocytosis autophagy

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Comprehensive analysis of chromothripsis in 2,658 human cancers using whole-genome sequencing

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NATURE GENETICS 2020年第3期52卷 331-+页

作者： Cortes-Ciriano, Isidro Lee, Jake June-Koo Xi, Ruibin Jain, Dhawal Jung, Youngsook L. Yang, Lixing Gordenin, Dmitry Klimczak, Leszek J. Zhang, Cheng-Zhong Pellman, David S. Park, Peter J. Akdemir, Kadir C. Alvarez, Eva G. Baez-Ortega, Adrian Beroukhim, Rameen Boutros, Paul C. Bowtell, David D. L. Brors, Benedikt Burns, Kathleen H. Campbell, Peter J. Chan, Kin Chen, Ken Dueso-Barroso, Ana Dunford, Andrew J. Edwards, Paul A. Estivill, Xavier Etemadmoghadam, Dariush Feuerbach, Lars Fink, J. Lynn Frenkel-Morgenstern, Milana Garsed, Dale W. Gerstein, Mark Gordenin, Dmitry A. Haan, David Haber, James E. Hess, Julian M. Hutter, Barbara Imielinski, Marcin Jones, David T. W. Ju, Young Seok Kazanov, Marat D. Koh, Youngil Korbel, Jan O. Kumar, Kiran Lee, Eunjung Alice Li, Yilong Lynch, Andy G. Macintyre, Geoff Markowetz, Florian Martincorena, Inigo Martinez-Fundichely, Alexander Miyano, Satoru Nakagawa, Hidewaki Navarro, Fabio C. P. Ossowski, Stephan Pearson, John, V Puiggros, Montserrat Rippe, Karsten Roberts, Nicola D. Roberts, Steven A. Rodriguez-Martin, Bernardo Schumacher, Steven E. Scully, Ralph Shackleton, Mark Sidiropoulos, Nikos Sieverling, Lina Stewart, Chip Torrents, David Tubio, Jose M. C. Villasante, Izar Waddell, Nicola Wala, Jeremiah A. Weischenfeldt, Joachim Yao, Xiaotong Yoon, Sung-Soo Zamora, Jorge Harvard Med Sch Dept Biomed Informat Boston MA 02115 USA Ludwig Ctr Harvard Boston MA 02215 USA Univ Cambridge Ctr Mol Sci Informat Dept Chem Cambridge England Peking Univ Sch Math Sci Beijing Peoples R China Peking Univ Ctr Stat Sci Beijing Peoples R China Univ Chicago Ben May Dept Canc Res Chicago IL 60637 USA Univ Chicago Dept Human Genet Chicago IL 60637 USA NIEHS Genome Integr & Struct Biol NIH Durham NC USA NIEHS Integrat Bioinformat Grp NIH Durham NC USA Dana Farber Canc Inst Dept Data Sci Boston MA 02115 USA Dana Farber Canc Inst Dept Pediat Oncol Boston MA 02115 USA Harvard Med Sch Blavatnik Inst Dept Cell Biol Boston MA 02115 USA Howard Hughes Med Inst Boston MA 02115 USA European Bioinformat Inst European Mol Biol Lab Hinxton England Univ Texas MD Anderson Canc Ctr Houston TX 77030 USA Univ Santiago de Compostela Dept Zool Genet & Phys Anthropol Santiago De Compostela Spain Univ Santiago de Compostela Ctr Res Mol Med & Chron Dis CIMUS Santiago De Compostela Spain Univ Vigo Biomed Res Ctr CINBIO Vigo Spain Univ Cambridge Dept Vet Med Transmissible Canc Grp Cambridge England Broad Inst MIT & Harvard Cambridge MA 02142 USA Dana Farber Canc Inst Dept Med Oncol Boston MA 02115 USA Harvard Med Sch Boston MA 02115 USA Ontario Inst Canc Res Computat Biol Program Toronto ON Canada Univ Toronto Dept Med Biophys Toronto ON Canada Univ Toronto Dept Pharmacol Toronto ON Canada Univ Calif Los Angeles Los Angeles CA USA Peter MacCallum Canc Ctr Victoria Australia Univ Melbourne Sir Peter MacCallum Dept Oncol Melbourne Vic Australia German Canc Res Ctr Div Appl Bioinformat Heidelberg Germany German Canc Res Ctr German Canc Consortium DKTK Heidelberg Germany Natl Ctr Tumor Dis NCT Heidelberg Heidelberg Germany Johns Hopkins Sch Med Baltimore MD USA Univ Cambridge Dept Haematol Cambridge England Wellcome Sanger Inst Hinxton England Univ Ottawa Fac Med Dept Biochem Microbiol & Immunol Ottawa ON Canada Barcelona Super

Analysis of whole-genome sequencing data across 2,658 tumors spanning 38 cancer types shows that chromothripsis is pervasive, with a frequency of more than 50% in several cancer types, contributing to oncogene amplification, gene inactivation and cancer genome evolution. Chromothripsis is a mutational phenomenon characterized by massive, clustered genomic rearrangements that occurs in cancer and other diseases. Recent studies in selected cancer types have suggested that chromothripsis may be more common than initially inferred from low-resolution copy-number data. Here, as part of the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA), we analyze patterns of chromothripsis across 2,658 tumors from 38 cancer types using whole-genome sequencing data. We find that chromothripsis events are pervasive across cancers, with a frequency of more than 50% in several cancer types. Whereas canonical chromothripsis profiles display oscillations between two copy-number states, a considerable fraction of events involve multiple chromosomes and additional structural alterations. In addition to non-homologous end joining, we detect signatures of replication-associated processes and templated insertions. Chromothripsis contributes to oncogene amplification and to inactivation of genes such as mismatch-repair-related genes. These findings show that chromothripsis is a major process that drives genome evolution in human cancer.

关键词： Cancer Computational biology and bioinformatics Genomics

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Patterns of somatic structural variation in human cancer genomes (vol 578, pg 112, 2020)

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NATURE 2023年第7948期614卷 E38-E38页

作者： Li, Yilong Roberts, Nicola D. Wala, Jeremiah A. Shapira, Ofer Schumacher, Steven E. Kumar, Kiran Khurana, Ekta Waszak, Sebastian Korbel, Jan O. Haber, James E. Imielinski, Marcin Weischenfeldt, Joachim Beroukhim, Rameen Campbell, Peter J. Cancer Genome Project Wellcome Trust Sanger Institute Hinxton UK Totient Inc Cambridge MA USA Wellcome Sanger Institute Wellcome Genome Campus Hinxton UK Department of Haematology University of Cambridge Cambridge UK Cambridge University Hospitals NHS Foundation Trust Cambridge UK Korea Advanced Institute of Science and Technology Daejeon South Korea Department of Zoology Genetics and Physical Anthropology University of Santiago de Compostela Santiago de Compostela Spain Centre for Research in Molecular Medicine and Chronic Diseases (CIMUS) University of Santiago de Compostela Santiago de Compostela Spain The Biomedical Research Centre (CINBIO) University of Vigo Vigo Spain Centre for Research in Molecular Medicine and Chronic Diseases (CiMUS) Universidade de Santiago de Compostela Santiago de Compostela Spain Department of Zoology Genetics and Physical Anthropology (CiMUS) Universidade de Santiago de Compostela Santiago de Compostela Spain The Biomedical Research Centre (CINBIO) Universidade de Vigo Vigo Spain The Broad Institute of Harvard and MIT Cambridge MA USA Bioinformatics and Integrative Genomics Harvard University Cambridge MA USA Department of Cancer Biology Dana-Farber Cancer Institute Boston MA USA Broad Institute of MIT and Harvard Cambridge MA USA Department of Medical Oncology Dana-Farber Cancer Institute Boston MA USA Harvard Medical School Boston MA USA Massachusetts General Hospital Center for Cancer Research Charlestown MA USA Dana-Farber Cancer Institute Boston MA USA Department of Biostatistics and Computational Biology Dana-Farber Cancer Institute and Harvard Medical School Boston MA USA Weill Cornell Medical College New York NY USA Department of Physiology and Biophysics Weill Cornell Medicine New York NY USA Institute for Computational Biomedicine Weill Cornell Medicine New York NY USA Controlled Department and Institution New York NY USA Englander Institute for Precision Medicine Weill Cornell Medicine Ne

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The evolutionary history of 2,658 cancers (vol 578, pg 122, 2020)

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NATURE 2023年第7948期614卷 E42-E42页

作者： Gerstung, Moritz Jolly, Clemency Leshchiner, Ignaty Dentro, Stefan C. Gonzalez, Santiago Rosebrock, Daniel mitchell, Thomas J. Rubanova, Yulia Anur, Pavana Yu, Kaixian Tarabichi, Maxime Deshwar, Amit Wintersinger, Jeff Kleinheinz, Kortine Vazquez-Garcia, Ignacio Haase, Kerstin Jerman, Lara Sengupta, Subhajit Macintyre, Geoff Malikic, Salem Donmez, Nilgun Livitz, Dimitri G. Cmero, Marek Demeulemeester, Jonas Schumacher, Steven Fan, Yu Yao, Xiaotong Lee, Juhee Schlesner, Matthias Boutros, Paul C. Bowtell, David D. Zhu, Hongtu Getz, Gad Imielinski, Marcin Beroukhim, Rameen Sahinalp, S. Cenk Ji, Yuan Peifer, Martin Markowetz, Florian Mustonen, Ville Yuan, Ke Wang, Wenyi Morris, Quaid D. Spellman, Paul T. Wedge, David C. Van Loo, Peter European Molecular Biology Laboratory European Bioinformatics Institute (EMBL-EBI) Cambridge UK European Molecular Biology Laboratory Genome Biology Unit Heidelberg Germany Wellcome Sanger Institute Cambridge UK Genome Biology Unit European Molecular Biology Laboratory (EMBL) Heidelberg Germany University of Ljubljana Ljubljana Slovenia The Francis Crick Institute London UK Big Data Institute University of Oxford Oxford UK Wellcome Sanger Institute Wellcome Genome Campus Hinxton UK Big Data Institute Li Ka Shing Centre University of Oxford Oxford UK University of Cambridge Cambridge UK Cambridge University Hospitals NHS Foundation Trust Cambridge UK Department of Applied Mathematics and Theoretical Physics Centre for Mathematical Sciences University of Cambridge Cambridge UK Department of Epidemiology and Biostatistics Memorial Sloan Kettering Cancer Center New York NY USA Department of Statistics Columbia University New York NY USA Department of Haematology University of Cambridge Cambridge UK University of Leuven Leuven Belgium Broad Institute of MIT and Harvard Cambridge MA USA Center for Cancer Research Massachusetts General Hospital Charlestown MA USA Department of Pathology Massachusetts General Hospital Boston MA USA Harvard Medical School Boston MA USA Center for Cancer Research Massachusetts General Hospital Boston MA USA Dana-Farber Cancer Institute Boston MA USA Department of Medical Oncology Dana-Farber Cancer Institute Boston MA USA Department of Cancer Biology Dana-Farber Cancer Institute Boston MA USA Oxford NIHR Biomedical Research Centre Oxford UK Oxford NIHR Biomedical Research Centre University of Oxford Oxford UK University of Toronto Toronto Ontario Canada Vector Institute Toronto Ontario Canada Vector Institute Toronto ON Canada Department of Computer Science University of Toronto Toronto ON Canada Ontario Institute for Cancer Research Toronto Ontario Canada University of California Los Angeles

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Exploiting Temporal Collateral Sensitivity in Tumor Clonal Evolution

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CELL 2016年第1期165卷 234-246页

作者： Zhao, Boyang Sedlak, Joseph C. Srinivas, Raja Creixell, Pau Pritchard, Justin R. Tidor, Bruce Lauffenburger, Douglas A. Hemann, Michael T. MIT Computat & Syst Biol Program 77 Massachusetts Ave Cambridge MA 02139 USA MIT David H Koch Inst Integrat Canc Res 77 Massachusetts Ave Cambridge MA 02139 USA MIT Dept Biol 77 Massachusetts Ave Cambridge MA 02139 USA MIT Dept Biol Engn 77 Massachusetts Ave Cambridge MA 02139 USA MIT Comp Sci & Artificial Intelligence Lab 77 Massachusetts Ave Cambridge MA 02139 USA MIT Dept Elect Engn & Comp Sci Cambridge MA 02139 USA Harvard Univ Sch Med Harvard MIT MD PhD Program Boston MA 02115 USA ARIAD Pharmaceut Inc Cambridge MA 02139 USA

The prevailing approach to addressing secondary drug resistance in cancer focuses on treating the resistance mechanisms at relapse. However, the dynamic nature of clonal evolution, along with potential fitness costs and cost compensations, may present exploitable vulnerabilities-a notion that we term "temporal collateral sensitivity.'' Using a combined pharmacological screen and drug resistance selection approach in a murine model of Ph+ acute lymphoblastic leukemia, we indeed find that temporal and/or persistent collateral sensitivity to non-classical BCR-ABL1 drugs arises in emergent tumor subpopulations during the evolution of resistance toward initial treatment with BCR-ABL1-targeted inhibitors. We determined the sensitization mechanism via genotypic, phenotypic, signaling, and binding measurements in combination with computational models and demonstrated significant overall survival extension in mice. Additional stochastic mathematical models and small-molecule screens extended our insights, indicating the value of focusing on evolutionary trajectories and pharmacological profiles to identify new strategies to treat dynamic tumor vulnerabilities.

关键词： CLONAL selection theory DRUG resistance in cancer cells SUBSTANCE abuse -- Relapse CANCER research SENSITIZATION (Neuropsychology)

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Author Correction: Genomic footprints of activated telomere maintenance mechanisms in cancer (Dec, 10.1038/s41467-019-13824-9, 2022)

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NATURE COMMUNICATIONS 2022年第1期13卷 1-1页

作者： Sieverling, Lina Hong, Chen Koser, Sandra D. Ginsbach, Philip Kleinheinz, Kortine Hutter, Barbara Braun, Delia M. Cortes-Ciriano, Isidro Xi, Ruibin Kabbe, Rolf Park, Peter J. Eils, Roland Schlesner, Matthias Brors, Benedikt Rippe, Karsten Jones, David T. W. Feuerbach, Lars Division of Applied Bioinformatics German Cancer Research Center (DKFZ) 69120 Heidelberg Germany Faculty of Biosciences Heidelberg University 69120 Heidelberg Germany Division of Applied Bioinformatics German Cancer Research Center (DKFZ) Heidelberg Germany Faculty of Biosciences Heidelberg University Heidelberg Germany Division of Theoretical Bioinformatics German Cancer Research Center (DKFZ) 69120 Heidelberg Germany Department for Bioinformatics and Functional Genomics Institute for Pharmacy and Molecular Biotechnology (IPMB) and BioQuant 69120 Heidelberg Germany Division of Theoretical Bioinformatics German Cancer Research Center (DKFZ) Heidelberg Germany Institute of Pharmacy and Molecular Biotechnology and BioQuant Heidelberg University Heidelberg Germany German Cancer Consortium (DKTK) Heidelberg Germany National Center for Tumor Diseases (NCT) Heidelberg Heidelberg Germany Heidelberg Center for Personalized Oncology (DKFZ-HIPO) German Cancer Research Center (DKFZ) Heidelberg Germany German Cancer Consortium (DKTK) German Cancer Research Center (DKFZ) Heidelberg Germany Division of Chromatin Networks German Cancer Research Center (DKFZ) and BioQuant 69120 Heidelberg Germany Department of Biomedical Informatics Harvard Medical School Boston Massachusetts 02115 USA Department of Chemistry Centre for Molecular Science Informatics University of Cambridge Cambridge CB2 1EW UK Ludwig Center at Harvard Medical School Boston Massachusetts 02115 USA Department of Biomedical Informatics Harvard Medical School Boston MA USA Department of Chemistry Centre for Molecular Science Informatics University of Cambridge Cambridge UK Ludwig Center at Harvard Medical School Boston MA USA School of Mathematical Sciences and Center for Statistical Science Peking University Beijing 100871 China Heidelberg University Heidelberg Germany New BIH Digital Health Center Berlin Institute of Health (BIH) and Charité - Universitätsmedizin Berlin Berlin Germany Bioi

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Schizophrenia risk from complex variation of complement component 4

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NATURE 2016年第7589期530卷 177-+页

作者： Sekar, Aswin Bialas, Allison R. de Rivera, Heather Davis, Avery Hammond, Timothy R. Kamitaki, Nolan Tooley, Katherine Presumey, Jessy Baum, Matthew Van Doren, Vanessa Genovese, Giulio Rose, Samuel A. Handsaker, Robert E. Daly, Mark J. Carroll, Michael C. Stevens, Beth McCarroll, Steven A. Harvard Univ Sch Med Dept Genet Boston MA 02115 USA Broad Inst MIT & Harvard Stanley Ctr Psychiat Res Cambridge MA 02142 USA Harvard Univ Sch Med MD PhD Program Boston MA 02115 USA Harvard Univ Sch Med Boston Childrens Hosp Dept NeurolFM Kirby Neurobiol Ctr Boston MA 02115 USA Boston Childrens Hosp Program Cellular & Mol Med Boston MA 02115 USA Massachusetts Gen Hosp Analyt & Translat Genet Unit Boston MA 02114 USA

Schizophrenia is a heritable brain illness with unknown pathogenic mechanisms. Schizophrenia's strongest genetic association at a population level involves variation in the major histocompatibility complex (MHC) locus, but the genes and molecular mechanisms accounting for this have been challenging to identify. Here we show that this association arises in part from many structurally diverse alleles of the complement component 4 (C4) genes. We found that these alleles generated widely varying levels of C4A and C4B expression in the brain, with each common C4 allele associating with schizophrenia in proportion to its tendency to generate greater expression of C4A. Human C4 protein localized to neuronal synapses, dendrites, axons, and cell bodies. In mice, C4 mediated synapse elimination during postnatal development. These results implicate excessive complement activity in the development of schizophrenia and may help explain the reduced numbers of synapses in the brains of individuals with schizophrenia.

关键词： Genetics Synaptic development Haplotypes Structural variation

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Pan-cancer analysis of whole genomes

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NATURE 2020年第7793期578卷 82-+页

作者： Campbell, Peter J. Getz, Gad Korbel, Jan O. Stuart, Joshua M. Jennings, Jennifer L. Stein, Lincoln D. Perry, Marc D. Nahal-Bose, Hardeep K. Ouellette, B. F. Francis Li, Constance H. Rheinbay, Esther Nielsen, G. Petur Sgroi, Dennis C. Wu, Chin-Lee Faquin, William C. Deshpande, Vikram Boutros, Paul C. Lazar, Alexander J. Hoadley, Katherine A. Louis, David N. Dursi, L. Jonathan Yung, Christina K. Bailey, Matthew H. Saksena, Gordon Raine, Keiran M. Buchhalter, Ivo Kleinheinz, Kortine Schlesner, Matthias Zhang, Junjun Wang, Wenyi Wheeler, David A. Ding, Li Simpson, Jared T. O'Connor, Brian D. Yakneen, Sergei Ellrott, Kyle Miyoshi, Naoki Butler, Adam P. Royo, Romina Shorser, Solomon, I Vazquez, Miguel Rausch, Tobias Tiao, Grace Waszak, Sebastian M. Rodriguez-Martin, Bernardo Shringarpure, Suyash Wu, Dai-Ying Demidov, German M. Delaneau, Olivier Hayashi, Shuto Imoto, Seiya Habermann, Nina Segre, Ayellet, V Garrison, Erik Cafferkey, Andy Alvarez, Eva G. Maria Heredia-Genestar, Jose Muyas, Francesc Drechsel, Oliver Bruzos, Alicia L. Temes, Javier Zamora, Jorge Baez-Ortega, Adrian Kim, Hyung-Lae Mashl, R. Jay Ye, Kai DiBiase, Anthony Huang, Kuan-lin Letunic, Ivica McLellan, Michael D. Newhouse, Steven J. Shmaya, Tal Kumar, Sushant Wedge, David C. Wright, Mark H. Yellapantula, Venkata D. Gerstein, Mark Khurana, Ekta Marques-Bonet, Tomas Navarro, Arcadi Bustamante, Carlos D. Siebert, Reiner Nakagawa, Hidewaki Easton, Douglas F. Ossowski, Stephan Tubio, Jose M. C. De La Vega, Francisco M. Estivill, Xavier Yuen, Denis Mihaiescu, George L. Omberg, Larsson Ferretti, Vincent Sabarinathan, Radhakrishnan Pich, Oriol Gonzalez-Perez, Abel Weiner, Amaro Taylor Fittall, Matthew W. Demeulemeester, Jonas Tarabichi, Maxime Roberts, Nicola D. Van Loo, Peter Cortes-Ciriano, Isidro Urban, Lara Park, Peter Bin Zhu Pitkaenen, Esa Li, Yilong Saini, Natalie Klimczak, Leszek J. Weischenfeldt, Joachim Sidiropoulos, Nikos Alexandrov, Ludmil B. Rabionet, Raquel Escaramis, Georgia Bosio, Mattia Holik, Aliaksei Z. Susak, Hana Prasad, Aparna Erkek, Ser Wellcome Sanger Inst Hinxton England Univ Cambridge Dept Haematol Cambridge England Broad Inst MIT & Harvard Cambridge MA 02142 USA Massachusetts Gen Hosp Ctr Canc Res Boston MA 02114 USA Massachusetts Gen Hosp Dept Pathol Boston MA 02114 USA Harvard Med Sch Boston MA 02115 USA European Bioinformat Inst EMBL European Mol Biol Lab EMBL EBI Hinxton England European Mol Biol Lab EMBL Genome Biol Unit Heidelberg Germany Univ Calif Santa Cruz Biomol Engn Dept Santa Cruz CA 95064 USA Ontario Inst Canc Res Adapt Oncol Initiat Toronto ON Canada ICGC Accelerating Res Genom Oncol ICGC ARGO Secre Int Canc Genome Consortium ICGC Toronto ON Canada Ontario Inst Canc Res Computat Biol Program Toronto ON Canada Univ Toronto Dept Mol Genet Toronto ON Canada Univ Calif San Francisco Dept Radiat Oncol San Francisco CA USA Ontario Inst Canc Res Genome Informat Program Toronto ON Canada Univ Toronto Dept Cell & Syst Biol Toronto ON Canada Ontario Inst Canc Res Genome Informat Toronto ON Canada Univ Toronto Dept Med Biophys Toronto ON Canada Massachusetts Gen Hosp Boston MA 02114 USA Univ Toronto Dept Pharmacol Toronto ON Canada Univ Calif Los Angeles Los Angeles CA USA Univ Texas MD Anderson Canc Ctr Dept Pathol Dept Genom Med Houston TX 77030 USA Univ Texas MD Anderson Canc Ctr Dept Pathol Dept Translat Mol Pathol Houston TX 77030 USA Univ North Carolina Dept Genet Chapel Hill NC 27515 USA Univ North Carolina Lineberger Comprehens Canc Ctr Chapel Hill NC 27515 USA Hosp Sick Children Toronto ON Canada Washington Univ Sch Med Alvin J Siteman Canc Ctr St Louis MO USA Washington Univ McDonnell Genome Inst St Louis MO 63110 USA German Canc Res Ctr Div Theoret Bioinformat Heidelberg Germany German Canc Res Ctr Heidelberg Ctr Personalized Oncol DKFZ HIPO Heidelberg Germany Heidelberg Univ Inst Pharm & Mol Biotechnol Heidelberg Germany Heidelberg Univ BioQuant Heidelberg Germany German Canc Res Ctr Bioinformat & Omics Data Analyt Heidelb

Cancer is driven by genetic change, and the advent of massively parallel sequencing has enabled systematic documentation of this variation at the whole-genome scale(1-3). Here we report the integrative analysis of 2,658 whole-cancer genomes and their matching normal tissues across 38 tumour types from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA). We describe the generation of the PCAWG resource, facilitated by international data sharing using compute clouds. On average, cancer genomes contained 4-5 driver mutations when combining coding and non-coding genomic elements;however, in around 5% of cases no drivers were identified, suggesting that cancer driver discovery is not yet complete. Chromothripsis, in which many clustered structural variants arise in a single catastrophic event, is frequently an early event in tumour evolution;in acral melanoma, for example, these events precede most somatic point mutations and affect several cancer-associated genes simultaneously. Cancers with abnormal telomere maintenance often originate from tissues with low replicative activity and show several mechanisms of preventing telomere attrition to critical levels. Common and rare germline variants affect patterns of somatic mutation, including point mutations, structural variants and somatic retrotransposition. A collection of papers from the PCAWG Consortium describes non-coding mutations that drive cancer beyond those in the TERT promoter(4);identifies new signatures of mutational processes that cause base substitutions, small insertions and deletions and structural variation(5,6);analyses timings and patterns of tumour evolution(7);describes the diverse transcriptional consequences of somatic mutation on splicing, expression levels, fusion genes and promoter activity(8,9);and evaluates a range of more-specialized features of cancer genomes(8,10-18).

关键词： Science Humanities and Social Sciences multidisciplinary

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