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11 results on '"Sergi, Castellví-Bel"'

1. Author Correction: Deciphering colorectal cancer genetics through multi-omic analysis of 100,204 cases and 154,587 controls of European and east Asian ancestries

Author

Ceres Fernandez-Rozadilla, Maria Timofeeva, Zhishan Chen, Philip Law, Minta Thomas, Stephanie Schmit, Virginia Díez-Obrero, Li Hsu, Juan Fernandez-Tajes, Claire Palles, Kitty Sherwood, Sarah Briggs, Victoria Svinti, Kevin Donnelly, Susan Farrington, James Blackmur, Peter Vaughan-Shaw, Xiao-ou Shu, Jirong Long, Qiuyin Cai, Xingyi Guo, Yingchang Lu, Peter Broderick, James Studd, Jeroen Huyghe, Tabitha Harrison, David Conti, Christopher Dampier, Mathew Devall, Fredrick Schumacher, Marilena Melas, Gad Rennert, Mireia Obón-Santacana, Vicente Martín-Sánchez, Ferran Moratalla-Navarro, Jae Hwan Oh, Jeongseon Kim, Sun Ha Jee, Keum Ji Jung, Sun-Seog Kweon, Min-Ho Shin, Aesun Shin, Yoon-Ok Ahn, Dong-Hyun Kim, Isao Oze, Wanqing Wen, Keitaro Matsuo, Koichi Matsuda, Chizu Tanikawa, Zefang Ren, Yu-Tang Gao, Wei-Hua Jia, John Hopper, Mark Jenkins, Aung Ko Win, Rish Pai, Jane Figueiredo, Robert Haile, Steven Gallinger, Michael Woods, Polly Newcomb, David Duggan, Jeremy Cheadle, Richard Kaplan, Timothy Maughan, Rachel Kerr, David Kerr, Iva Kirac, Jan Böhm, Lukka-Pekka Mecklin, Pekka Jousilahti, Paul Knekt, Lauri Aaltonen, Harri Rissanen, Eero Pukkala, Johan Eriksson, Tatiana Cajuso, Ulrika Hänninen, Johanna Kondelin, Kimmo Palin, Tomas Tanskanen, Laura Renkonen-Sinisalo, Brent Zanke, Satu Männistö, Demetrius Albanes, Stephanie Weinstein, Edward Ruiz-Narvaez, Julie Palmer, Daniel Buchanan, Elizabeth Platz, Kala Visvanathan, Cornelia Ulrich, Erin Siegel, Stefanie Brezina, Andrea Gsur, Peter Campbell, Jenny Chang-Claude, Michael Hoffmeister, Hermann Brenner, Martha Slattery, John Potter, Konstantinos Tsilidis, Matthias Schulze, Marc Gunter, Neil Murphy, Antoni Castells, Sergi Castellví-Bel, Leticia Moreira, Volker Arndt, Anna Shcherbina, Mariana Stern, Bens Pardamean, Timothy Bishop, Graham Giles, Melissa Southey, Gregory Idos, Kevin McDonnell, Zomoroda Abu-Ful, Joel Greenson, Katerina Shulman, Flavio Lejbkowicz, Kenneth Offit, Yu-Ru Su, Robert Steinfelder, Temitope Keku, Bethany van Guelpen, Thomas Hudson, Heather Hampel, Rachel Pearlman, Sonja Berndt, Richard Hayes, Marie Elena Martinez, Sushma Thomas, Douglas Corley, Paul Pharoah, Susanna Larsson, Yun Yen, Heinz-Josef Lenz, Emily White, Li Li, Kimberly Doheny, Elizabeth Pugh, Tameka Shelford, Andrew Chan, Marcia Cruz-Correa, Annika Lindblom, David Hunter, Amit Joshi, Clemens Schafmayer, Peter Scacheri, Anshul Kundaje, Deborah Nickerson, Robert Schoen, Jochen Hampe, Zsofia Stadler, Pavel Vodicka, Ludmila Vodickova, Veronika Vymetalkova, Nickolas Papadopoulos, Chistopher Edlund, William Gauderman, Duncan Thomas, David Shibata, Amanda Toland, Sanford Markowitz, Andre Kim, Stephen Chanock, Franzel van Duijnhoven, Edith Feskens, Lori Sakoda, Manuela Gago-Dominguez, Alicja Wolk, Alessio Naccarati, Barbara Pardini, Liesel FitzGerald, Soo Chin Lee, Shuji Ogino, Stephanie Bien, Charles Kooperberg, Christopher Li, Yi Lin, Ross Prentice, Conghui Qu, Stéphane Bézieau, Catherine Tangen, Elaine Mardis, Taiki Yamaji, Norie Sawada, Motoki Iwasaki, Christopher Haiman, Loic Le Marchand, Anna Wu, Chenxu Qu, Caroline McNeil, Gerhard Coetzee, Caroline Hayward, Ian Deary, Sarah Harris, Evropi Theodoratou, Stuart Reid, Marion Walker, Li Yin Ooi, Victor Moreno, Graham Casey, Stephen Gruber, Ian Tomlinson, Wei Zheng, Malcolm Dunlop, Richard Houlston, and Ulrike Peters

Subjects
Global Nutrition, Wereldvoeding, Nutrition and Disease, Voeding en Ziekte, Genetics, Life Science, VLAG
Abstract

In the version of this article initially published, the author affiliations incorrectly listed “Candiolo Cancer Institute FPO-IRCCS, Candiolo (TO), Italy” as “Candiolo Cancer Institute, Candiolo, Italy.” The change has been made to the HTML and PDF versions of the article.

Published
2023
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2. A novel founder MSH2 deletion in Ethiopian Jews is mainly associated with early-onset colorectal cancer

Author

Zohar Levi, Sari Lieberman, G Reznick Levi, M Goldenberg, Lior H. Katz, Elizabeth E. Half, Yael Goldberg, L Walsh, D Rothstein, Thomas J. Walsh, T Yablonski Peretz, Ayala Hubert, Ido Laish, Inbal Kedar, Colin C. Pritchard, Lina Basel-Salmon, S Naftaly Nathan, Mary Claire King, R Tomashov-Matar, A Abu Shtaya, Ola Aleme, I Lagovsky, and Sergi Castellví-Bel

Subjects
0301 basic medicine, Oncology, Cancer Research, medicine.medical_specialty, business.industry, Colorectal cancer, Genetic counseling, 030105 genetics & heredity, medicine.disease, digestive system diseases, Lynch syndrome, Human genetics, 03 medical and health sciences, 0302 clinical medicine, MSH2, 030220 oncology & carcinogenesis, Internal medicine, Epidemiology, Anticipation (genetics), Genetics, Medicine, DNA mismatch repair, business, Genetics (clinical)
Abstract

Lynch syndrome is an inherited cancer predisposition syndrome caused by germline defects in any of the mismatch repair (MMR) genes. Diagnosis of carriers makes precision prevention, early detection, and tailored treatment possible. Herein we report a novel founder deletion of 18,758 bp, mediated by Alu repeats on both sides, detected in Ethiopian Jews. The deletion, which encompasses exon 9–10 of the MSH2 coding sequence, is associated mainly with early-onset MSH2/MSH6-deficient colorectal cancer (CRC) and liposarcoma. Testing of 35 members of 5 seemingly unrelated families of Ethiopian origin yielded 10/21 (48%) carriers, of whom 9 had CRC. Age at first tumor diagnosis ranged from 16 to 89 years. Carriers from the oldest generations were diagnosed after age 45 years (mean 57), and carriers from the younger generation were diagnosed before age 45 years (mean 30). Awareness of this founder deletion is important to improve patient diagnosis, institute surveillance from an early age, and refer patients for genetic counseling addressing the risk of bi-allelic constitutional MMR deficiency syndrome.

Published
2021
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3. MCM9 is associated with germline predisposition to early-onset cancer—clinical evidence

Author

Stavit A. Shalev, Sergi Castellví-Bel, Maartje Nielsen, Yael Goldberg, Lilach Peled-Perets, and Ola Aleme

Subjects
Infertility, Oncology, medicine.medical_specialty, Candidate gene, Molecular medicine, Colorectal cancer, business.industry, Cancer, Case Report, Heterozygote advantage, QH426-470, medicine.disease, Phenotype, Germline, Internal medicine, Knockout mouse, Genetics, medicine, Medicine, business, Cancer genetics, Molecular Biology, Genetics (clinical)
Abstract

Mutated MCM9 has been associated with primary ovarian insufficiency. Although MCM9 plays a role in genome maintenance and has been reported as a candidate gene in a few patients with inherited colorectal cancer (CRC), it has not been clearly established as a cancer predisposition gene. We re-evaluated family members with MCM9-associated fertility problems. The heterozygote parents had a few colonic polys. Three siblings had early-onset cancer: one had metastatic cervical cancer and two had early-onset CRC. Moreover, a review of the literature on MCM9 carriers revealed that of nine bi-allelic carriers reported, eight had early-onset cancer. We provide clinical evidence for MCM9 as a cancer germline predisposition gene associated with early-onset cancer and polyposis, mainly in a recessive inheritance pattern. These observations, coupled with the phenotype in knockout mice, suggest that diagnostic testing for polyposis, CRC, and infertility should include MCM9 analysis. Early screening protocols may be beneficial for carriers.

Published
2021
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4. Discovery of common and rare genetic risk variants for colorectal cancer

Author

Charles M. Connolly, Deborah A. Nickerson, Jian Gong, Sébastien Küry, Barbara Pardini, Brent W. Zanke, Andrea Gsur, Jochen Hampe, Coral Arnau-Collell, M. Henar Alonso, Elio Riboli, Annika Lindblom, Ulrike Peters, Gad Rennert, Tabitha A. Harrison, Lori C. Sakoda, Caroline McNeil, Flavio Lejbkowicz, Hyun Min Kang, David J. Hunter, Martha L. Slattery, Miguel Rodríguez-Barranco, Christina Bamia, Satu Männistö, Timothy J. Key, W. James Gauderman, Gonçalo R. Abecasis, Sanford D. Markowitz, Laurence N. Kolonel, Mark A. Jenkins, Yi Lin, Robin Myte, Hedy S. Rennert, Neil Murphy, Antonia Trichopoulou, Christopher I. Li, Ross L. Prentice, Sai Chen, Stephanie J. Weinstein, Kristin E. Anderson, Hua Ling, Mitul Shah, Philipp Hofer, Wen Yi Huang, Sergi Castellví-Bel, Susanna C. Larsson, Maria Dolores Chirlaque, Wei Zheng, Stephanie L. Schmit, Cecelia A. Laurie, Soo-Chin Lee, David Forman, Andrea N. Burnett-Hartman, Giovanna Masala, Sarah C. Nelson, Michael O. Woods, Charles Kooperberg, Qing Zhang, Sonja I. Berndt, Christopher S. Carlson, Katja Butterbach, Hyeong Rok Kim, Rebecca D. Jackson, David Van Den Berg, Michael C. Bassik, Amanda J. Cross, Sushma S. Thomas, Clemens Schafmayer, Anna H. Wu, Douglas F. Easton, Robert W. Haile, Ludmila Vodickova, Graham G. Giles, Yu Ru Su, Jenny Chang-Claude, Lorena Moreno, Peter C. Scacheri, Stefanie Brezina, Min-Ho Shin, Steven Gallinger, Bethany Van Guelpen, Daniel D. Buchanan, Roger L. Milne, Stephen J. Chanock, Tin Louie, Tameka Shelford, Emily White, Kala Visvanathan, Loic Le Marchand, Veronika Vymetalkova, Roxann G. Ingersoll, Temitope O. Keku, Stephanie A. Bien, Fredrick R. Schumacher, Wan-Ling Hsu, Amanda E. Toland, John S. Grove, Noralane M. Lindor, Faye Elliott, Leon Raskin, Heather Hampel, Joshua D. Smith, Vicente Martín, David V. Conti, Sjoerd G. Elias, Henk J. van Kranen, Manish Gala, Daniela Seminara, Syed H.E. Zaidi, Suzanne M. Leal, Tilman Kühn, Korbinian Weigl, Marc J. Gunter, Cornelia M. Ulrich, Peyton Greenside, Victor Moreno, John D. Potter, Michael Hoffmeister, Eric J. Jacobs, Catherine M. Tangen, Jihyoun Jeon, Fränzel J.B. Van Duijnhoven, Andrew T. Chan, Stephen B. Gruber, John A. Baron, Alicja Wolk, Edith J. M. Feskens, Demetrius Albanes, Amit Joshi, Bette J. Caan, Polly A. Newcomb, Stéphane Bézieau, Elizabeth M. Gillanders, Anshul Kundaje, Elizabeth A. Platz, Michael Wainberg, Sun-Seog Kweon, C. Roland Wolf, Gemma Ibáñez-Sanz, Shuji Ogino, Emiko Kobayashi, Richard B. Hayes, Patrick S. Parfrey, Katarina Cuk, Stephen N. Thibodeau, Kenneth Offit, David Duggan, Sophia Harlid, Pavel Vodicka, Juergen Boehm, Christa Stegmaier, Jeroen R. Huyghe, Joseph Vijai, Sang-Hee Cho, Elizabeth W. Pugh, Rachel Pearlman, Alessio Naccarati, Marilena Melas, Graham Casey, Jane Romm, Stephan Buch, Phyllis J. Goodman, Albert de la Chapelle, John L. Hopper, Zsofia K. Stadler, Corinne E. Joshu, Liesel M. FitzGerald, Wolfgang Lieb, Aung Ko Win, Keith R. Curtis, Hermann Brenner, Christopher K. Edlund, Li Hsu, Conghui Qu, Peter T. Campbell, Robert E. Schoen, Heiner Boeing, D. Timothy Bishop, Kimberly F. Doheny, Sabina Sieri, Barbara L. Banbury, Mathieu Lemire, Jane C. Figueiredo, Gregory Idos, Katerina Shulman, Thomas J. Hudson, Melissa C. Southey, Duncan C. Thomas, Paul D.P. Pharoah, Mila Pinchev, Vittorio Perduca, Rocky Fischer, Volker Arndt, William M. Grady, Nasa Sinnott-Armstrong, N. Charlotte Onland-Moret, David M. Levine, Li Li, Dallas R. English, Health Research Board - Ireland, Department of Medical Genetics, HMNC Brain Health, Case Western Reserve University [Cleveland], National Cancer Institute, NIH, Division of Clinical Epidemiology and Aging Research, German Cancer Research Center - Deutsches Krebsforschungszentrum [Heidelberg] (DKFZ), WHO Collaborating Center for Food and Nutrition Policies, Department of Hygiene, Epidemiology and Medical Statistics, University of Athens Medical School, National Cancer Institute [Bethesda] (NCI-NIH), National Institutes of Health [Bethesda] (NIH), Service de Génétique, Centre hospitalier universitaire de Nantes (CHU Nantes), Department of Epidemiology, German Institute of Human Nutrition Potsdam-Rehbruecke, Division of Cancer Epidemiology, Cancer Genome Project, The Wellcome Trust Sanger Institute [Cambridge], Division of Signaling Biology, Ontario Cancer Institute, Consorcio de Investigación Biomédica en Red especializado en Epidemiología y Salud Pública (CIBERESP), Los Centros de Investigación Biomédica en Red (CIBER), National Institute of Standards and Technology [Gaithersburg] (NIST), Ohio State University [Columbus] (OSU), Centre for Cancer Genetic Epidemiology, University of Cambridge [UK] (CAM), Section of Epidemiology and Biostatistics, Leeds Institute of Molecular Medicine, Cancer Epidemiology Centre, Cancer Council Victoria, Division of Human Nutrition, Wageningen University and Research [Wageningen] (WUR), Division of Public Health Sciences, Fred Hutchinson Cancer Research Center [Seattle] (FHCRC), Northern and Yorkshire Cancer Registry and Information Service, Familial Gastrointestinal Cancer Registry, Mount Sinai Hospital [Toronto, Canada] (MSH), University of Melbourne, Nutrition and Metabolism Section, International Agency for Cancer Research (IACR), Department of Internal Medicine I, University Hospital Schleswig-Holstein, Campus Kiel, London School of Hygiene and Tropical Medicine (LSHTM), Fraunhofer Institute for Manufacturing Engineering and Automation (Fraunhofer IPA), Fraunhofer (Fraunhofer-Gesellschaft), Centre for Molecular , Environmental, Genetic and Analytic (MEGA) Epidemiology, University of Melbourne-Centre for Molecular, Melbourne School of Population Health, Department of Mathematics, University of Warwick, Warwick Mathematics Institute (WMI), University of Warwick [Coventry]-University of Warwick [Coventry], Department of Statistics, Penn State University, University of Pennsylvania [Philadelphia], Tata Memorial Centre, Cancer Epidemiology Unit, University of Oxford [Oxford], Thermo Fisher Scientific, Thermo Fisher Scientific Inc., Department of Molecular and Human Genetics, Baylor College of Medicine (BCM), Baylor University-Baylor University, National University Health System, Department of Community Medicine and Epidemiology, CHS National Cancer Control Center, Ontario Institute for Cancer Research [Canada] (OICR), Ontario Institute for Cancer Research, Laboratoire de Génie Electrique de Grenoble (G2ELab), Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Chronic Disease Epidemiology and Prevention Unit, National Institute for Health and Welfare [Helsinki], Dell-EMC, Molecular and Nutritional Epidemiology Unit (ISPO), Cancer Research and Prevention Institute, Clinical Genetics Service, Memorial Sloane Kettering Cancer Center [New York], Department of Pathology, Brigham and Women's Hospital [Boston], University Medical Center [Utrecht], Mathématiques Appliquées Paris 5 (MAP5 - UMR 8145), Université Paris Descartes - Paris 5 (UPD5)-Institut National des Sciences Mathématiques et de leurs Interactions (INSMI)-Centre National de la Recherche Scientifique (CNRS), Department of Oncology, Department of Epidemiology and Biostatistics, Imperial College London, Department of Visceral and Thoracic Surgery [Kiel, Germany], University Hospital Schleswig-Holstein [Kiel, Germany], Nutritional Epidemiology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, entre for Molecular, Environmental, Genetic and Analytic (MEGA) Epidemiology, Department of Laboratory Medicine and Department of Pathology, Mayo Clinic College of Medicine, Department of Molecular Virology, Immunology and Medical Genetics [Colombus], Ohio State University [Columbus] (OSU)-College of Medicine and Public Health [Colombus], Department of Hygiene, Epidemiology and Medical Statistics, University of Athens Medical School [Athens], Department of Medical Biosciences and Pathology, Umeå University, Institute of Experimental Medicine, Czech Academy of Sciences [Prague] (CAS), Dundee Technopole, CXR Biosciences Ltd, Karolinska Institutet [Stockholm], CINTRA / SEEE Nanyang Technological University, Nanyang Technological University [Singapour], Center for Astrophysical Sciences [Baltimore], Johns Hopkins University (JHU), Computer Science and Artificial Intelligence Laboratory (CSAIL), Massachusetts Institute of Technology (MIT), Department of Preventive Medicine, University of Southern California (USC), Biomedical Research Centre Network for Rare Diseases, CIBER de Enfermedades Raras (CIBERER), Medstar Research Institute, Department of Genome Sciences [Seattle] (GS), University of Washington [Seattle], Department of Internal Medicine, Epidemiology, Human Genetics, University of Michigan [Ann Arbor], University of Michigan System-University of Michigan System, Wageningen University and Research Centre [Wageningen] (WUR), Mount Sinai Hospital (MSH), Fraunhofer Institute for Manufacturing Engineering and Automation [Stuttgart] (IPA), Université Joseph Fourier - Grenoble 1 (UJF)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP)-Institut Polytechnique de Grenoble - Grenoble Institute of Technology-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA), Czech Academy of Sciences [Prague] (ASCR), Huyghe, Jeroen R [0000-0001-6027-9806], Harrison, Tabitha A [0000-0002-4173-7530], Chen, Sai [0000-0003-3106-5643], Schmit, Stephanie L [0000-0001-5931-1194], Jeon, Jihyoun [0000-0001-7003-3412], Schumacher, Fredrick R [0000-0002-3073-7463], Nelson, Sarah C [0000-0002-2109-6465], Sinnott-Armstrong, Nasa A [0000-0003-4490-0601], Alonso, M Henar [0000-0003-0285-5451], Arndt, Volker [0000-0001-9320-8684], Bézieau, Stéphane [0000-0003-0095-1319], Bishop, D Timothy [0000-0002-8752-8785], Brezina, Stefanie [0000-0001-5238-6900], Buchanan, Daniel D [0000-0003-2225-6675], Chanock, Stephen J [0000-0002-2324-3393], de la Chapelle, Albert [0000-0001-9345-9248], Easton, Douglas F [0000-0003-2444-3247], Hampe, Jochen [0000-0002-2421-6127], Hayes, Richard B [0000-0002-0918-661X], Hofer, Philipp [0000-0003-2550-6019], Huang, Wen-Yi [0000-0002-4440-3368], Hudson, Thomas J [0000-0002-1376-4849], Jacobs, Eric J [0000-0002-8458-7659], Jenkins, Mark A [0000-0002-8964-6160], Joshi, Amit D [0000-0001-7581-6934], Küry, Sébastien [0000-0001-5497-0465], Larsson, Susanna C [0000-0003-0118-0341], Laurie, Cecelia A [0000-0001-6569-2501], Martín, Vicente [0000-0003-0552-2804], Masala, Giovanna [0000-0002-5758-9069], Milne, Roger L [0000-0001-5764-7268], Naccarati, Alessio [0000-0001-5774-0905], Newcomb, Polly A [0000-0001-8786-0043], Pardini, Barbara [0000-0001-9571-4257], Perduca, Vittorio [0000-0003-0339-0473], Pharoah, Paul DP [0000-0001-8494-732X], Raskin, Leon [0000-0003-1195-7214], Rennert, Gad [0000-0002-8512-068X], Shin, Min-Ho [0000-0002-2217-5624], Toland, Amanda E [0000-0002-0271-1792], Vijai, Joseph [0000-0002-7933-151X], Weigl, Korbinian [0000-0003-4453-2036], Win, Aung Ko [0000-0002-2794-5261], Wolk, Alicja [0000-0001-7387-6845], Zheng, Wei [0000-0003-1226-070X], Bassik, Michael C [0000-0001-5185-8427], Moreno, Victor [0000-0002-2818-5487], Peters, Ulrike [0000-0001-5666-9318], and Apollo - University of Cambridge Repository

Subjects
Male, Nutrition and Disease, Colorectal cancer, IDENTIFIES 6, Genome-wide association study, 0302 clinical medicine, Risk Factors, Voeding en Ziekte, Genotype, ComputingMilieux_MISCELLANEOUS, Avaluació del risc per la salut, Genetics & Heredity, Genetics, 0303 health sciences, COLON-CANCER, 11 Medical And Health Sciences, Middle Aged, 3. Good health, Medical genetics, Female, RNA, Long Noncoding, Colorectal Neoplasms, Life Sciences & Biomedicine, Signal Transduction, EXPRESSION, medicine.medical_specialty, SUSCEPTIBILITY LOCI, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biology, Polymorphism, Single Nucleotide, Article, Health risk assessment, 03 medical and health sciences, QUALITY-CONTROL, Càncer colorectal, Journal Article, medicine, Life Science, Humans, Genetic Predisposition to Disease, GENOME-WIDE ASSOCIATION, METAANALYSIS, VLAG, Aged, 030304 developmental biology, Global Nutrition, [SDV.GEN]Life Sciences [q-bio]/Genetics, Wereldvoeding, Science & Technology, ORGAN SIZE, MUTATIONS, Haplotype, Case-control study, 06 Biological Sciences, medicine.disease, Genetic architecture, Case-Control Studies, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Human genome, LYSOPHOSPHATIDIC ACID, 030217 neurology & neurosurgery, Developmental Biology, Genome-Wide Association Study
Abstract

To further dissect the genetic architecture of colorectal cancer (CRC), we performed whole-genome sequencing of 1,439 cases and 720 controls, imputed discovered sequence variants and Haplotype Reference Consortium panel variants into genome-wide association study data, and tested for association in 34,869 cases and 29,051 controls. Findings were followed up in an additional 23,262 cases and 38,296 controls. We discovered a strongly protective 0.3% frequency variant signal at CHD1. In a combined meta-analysis of 125,478 individuals, we identified 40 new independent signals at P, Reporting Summary. Further information on experimental design is available in the Life Sciences Reporting Summary linked to this article.

Published
2018
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5. The transcription factor GATA6 enables self-renewal of colon adenoma stem cells by repressing BMP gene expression

Author

Carme Cortina, Marta Sevillano, Ana Silvina Nacht, Gavin Whissell, Peter Jung, Alexandre Calon, Guillermo P. Vicent, Sergi Castellví-Bel, Paola Martinelli, Xavier Hernando-Momblona, Eduard Batlle, Anna Abulí, Francisco X. Real, Camille Stephan-Otto Attolini, Elena Sancho, Elisa Montagni, and Antoni Castells

Subjects
Adenoma, Male, endocrine system, Fluorescent Antibody Technique, Antineoplastic Agents, Biology, Mice, Cancer stem cell, GATA6 Transcription Factor, Animals, Humans, Transcription factor, Cell Proliferation, Regulation of gene expression, GATA6, Stem Cells, LGR5, Wnt signaling pathway, Bone Morphogenetic Protein Receptors, Cell Biology, TCF4, digestive system diseases, Cell biology, Gene Expression Regulation, Neoplastic, Wnt Proteins, Have You Seen?, Pyrimidines, Pyrazoles, Female, Stem cell, Colorectal Neoplasms
Abstract

Aberrant activation of WNT signalling and loss of BMP signals represent the two main alterations leading to the initiation of colorectal cancer (CRC). Here we screen for genes required for maintaining the tumour stem cell phenotype and identify the zinc-finger transcription factor GATA6 as a key regulator of the WNT and BMP pathways in CRC. GATA6 directly drives the expression of LGR5 in adenoma stem cells whereas it restricts BMP signalling to differentiated tumour cells. Genetic deletion of Gata6 from mouse colon adenomas increases the levels of BMP factors, which signal to block self-renewal of tumour stem cells. In human tumours, GATA6 competes with β-catenin/TCF4 for binding to a distal regulatory region of the BMP4 locus that has been linked to increased susceptibility to development of CRC. Hence, GATA6 creates an environment permissive for CRC initiation by lowering the threshold of BMP signalling required for tumour stem cell expansion.

Published
2014
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6. Association of MUTYH and MSH6 germline mutations in colorectal cancer patients

Author

Clara Ruiz-Ponte, Sergi Castellví-Bel, Teresa Ocaña, María Dolores Giráldez, Jenifer Muñoz, Victoria Gonzalo, Nuria Gómez-Fernández, Rodrigo Jover, Antoni Castells, Leticia Moreira, Pilar Garre, Ana Sánchez-de-Abajo, Trinidad Caldés, Francesc Balaguer, Joan Clofent, Montserrat Andreu, Xavier Llor, and Angel Carracedo

Subjects
Male, Cancer Research, DNA repair, DNA Mutational Analysis, Nonsense mutation, medicine.disease_cause, Polymerase Chain Reaction, Germline, DNA Glycosylases, Germline mutation, MUTYH, Genetics, medicine, Humans, Missense mutation, Genetic Predisposition to Disease, neoplasms, Germ-Line Mutation, Genetics (clinical), Aged, Mutation, business.industry, Immunohistochemistry, digestive system diseases, DNA-Binding Proteins, MSH6, Oncology, Cancer research, Female, Colorectal Neoplasms, business
Abstract

Colorectal cancer (CRC) risk associated with germline monoallelic MUTYH mutations remains controversial, although a slightly increased risk for this disease has been suggested. MUTYH and MSH6 proteins act in cooperation during the DNA repair process. Based on this interaction, it was hypothesized that the combination of heterozygote germline mutations in both genes could result in an increased CRC risk. To further clarify the interaction between MUTYH and MSH6, we analyzed the prevalence of MSH6 mutations in a cohort of CRC patients and controls previously tested for MUTYH mutations: CRC patients with and without a monoallelic MUTYH mutation (group I, n = 26; group II, n = 50, respectively), and healthy carriers with a monoallelic MUTYH mutation (group III, n = 21). In group I, we found three patients (11.5%) with MSH6 mutations, a missense mutation (p.R635G), a change in the 3′UTR region (c.*4098A > C) and a nonsense mutation (p.Q982X). In group II and III, no mutations were detected. In CRC patients, MSH6 mutations were more frequently found in MUTYH mutation carriers than in noncarriers (11.5% vs. 0%, P = 0.037). CRC patients carrying monoallelic MUTYH mutations harbor more frequently concomitant MSH6 mutations than patients without them, thus suggesting that both genes could act cooperatively and confer together an increased CRC risk.

Published
2009
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7. A genome-wide association study identifies colorectal cancer susceptibility loci on chromosomes 10p14 and 8q23.3

Author

Sari Tuupanen, Melissa C. Southey, Ian Chandler, Enric Domingo, Paul D.P. Pharoah, Luis G. Carvajal-Carmona, D. Gareth Evans, Malcolm G. Dunlop, Trinidad Caldés, Graham G. Giles, Zoe Kemp, Harry Campbell, David J. Kerr, Alan M. Pittman, Eamonn R. Maher, D. Timothy Bishop, Jayaram Vijayakrishnan, Hans Morreau, Albert Tenesa, Asta Försti, Jean-Baptiste Cazier, Kimberley Howarth, Ella Barclay, Rebecca A. Barnetson, Tom van Wezel, Juul T. Wijnen, James G. D. Prendergast, Maggie Gorman, Julian Peto, Anneke Lucassen, Antoni Castells, Jochen Hampe, José A. G. Agúndez, Susan M. Farrington, Kate Sullivan, Henry Völzke, Richard Gray, Ulrich John, King Yip Cheng, Pavel Vodicka, Emma Jaeger, Peter Broderick, Judy W. C. Ho, Mobshra Qureshi, Lauri A. Aaltonen, Stephan Buch, Sarah Fielding, Sarah L. Spain, Lynn Martin, Andrew Rowan, Wendy Wood, Emily L. Webb, John M. Luk, Angel Carracedo, Clara Ruiz-Ponte, Alessio Naccarati, Steven J. Lubbe, Ian Tomlinson, Lara Lipton, John L. Hopper, Iina Niittymäki, Axel Walther, José M. Ladero, Pak C. Sham, Stefan Schreiber, Sergi Castellví-Bel, Miguel de la Hoya, Clemens Schafmayer, Gianluca Severi, Auli Karhu, Steven Penegar, Thibaud Koessler, Kari Hemminki, Richard S. Houlston, and Huw Thomas

Subjects
Adult, Male, Genetic Linkage, Colorectal cancer, Eukaryotic Initiation Factor-3, Single-nucleotide polymorphism, Genome-wide association study, Locus (genetics), Biology, Polymorphism, Single Nucleotide, 03 medical and health sciences, 0302 clinical medicine, Genetic linkage, Genetics, medicine, Humans, Genetic Predisposition to Disease, Allele, Genotyping, Alleles, Aged, 030304 developmental biology, 0303 health sciences, Chromosomes, Human, Pair 10, Genome, Human, Cancer, Middle Aged, medicine.disease, Pedigree, 3. Good health, 030220 oncology & carcinogenesis, Female, Colorectal Neoplasms, Chromosomes, Human, Pair 8
Abstract

To identify colorectal cancer (CRC) susceptibility alleles, we conducted a genome-wide association study. In phase 1, we genotyped 550,163 tagSNPs in 940 familial colorectal tumor cases (627 CRC, 313 high-risk adenoma) and 965 controls. In phase 2, we genotyped 42,708 selected SNPs in 2,873 CRC cases and 2,871 controls. In phase 3, we evaluated 11 SNPs showing association at P < 10(-4) in a joint analysis of phases 1 and 2 in 4,287 CRC cases and 3,743 controls. Two SNPs were taken forward to phase 4 genotyping (10,731 CRC cases and 10,961 controls from eight centers). In addition to the previously reported 8q24, 15q13 and 18q21 CRC risk loci, we identified two previously unreported associations: rs10795668, located at 10p14 (P = 2.5 x 10(-13) overall; P = 6.9 x 10(-12) replication), and rs16892766, at 8q23.3 (P = 3.3 x 10(-18) overall; P = 9.6 x 10(-17) replication), which tags a plausible causative gene, EIF3H. These data provide further evidence for the 'common-disease common-variant' model of CRC predisposition.

Published
2008
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8. Who requires genetic testing?

Author

Victoria Gonzalo, M. Dolores Giráldez, Sergi Castellví-Bel, Francesc Balaguer, Antoni Castells, and Teresa Ocaña

Subjects
Oncology, medicine.medical_specialty, Hepatology, medicine.diagnostic_test, Colorectal cancer, business.industry, Gastroenterology, Cancer, medicine.disease, Bioinformatics, Lynch syndrome, Colorectal surgery, Familial adenomatous polyposis, Internal medicine, medicine, Lifetime risk, Family history, business, Genetic testing
Abstract

Colorectal cancer (CRC) is the second most common cancer worldwide and the second leading cause of cancer mortality in Western countries. The lifetime risk of CRC in the average-risk person—one aged above 50 years and without a personal or family history of this neoplasm—is 5% to 6%. This risk may be as high as 20% if first-or second-degree relatives have CRC and reaches a lifetime risk of 80% to 100% in hereditary syndromes. Knowledge of the genetic basis for CRC has been applied to genetic testing, genotypic-phenotypic correlations, and provision of a rationale for chemopreventive and therapeutic approaches. This article reviews the most relevant recent advances in the genetics of polyposis and nonpolyposis colorectal syndromes, emphasizing their clinical application in gene testing.

Published
2008
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9. Screening for FMR1 and FMR2 mutations in 222 individuals from Spanish special schools: identification of a case of FRAXE-associated mental retardation

Author

Celia Badenas, Maria Pia Villa, Xavier Estivill, C Brun, Sergi Castellví-Bel, Montserrat Milà, Aurora Sánchez, and Dolores Jiménez

Subjects
Adult, Male, congenital, hereditary, and neonatal diseases and abnormalities, X Chromosome, Adolescent, Nerve Tissue Proteins, Biology, medicine.disease_cause, Fragile X Mental Retardation Protein, Trinucleotide Repeats, Genetics, medicine, Humans, Genetic Testing, Child, Gene, Genetics (clinical), Genetic testing, Mutation, Schools, medicine.diagnostic_test, Mosaicism, Chromosome Fragile Sites, Chromosome Fragility, Chromosomal fragile site, Nuclear Proteins, Proteins, RNA-Binding Proteins, DNA Methylation, medicine.disease, FMR1, Fragile X syndrome, Phenotype, Psychotic Disorders, Spain, Chromosome Fragile Site, Child, Preschool, Fragile X Syndrome, Trans-Activators, Female, Trinucleotide repeat expansion
Abstract

Fragile X syndrome is the most common inherited form of familial mental retardation. It results from a (CGG)n trinucleotide expansion in the FMR1 gene leading to the typical Martin-Bell phenotype. Clinical features vary depending on age and sex. Expansion of a (CCG)n repeat in the FMR2 gene corresponds to the FRAXE fragile site which lies distal to FRAXA and is also associated with mental retardation, but it is less frequent and lacks a consistent phenotype. Analysis of repeat expansions in these two genes allows the molecular diagnosis of these different entities. We report here the screening of the FRAXA and FRAXE mutations in 222 unrelated mentally retarded individuals attending Spanish special schools. PCR and/or Southern blotting methods were used. We detected full mutations in the FMR1 gene in 11 boys (4.9%) and 1 boy (0.5%) with a CCG repeat expansion in the FMR2 gene. The latter shows mild mental retardation with psychotic behaviour and no remarkable physical traits. Molecular studies revealed a mosaicism for methylation in the FMR2 gene. This case supports the observation that expansions greater than 100 repeats can be partially methylated and cause the phenotype.

Published
1997
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10. Molecular analysis of the APC and MUTYH genes in Galician and Catalonian FAP families: a different spectrum of mutations?

Author

Ana Vega, Sergi Castellví-Bel, Ceres Fernandez-Rozadilla, Angel Carracedo, Irene Madrigal, Montserrat Milà, Begoña Graña, Antoni Castells, Clara Ruiz-Ponte, Nuria Gómez-Fernández, Francesc Balaguer, Jenifer Muñoz, and Universidade de Santiago de Compostela. Departamento de Ciencias Forenses, Anatomía Patolóxica, Xinecoloxía e Obstetricia, e Pediatría

Subjects
Adult, Male, lcsh:Internal medicine, Genes, APC, lcsh:QH426-470, Adolescent, Adenomatous polyposis coli, Colorectal cancer, DNA Glycosylases, Familial adenomatous polyposis, Young Adult, Germline mutation, Gene Frequency, MUTYH, Ethnicity, Genetics, medicine, Humans, Genetics(clinical), lcsh:RC31-1245, Allele frequency, Germ-Line Mutation, In Situ Hybridization, Fluorescence, Genetics (clinical), Sequence Deletion, biology, Sequence Analysis, DNA, Nucleic acid amplification technique, Middle Aged, medicine.disease, Human genetics, lcsh:Genetics, Adenomatous Polyposis Coli, Spain, biology.protein, Female, Nucleic Acid Amplification Techniques, Research Article
Abstract

Background Familial adenomatous polyposis (FAP) is an autosomal dominant-inherited colorectal cancer syndrome, caused by germline mutations in the APC gene. Recently, biallelic mutations in MUTYH have also been identified in patients with multiple colorectal adenomas and in APC-negative patients with FAP. The aim of this work is therefore to determine the frequency of APC and MUTYH mutations among FAP families from two Spanish populations. Methods Eighty-two unrelated patients with classical or attenuated FAP were screened for APC germline mutations. MUTYH analysis was then conducted in those APC-negative families and in 9 additional patients from a previous study. Direct sequencing, SSCP analysis and TaqMan genotyping were used to identify point and frameshift mutations, meanwhile large rearrangements in the APC gene were screened by multiplex ligation-dependent probe amplification (MLPA). Results APC germline mutations were found in 39% of the patients and, despite the great number of genetic variants described so far in this gene, seven new mutations were identified. The two hotspots at codons 1061 and 1309 of the APC gene accounted for 9,4% of the APC-positive families, although they were underrepresented in Galician samples. The deletion at codon 1061 was not found in 19 APC-positive Galician patients but represented 23% of the Catalonian positive families (p = 0,058). The same trend was observed at codon 1309, even though statistical analysis showed no significance between populations. Twenty-four percent of the APC-negative patients carried biallelic MUTYH germline mutations, and showed an attenuated polyposis phenotype generally without extracolonic manifestations. New genetic variants were found, as well as the two hotspots already reported (p.Tyr165Cys and p.Gly382Asp). Conclusion The results we present indicate that in Galician patients the frequency of the hotspot at codon 1061 in APC differs significantly from the Catalonian and also other Caucasian populations. Similar results had already been obtained in a previous study and could be due to the genetic isolation of the Galician population. MUTYH analysis is also recommended for all APC-negative families, even if a recessive inheritance is not confirmed.

Published
2009
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11. A female compound heterozygote (pre- and full mutation) for the CGG FMR1 expansion

Author

Xavier Estivill, Celia Badenas, Sergi Castellví-Bel, Ramon Giné, Aurora Sánchez, C. Vazquez, and Montserrat Milà

Subjects
Adult, Male, congenital, hereditary, and neonatal diseases and abnormalities, X Chromosome, Genetic Carrier Screening, Nerve Tissue Proteins, Biology, Compound heterozygosity, Methylation, Fragile X Mental Retardation Protein, Trinucleotide Repeats, Reference Values, Intellectual Disability, Atlantic Islands, Genetics, medicine, Humans, Index case, Genetics (clinical), X chromosome, Chromosome Mapping, RNA-Binding Proteins, medicine.disease, FMR1, Pedigree, nervous system diseases, Fragile X syndrome, Fragile X Syndrome, Mutation, Mutation (genetic algorithm), Microsatellite, Female
Abstract

Fragile X syndrome is the most common cause of inherited mental retardation. The incidence has been estimated to be 1 in 1250 males and 1 in 2000 females. Molecular studies have shown that 95% of fragile X syndrome cases are caused by the expansion of a CGG triplet in the FMR1 gene with hypermethylation of the adjacent CpG island. In spite of the high incidence of this syndrome, a female with both FMR1 genes in the expanded form has never been reported. We presenting mental retardation and attention problems. Molecular analysis has revealed that both of her FMR1 genes have the CGG expansion, one with a premutation and the other with a full mutation. We have studied the CGG repeat in the FMR1 gene in 64 members of her family and detected 33 normal individuals, 14 carriers with the premutation (1 male and 13 females), and 18 individuals with full mutations (8 males and 10 females). The index case illustrates that the possibility of both parents being carriers of the fragile X syndrome premutation should be considered in consanguineous families or in small communities.

Published
1996
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