The University of Southampton
University of Southampton Institutional Repository

Common variation near CDKN1A, POLD3 and SHROOM2 influences colorectal cancer risk

Common variation near CDKN1A, POLD3 and SHROOM2 influences colorectal cancer risk
Common variation near CDKN1A, POLD3 and SHROOM2 influences colorectal cancer risk

We performed a meta-analysis of five genome-wide association studies to identify common variants influencing colorectal cancer (CRC) risk comprising 8,682 cases and 9,649 controls. Replication analysis was performed in case-control sets totaling 21,096 cases and 19,555 controls. We identified three new CRC risk loci at 6p21 (rs1321311, near CDKN1A; P = 1.14 × 10 -10), 11q13.4 (rs3824999, intronic to POLD3; P = 3.65 × 10 -10) and Xp22.2 (rs5934683, near SHROOM2; P = 7.30 × 10 -10) This brings the number of independent loci associated with CRC risk to 20 and provides further insight into the genetic architecture of inherited susceptibility to CRC.

1061-4036
770-776
Dunlop, Malcolm G.
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Dobbins, Sara E.
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Dunlop, Malcolm G., Dobbins, Sara E., Farrington, Susan Mary, Jones, Angela M., Palles, Claire, Whiffin, Nicola, Tenesa, Albert, Spain, Sarah, Broderick, Peter, Ooi, Li Yin, Domingo, Enric, Smillie, Claire, Henrion, Marc, Frampton, Matthew, Martin, Lynn, Grimes, Graeme, Gorman, Maggie, Semple, Colin, Ma, Yusanne P., Barclay, Ella, Prendergast, James, Cazier, Jean Baptiste, Olver, Bianca, Penegar, Steven, Lubbe, Steven, Chander, Ian, Carvajal-Carmona, Luis G., Ballereau, Stephane, Lloyd, Amy, Vijayakrishnan, Jayaram, Zgaga, Lina, Rudan, Igor, Theodoratou, Evropi, Thomas, Huw, Maher, Eamonn, Evans, Gareth, Walker, Lisa, Halliday, Dorothy, Lucassen, Anneke, Paterson, Joan, Hodgson, Shirley, Homfray, Tessa, Side, Lucy, Izatt, Louise, Donaldson, Alan, Tomkins, Susan, Morrison, Patrick, Brewer, Carole, Henderson, Alex, Davidson, Rosemarie, Murday, Victoria, Cook, Jaqueline, Haites, Neva, Bishop, Timothy, Sheridan, Eamonn, Green, Andrew, Marks, Christopher, Carpenter, Sue, Broughton, Mary, Greenhalge, Lynn, Suri, Mohnish, Starr, John M., Deary, Ian, Kirac, Iva, Kovacevia, Dujo, Aaltonen, Lauri A., Renkonen-Sinisalo, Laura, Mecklin, Jukka Pekka, Matsuda, Koichi, Nakamura, Yusuke, Okada, Yukinori, Gallinger, Steven, Duggan, David J., Conti, David, Newcomb, Polly, Hopper, John, Jenkins, Mark A., Schumacher, Fredrick, Casey, Graham, Easton, Douglas, Shah, Mitul, Pharoah, Paul, Lindblom, Annika, Liu, Tao, Edler, David, Lenander, Claes, Dalén, Johan, Hjern, Fredrik, Lundqvist, Nils, Lindforss, Ulrik, Påhlman, Lars, Smedh, Kennet, Törnqvist, Anders, Holm, Jörn, Janson, Martin, Andersson, Magnus, Ekelund, Susanne, Olsson, Louise, Smith, Christopher G., West, Hannah, Cheadle, Jeremy P., MacDonald, Graham, Samuel, Leslie M., Ahmad, Athar, Corrie, Philippa, Jodrell, Duncan, Palmer, Cheryl, Wilson, Charles, O'Hagan, Julie, Smith, David, McDermott, Ray, Walshe, Janice, Cassidy, James, McDonald, Alec, Mohammed, Nazia, White, Jeff, Yosef, Hosney, Breathnach, Oscar, Grogan, Liam, Thomas, Robert, Eatock, Martin, Henry, Paul, Houston, Russell, Johnston, Patrick, Wilson, Richard, Geh, Ian, Danwata, Falalu, Hindley, Andrew, Susnerwala, Shabbir, Bradley, Chris, Conn, Andrew, Raine, Anne, Twelves, Chris, Falk, Stephen, Hopkins, Kirstin, Tahir, Saad, Dhadda, Amandeep, Maraveyas, Anthony, Sgouros, Joseph, Teo, Mark, Ahmad, Rizvana, Cleator, Susan, Creak, Antonia, Lowdell, Charles, Riddle, Philippa, Benstead, Kim, Farrugia, David, Reed, Nicholas, Shepherd, Stephen, Levine, Edward, Mullamitha, Saifee, Saunders, Mark, Valle, Juan, Wilson, Gregory, Jones, Adam, Weaver, Andrew, Clark, Peter I., Haylock, Brain, Iqbal, Mussawar I., Myint, Arthur S., Beesley, Sharon, Sevitt, Timothy, Nicoll, Jonathan, Daniel, Francis, Ford, Victoria, Talbot, Toby, Butt, Mohammad, Hamid, Abdel, MacK, Paul, Roy, Raj, Osborne, Richard, McKinna, Fiona, Alsab, Heidar, Basu, Devyanee, Murray, Phillip, Sizer, Bruce, Azam, Faisal A., Neupane, Rekha, Waterston, Ashita, Glaholm, John, Blesing, Claire, Lowndes, Sarah, Medisetti, Aruna, Gaya, Andrew, Leslie, Martin, Maisey, Nicholas, Ross, Paul, Dunn, Grainne, Al-Salihi, Omar, Wasan, Harpreet S., Tan, Li Tee, Dent, Jo, Hofmann, Uschi, Joffe, Johnathan K., Sherwin, Elizabeth, Soomal, Rabinder, Chakrabarti, Amitabha, Joseph, Shibu, Van Der Voet, Johannes, Wadd, Nicholas J., Wilson, David, Anjarwalia, Salim, Hall, Julia, Hughes, Rob, Polychronis, Andrew, Scarffe, John H., Hill, Mark, James, Rodger D., Shah, Riyaz, Summers, Jeffrey, Hartley, Andrew, Carney, Desmond, McCaffrey, John, Bystricky, Brano, O'Reilly, Seamus, Gupta, Rajnish, Al-Mishlab, Talib, Gidden, Fiona, O'Hara, Richard, Stewart, Jill, Ashford, Richard, Glynne-Jones, Robert, Harrison, Mark, Mawdsley, Suzannah, Barlow, Hilary, Tighe, Mary, Walther, Julie, Neal, Janet, Rees, Charlotte, Bridgewater, John, Karp, Stephen, McGovern, Ursula, Atherton, Philip J., El-Deeb, Hany, MacMillan, Craig, Patel, Kinnari, Bessell, Eric Michael, Dickinson, Peter D., Potter, Vanessa, Jephcott, Catherine, McAdam, Karen, Wrigley, Jessica, Muthuramalingam, Sethupathi, O'Callaghan, Anne, Melcher, Lucinda, Braconi, Chiara, Geh, Ju Ian, Palmer, Dan, Narayana, Priya, Steven, Neil, Gaya, Andres, Rudman, Sarah, Chakraborti, Prabir, Kelly, Kay, MacGregor, Carol, Whillis, David, Freebairn, Alice, Gildersleve, James, Sharif, Sahid, Astras, George, Hickish, Tamas, Beech, Darren, Ellis, Richard, Kulkarni, Rajendra, Shankland, K., Begent, Richard, Mayer, Astrid, Meyer, Timothy, Strauss, Sandra, Hall, Viriginia, Raj, Sanjay, Chau, Ian, Cunningham, David, Birtle, Alison, Biswas, Ashoke, Wise, Marcus, Cummins, Sebastian, Essapen, Sharadah, Middleton, Gary, Topham, Claire, Langley, Ruth, Webb, Andrew, Wilkins, Marie, Iveson, Timothy John, Askill, Colin, Wagstaff, John, Azzabi, Ashraf, Bateman, Adrian, Prejbisz, Jan, Tsang, David, Ali, Nasim, Jones, Amanda, O'Neill, Paul, Cottrill, Christopher, Propper, David, Lofts, Fiona Jane, Kennedy, James, Anthoney, David A., Cooper, Rachel, Crellin, Adrian, Melcher, Alan, Seymour, Matthew, Baughan, Christopher, Alexander, Emma, Crown, John, Fennelly, David, Adab, Fawzi, Giridharan, Selvaraj, Pedley, Ian, Wright, Kathryn, Bliss, Peter, Cogill, Geoffrey, Lo, Nangi, Toy, Elizabeth, Hochhauser, Daniel, Ledermann, Jonathan, Brewster, Alison, Maughan, Timothy, Mort, Diana, Mukherjee, Somnath, Dobrowsky, Werner, Calvert, Paula, Leonard, Gregory, Ford, Hugo, Moody, Anne Margeret, Goriah, Sonia, Wilkins, Margeret, Clive, Sally, Dawson, Lesley, McLean, Catriona, Phillips, Hamish Andrew, Gopi, Kakumudi, Tomlinson, Marjorie, Clenton, Susan, Furniss, Debra, Hornbuckle, Joanne, Pledge, Simon, Wadsley, Jonathan, Abbas, Mohammed, Marshall, Ernest, Harper-Wynne, Catherine, Barnes, Anne, Kumar, Satish, Vigneswaran, Vallipuram, Gollins, Simon, Genton, M., Sparrow, Geoff, Bale, Catherine, Fuller, C., Mullard, Anna, Stuart, Nicholas, Williams, Rachel, Keane, MacCon, Maughen, Tim, Adams, Richard, Madi, Ayman, Hodgkinson, Elizabeth, Rogers, Penny, Pope, Malcolm, Kaplan, Rick, Meade, Angela, Parmar, Mahesh, Kenny, Sarah, Fisher, David, Harper, Lynda, Mitchell, Jena, Nichols, Laura, Sydes, Benjamin, Clement, Louise, Kay, Edward, Courtney, Cheryl, Gallagher, Madalena, Murphy, Claire, Thompson, Lindsay, Beall, Sarah, Hassan, Sharma, Gracie, Richard, Griffiths, Gareth, Mason, Malcolm, Parker, Chris, Rudd, Robin, Johnson, Patrick, Whelan, Jeremy, Northover, John, Brown, Julia, Aapro, Matti, Stout, Ronald, Midgley, Rachel, Kerr, David J., Campbell, Harry, Tomlinson, Ian P. and Houlston, Richard S. (2012) Common variation near CDKN1A, POLD3 and SHROOM2 influences colorectal cancer risk. Nature Genetics, 44 (7), 770-776. (doi:10.1038/ng.2293).

Record type: Article

Abstract

We performed a meta-analysis of five genome-wide association studies to identify common variants influencing colorectal cancer (CRC) risk comprising 8,682 cases and 9,649 controls. Replication analysis was performed in case-control sets totaling 21,096 cases and 19,555 controls. We identified three new CRC risk loci at 6p21 (rs1321311, near CDKN1A; P = 1.14 × 10 -10), 11q13.4 (rs3824999, intronic to POLD3; P = 3.65 × 10 -10) and Xp22.2 (rs5934683, near SHROOM2; P = 7.30 × 10 -10) This brings the number of independent loci associated with CRC risk to 20 and provides further insight into the genetic architecture of inherited susceptibility to CRC.

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More information

Published date: 1 July 2012
Additional Information: Funding Information: For the Helsinki study, the work was supported by grants from the Academy of Finland (Finnish Centre of Excellence Program; 20062011), the Finnish Cancer Society and the Sigrid Juselius Foundation. This work of the Colon Cancer Family Registry (CFR) was supported by the US National Cancer Institute, National Institutes of Health (CA95011), and through cooperative agreements with members of the Colon CFR and Principal Investigators. Collaborating centers include the Australasian Colorectal Cancer Family Registry (U01 CA097735), the Familial Colorectal Neoplasia Collaborative Group (U01 CA074799), the Ontario Registry for Studies of Familial Colorectal Cancer (U01 CA074783) and the Seattle Colorectal Cancer Family Registry (U01 CA074794). The Colon CFR GWAS was supported by funding from the US National Cancer Institute, National Institutes of Health (U01CA122839 to G.C.). Funding Information: Cancer Research UK provided principal funding for this study individually to R.S.H. (C1298/A8362–Bobby Moore Fund for Cancer Research UK), I.P.T. and M.G.D. At the Institute of Cancer Research, additional funding was provided by a Centre Grant from Core as part of the Digestive Cancer Campaign, the National Cancer Research Network and the NHS via the Biological Research Centre of the NIHR at the Royal Marsden Hospital NHS Trust. S.L. received a PhD studentship from Cancer Research UK, I.C. received a Clinical Research Training Fellowship from St. George’s Hospital Medical School, and N.W. received a PhD Studentship from the Institute of Cancer Research. M.H. was in receipt of a PostDoctoral Training post from the Leukaemia Lymphoma Research Fund. In Oxford, additional funding was provided by the Oxford Comprehensive Biomedical Research Centre (E.D., C.P. and I.P.T.) and the European Union Framework Programme 7 (FP7) CHIBCHA grant (A.M.J., L.G.C.C. and I.P.T.). Core infrastructure support to the Wellcome Trust Centre for Human Genetics, Oxford, was provided by grant (090532/Z/09/Z). We are grateful to many colleagues within the UK Clinical Genetics Departments (for CORGI) and to many collaborators who participated in the VICTOR and QUASAR2 trials. We also thank colleagues from the UK National Cancer Research Network (for NSCCG). In Edinburgh, funding was provided by a Cancer Research UK Programme Grant (C348/A12076) and a Centre Grant from the CORE Charity. E.T. was funded by a Cancer Research UK Fellowship (C31250/A10107). L.Y.O. is supported by a Cancer Research UK Research Training Fellowship (C10195/A12996). C. Smillie is supported by an MRC Research Studentship to the MRC Human Genetics Unit (HGU). We gratefully acknowledge the work of M. Walker and S. Reid in technical support, R. Wilson (SOCCS3 and COGS study coordinator), G. Barr for data entry in SOCCS studies, the research nurse recruitment teams, the Wellcome Trust Clinical Research Facility for sample preparation and all surgeons, oncologists and pathologists throughout Scotland at contributing centers. Lothian Birth Cohort Illumina genotyping was supported by the UK Biotechnology and Biological Sciences Research Council (BBSRC). Phenotype collection in the Lothian Birth Cohort 1921 was supported by the BBSRC, The Royal Society and The Chief Scientist Office of the Scottish Government. Phenotype collection in the Lothian Birth Cohort 1936 was supported by Research into Ageing (continues as part of Age UK’s The Disconnected Mind project). The work on the Lothian Birth Cohorts was undertaken at the University of Edinburgh Centre for Cognitive Ageing and Cognitive Epidemiology, part of the crosscouncil Lifelong Health and Wellbeing Initiative (G0700704/84698). Funding from the BBSRC, EPSRC, ESRC and MRC is gratefully acknowledged. For the Cambridge study, we thank the SEARCH study team and all the participants in the study. SEARCH is funded by a grant from Cancer Research UK (C490/A10124). In Cardiff, the work was supported by the Kidani Trust, Tenovus, Cancer Research Wales, The Bobby Moore Fund from CRUK (C10314/A4886), the Wales Assembly Government NISCHR Cancer Genetics BRU and the Wales Gene Park (all to J.P.C.). We acknowledge the use of DNA from the blood samples collected from COIN and COINB funded by Cancer Research UK and the MRC. We also acknowledge the use of DNA from the NBS (UKBS) collection, funded by the Wellcome Trust (076113/C/04/Z), by the Juvenile Diabetes Research Foundation (WT061858) and by the NIHR of England. The COINB Collaborative Group includes H. Wasan, T. Maughan, R. Adams, R. Wilson, A. Madi, E. Hodgkinson, M. Pope, P. Rogers and J. Cassidy. Research was also funded by the European Union FP7 (FP7/2072013) under grant 258236, FP7 collaborative project SYSCOL. The Swedish sample and data resource were funded by the Swedish Cancer Society, the Swedish Scientific Research Council and the Stockholm Cancer Foundation. We acknowledge the contribution to recruitment and data collection of the Swedish LowRisk Colorectal Cancer Study Group. Funding Information: The Japanese study was conducted as part of the BioBank Japan Project that was supported by the Ministry of Education, Culture, Sports, Science and Technology of the Japanese government.

Identifiers

Local EPrints ID: 470239
URI: http://eprints.soton.ac.uk/id/eprint/470239
ISSN: 1061-4036
PURE UUID: 83edb24b-03d8-498e-87e6-f3735579a112
ORCID for Anneke Lucassen: ORCID iD orcid.org/0000-0003-3324-4338
ORCID for Timothy John Iveson: ORCID iD orcid.org/0000-0002-4681-2712
ORCID for Gareth Griffiths: ORCID iD orcid.org/0000-0002-9579-8021

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Date deposited: 05 Oct 2022 16:32
Last modified: 18 Mar 2024 03:29

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Contributors

Author: Malcolm G. Dunlop
Author: Sara E. Dobbins
Author: Susan Mary Farrington
Author: Angela M. Jones
Author: Claire Palles
Author: Nicola Whiffin
Author: Albert Tenesa
Author: Sarah Spain
Author: Peter Broderick
Author: Li Yin Ooi
Author: Enric Domingo
Author: Claire Smillie
Author: Marc Henrion
Author: Matthew Frampton
Author: Lynn Martin
Author: Graeme Grimes
Author: Maggie Gorman
Author: Colin Semple
Author: Yusanne P. Ma
Author: Ella Barclay
Author: James Prendergast
Author: Jean Baptiste Cazier
Author: Bianca Olver
Author: Steven Penegar
Author: Steven Lubbe
Author: Ian Chander
Author: Luis G. Carvajal-Carmona
Author: Stephane Ballereau
Author: Amy Lloyd
Author: Jayaram Vijayakrishnan
Author: Lina Zgaga
Author: Igor Rudan
Author: Evropi Theodoratou
Author: Huw Thomas
Author: Eamonn Maher
Author: Gareth Evans
Author: Lisa Walker
Author: Dorothy Halliday
Author: Anneke Lucassen ORCID iD
Author: Joan Paterson
Author: Shirley Hodgson
Author: Tessa Homfray
Author: Lucy Side
Author: Louise Izatt
Author: Alan Donaldson
Author: Susan Tomkins
Author: Patrick Morrison
Author: Carole Brewer
Author: Alex Henderson
Author: Rosemarie Davidson
Author: Victoria Murday
Author: Jaqueline Cook
Author: Neva Haites
Author: Timothy Bishop
Author: Eamonn Sheridan
Author: Andrew Green
Author: Christopher Marks
Author: Sue Carpenter
Author: Mary Broughton
Author: Lynn Greenhalge
Author: Mohnish Suri
Author: John M. Starr
Author: Ian Deary
Author: Iva Kirac
Author: Dujo Kovacevia
Author: Lauri A. Aaltonen
Author: Laura Renkonen-Sinisalo
Author: Jukka Pekka Mecklin
Author: Koichi Matsuda
Author: Yusuke Nakamura
Author: Yukinori Okada
Author: Steven Gallinger
Author: David J. Duggan
Author: David Conti
Author: Polly Newcomb
Author: John Hopper
Author: Mark A. Jenkins
Author: Fredrick Schumacher
Author: Graham Casey
Author: Douglas Easton
Author: Mitul Shah
Author: Paul Pharoah
Author: Annika Lindblom
Author: Tao Liu
Author: David Edler
Author: Claes Lenander
Author: Johan Dalén
Author: Fredrik Hjern
Author: Nils Lundqvist
Author: Ulrik Lindforss
Author: Lars Påhlman
Author: Kennet Smedh
Author: Anders Törnqvist
Author: Jörn Holm
Author: Martin Janson
Author: Magnus Andersson
Author: Susanne Ekelund
Author: Louise Olsson
Author: Christopher G. Smith
Author: Hannah West
Author: Jeremy P. Cheadle
Author: Graham MacDonald
Author: Leslie M. Samuel
Author: Athar Ahmad
Author: Philippa Corrie
Author: Duncan Jodrell
Author: Cheryl Palmer
Author: Charles Wilson
Author: Julie O'Hagan
Author: David Smith
Author: Ray McDermott
Author: Janice Walshe
Author: James Cassidy
Author: Alec McDonald
Author: Nazia Mohammed
Author: Jeff White
Author: Hosney Yosef
Author: Oscar Breathnach
Author: Liam Grogan
Author: Robert Thomas
Author: Martin Eatock
Author: Paul Henry
Author: Russell Houston
Author: Patrick Johnston
Author: Richard Wilson
Author: Ian Geh
Author: Falalu Danwata
Author: Andrew Hindley
Author: Shabbir Susnerwala
Author: Chris Bradley
Author: Andrew Conn
Author: Anne Raine
Author: Chris Twelves
Author: Stephen Falk
Author: Kirstin Hopkins
Author: Saad Tahir
Author: Amandeep Dhadda
Author: Anthony Maraveyas
Author: Joseph Sgouros
Author: Mark Teo
Author: Rizvana Ahmad
Author: Susan Cleator
Author: Antonia Creak
Author: Charles Lowdell
Author: Philippa Riddle
Author: Kim Benstead
Author: David Farrugia
Author: Nicholas Reed
Author: Stephen Shepherd
Author: Edward Levine
Author: Saifee Mullamitha
Author: Mark Saunders
Author: Juan Valle
Author: Gregory Wilson
Author: Adam Jones
Author: Andrew Weaver
Author: Peter I. Clark
Author: Brain Haylock
Author: Mussawar I. Iqbal
Author: Arthur S. Myint
Author: Sharon Beesley
Author: Timothy Sevitt
Author: Jonathan Nicoll
Author: Francis Daniel
Author: Victoria Ford
Author: Toby Talbot
Author: Mohammad Butt
Author: Abdel Hamid
Author: Paul MacK
Author: Raj Roy
Author: Richard Osborne
Author: Fiona McKinna
Author: Heidar Alsab
Author: Devyanee Basu
Author: Phillip Murray
Author: Bruce Sizer
Author: Faisal A. Azam
Author: Rekha Neupane
Author: Ashita Waterston
Author: John Glaholm
Author: Claire Blesing
Author: Sarah Lowndes
Author: Aruna Medisetti
Author: Andrew Gaya
Author: Martin Leslie
Author: Nicholas Maisey
Author: Paul Ross
Author: Grainne Dunn
Author: Omar Al-Salihi
Author: Harpreet S. Wasan
Author: Li Tee Tan
Author: Jo Dent
Author: Uschi Hofmann
Author: Johnathan K. Joffe
Author: Elizabeth Sherwin
Author: Rabinder Soomal
Author: Amitabha Chakrabarti
Author: Shibu Joseph
Author: Johannes Van Der Voet
Author: Nicholas J. Wadd
Author: David Wilson
Author: Salim Anjarwalia
Author: Julia Hall
Author: Rob Hughes
Author: Andrew Polychronis
Author: John H. Scarffe
Author: Mark Hill
Author: Rodger D. James
Author: Riyaz Shah
Author: Jeffrey Summers
Author: Andrew Hartley
Author: Desmond Carney
Author: John McCaffrey
Author: Brano Bystricky
Author: Seamus O'Reilly
Author: Rajnish Gupta
Author: Talib Al-Mishlab
Author: Fiona Gidden
Author: Richard O'Hara
Author: Jill Stewart
Author: Richard Ashford
Author: Robert Glynne-Jones
Author: Mark Harrison
Author: Suzannah Mawdsley
Author: Hilary Barlow
Author: Mary Tighe
Author: Julie Walther
Author: Janet Neal
Author: Charlotte Rees
Author: John Bridgewater
Author: Stephen Karp
Author: Ursula McGovern
Author: Philip J. Atherton
Author: Hany El-Deeb
Author: Craig MacMillan
Author: Kinnari Patel
Author: Eric Michael Bessell
Author: Peter D. Dickinson
Author: Vanessa Potter
Author: Catherine Jephcott
Author: Karen McAdam
Author: Jessica Wrigley
Author: Sethupathi Muthuramalingam
Author: Anne O'Callaghan
Author: Lucinda Melcher
Author: Chiara Braconi
Author: Ju Ian Geh
Author: Dan Palmer
Author: Priya Narayana
Author: Neil Steven
Author: Andres Gaya
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