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1. Fine-mapping analysis including over 254,000 East Asian and European descendants identifies 136 putative colorectal cancer susceptibility genes

Author

Zhishan Chen, Xingyi Guo, Ran Tao, Jeroen R. Huyghe, Philip J. Law, Ceres Fernandez-Rozadilla, Jie Ping, Guochong Jia, Jirong Long, Chao Li, Quanhu Shen, Yuhan Xie, Maria N. Timofeeva, Minta Thomas, Stephanie L. Schmit, Virginia Díez-Obrero, Matthew Devall, Ferran Moratalla-Navarro, Juan Fernandez-Tajes, Claire Palles, Kitty Sherwood, Sarah E. W. Briggs, Victoria Svinti, Kevin Donnelly, Susan M. Farrington, James Blackmur, Peter G. Vaughan-Shaw, Xiao-Ou Shu, Yingchang Lu, Peter Broderick, James Studd, Tabitha A. Harrison, David V. Conti, Fredrick R. Schumacher, Marilena Melas, Gad Rennert, Mireia Obón-Santacana, Vicente Martín-Sánchez, 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 L. Hopper, Mark A. Jenkins, Aung Ko Win, Rish K. Pai, Jane C. Figueiredo, Robert W. Haile, Steven Gallinger, Michael O. Woods, Polly A. Newcomb, David Duggan, Jeremy P. Cheadle, Richard Kaplan, Rachel Kerr, David Kerr, Iva Kirac, Jan Böhm, Jukka-Pekka Mecklin, Pekka Jousilahti, Paul Knekt, Lauri A. Aaltonen, Harri Rissanen, Eero Pukkala, Johan G. Eriksson, Tatiana Cajuso, Ulrika Hänninen, Johanna Kondelin, Kimmo Palin, Tomas Tanskanen, Laura Renkonen-Sinisalo, Satu Männistö, Demetrius Albanes, Stephanie J. Weinstein, Edward Ruiz-Narvaez, Julie R. Palmer, Daniel D. Buchanan, Elizabeth A. Platz, Kala Visvanathan, Cornelia M. Ulrich, Erin Siegel, Stefanie Brezina, Andrea Gsur, Peter T. Campbell, Jenny Chang-Claude, Michael Hoffmeister, Hermann Brenner, Martha L. Slattery, John D. Potter, Kostas K. Tsilidis, Matthias B. Schulze, Marc J. Gunter, Neil Murphy, Antoni Castells, Sergi Castellví-Bel, Leticia Moreira, Volker Arndt, Anna Shcherbina, D. Timothy Bishop, Graham G. Giles, Melissa C. Southey, Gregory E. Idos, Kevin J. McDonnell, Zomoroda Abu-Ful, Joel K. Greenson, Katerina Shulman, Flavio Lejbkowicz, Kenneth Offit, Yu-Ru Su, Robert Steinfelder, Temitope O. Keku, Bethany van Guelpen, Thomas J. Hudson, Heather Hampel, Rachel Pearlman, Sonja I. Berndt, Richard B. Hayes, Marie Elena Martinez, Sushma S. Thomas, Paul D. P. Pharoah, Susanna C. Larsson, Yun Yen, Heinz-Josef Lenz, Emily White, Li Li, Kimberly F. Doheny, Elizabeth Pugh, Tameka Shelford, Andrew T. Chan, Marcia Cruz-Correa, Annika Lindblom, David J. Hunter, Amit D. Joshi, Clemens Schafmayer, Peter C. Scacheri, Anshul Kundaje, Robert E. Schoen, Jochen Hampe, Zsofia K. Stadler, Pavel Vodicka, Ludmila Vodickova, Veronika Vymetalkova, Christopher K. Edlund, W. James Gauderman, David Shibata, Amanda Toland, Sanford Markowitz, Andre Kim, Stephen J. Chanock, Franzel van Duijnhoven, Edith J. M. Feskens, Lori C. Sakoda, Manuela Gago-Dominguez, Alicja Wolk, Barbara Pardini, Liesel M. FitzGerald, Soo Chin Lee, Shuji Ogino, Stephanie A. Bien, Charles Kooperberg, Christopher I. Li, Yi Lin, Ross Prentice, Conghui Qu, Stéphane Bézieau, Taiki Yamaji, Norie Sawada, Motoki Iwasaki, Loic Le Marchand, Anna H. Wu, Chenxu Qu, Caroline E. McNeil, Gerhard Coetzee, Caroline Hayward, Ian J. Deary, Sarah E. Harris, Evropi Theodoratou, Stuart Reid, Marion Walker, Li Yin Ooi, Ken S. Lau, Hongyu Zhao, Li Hsu, Qiuyin Cai, Malcolm G. Dunlop, Stephen B. Gruber, Richard S. Houlston, Victor Moreno, Graham Casey, Ulrike Peters, Ian Tomlinson, and Wei Zheng

Subjects
Science
Abstract

Abstract Genome-wide association studies (GWAS) have identified more than 200 common genetic variants independently associated with colorectal cancer (CRC) risk, but the causal variants and target genes are mostly unknown. We sought to fine-map all known CRC risk loci using GWAS data from 100,204 cases and 154,587 controls of East Asian and European ancestry. Our stepwise conditional analyses revealed 238 independent association signals of CRC risk, each with a set of credible causal variants (CCVs), of which 28 signals had a single CCV. Our cis-eQTL/mQTL and colocalization analyses using colorectal tissue-specific transcriptome and methylome data separately from 1299 and 321 individuals, along with functional genomic investigation, uncovered 136 putative CRC susceptibility genes, including 56 genes not previously reported. Analyses of single-cell RNA-seq data from colorectal tissues revealed 17 putative CRC susceptibility genes with distinct expression patterns in specific cell types. Analyses of whole exome sequencing data provided additional support for several target genes identified in this study as CRC susceptibility genes. Enrichment analyses of the 136 genes uncover pathways not previously linked to CRC risk. Our study substantially expanded association signals for CRC and provided additional insight into the biological mechanisms underlying CRC development.

Published
2024
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2. Development, Evaluation, and Implementation of a Pan-African Cancer Research Network: Men of African Descent and Carcinoma of the Prostate

Author

Caroline Andrews, Brian Fortier, Amy Hayward, Ruth Lederman, Lindsay Petersen, Jo McBride, Desiree C. Petersen, Olabode Ajayi, Paidamoyo Kachambwa, Moleboheng Seutloali, Aubrey Shoko, Mamokhosana Mokhosi, Reinhard Hiller, Marcia Adams, Chrissie Ongaco, Elizabeth Pugh, Jane Romm, Tameka Shelford, Frank Chinegwundoh, Ben Adusei, Sunny Mante, Nana Yaa Snyper, Ilir Agalliu, David W. Lounsbury, Thomas Rohan, Alex Orfanos, Yuri Quintana, Judith S. Jacobson, Alfred I. Neugut, Edward Gelmann, Joseph Lachance, Cherif Dial, Thierno Amadou Diallo, Mohamed Jalloh, Serigne Magueye Gueye, Papa Moussa Sène Kane, Halimatou Diop, Anna Julienne Ndiaye, Amina Sow Sall, Ndeye Coumba Toure-Kane, Ezenwa Onyemata, Alash’le Abimiku, Andrew A. Adjei, Richard Biritwum, Richard Gyasi, Mathew Kyei, James E. Mensah, Julian Okine, Vicky Okyne, Isabella Rockson, Evelyn Tay, Yao Tettey, Edward Yeboah, Wenlong C. Chen, Elvira Singh, Michael B. Cook, Christine N. Duffy, Ann Hsing, Cassandra Claire Soo, Pedro Fernandez, Hayley Irusen, Oseremen Aisuodionoe-Shadrach, Abubakar Mustapha Jamda, Peter Oluwole Olabode, Maxwell Madueke Nwegbu, Olalekan Hafees Ajibola, Olushola Jeremiah Ajamu, Yakubu Garba Ambuwa, Akindele Olupelumi Adebiyi, Michael Asuzu, Olufemi Ogunbiyi, Olufemi Popoola, Olayiwola Shittu, Olukemi Amodu, Emeka Odiaka, Ifeoluwa Makinde, Maureen Joffe, Audrey Pentz, and Timothy R. Rebbeck

Subjects
Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Purpose: Cancer of the prostate (CaP) is the leading cancer among men in sub-Saharan Africa (SSA). A substantial proportion of these men with CaP are diagnosed at late (usually incurable) stages, yet little is known about the etiology of CaP in SSA. Methods: We established the Men of African Descent and Carcinoma of the Prostate Network, which includes seven SSA centers partnering with five US centers to study the genetics and epidemiology of CaP in SSA. We developed common data elements and instruments, regulatory infrastructure, and biosample collection, processing, and shipping protocols. We tested this infrastructure by collecting epidemiologic, medical record, and genomic data from a total of 311 patients with CaP and 218 matched controls recruited at the seven SSA centers. We extracted genomic DNA from whole blood, buffy coat, or buccal swabs from 265 participants and shipped it to the Center for Inherited Disease Research (Baltimore, MD) and the Centre for Proteomics and Genomics Research (Cape Town, South Africa), where genotypes were generated using the UK Biobank Axiom Array. Results: We used common instruments for data collection and entered data into the shared database. Double-entered data from pilot participants showed a 95% to 98% concordance rate, suggesting that data can be collected, entered, and stored with a high degree of accuracy. Genotypes were obtained from 95% of tested DNA samples (100% from blood-derived DNA samples) with high concordance across laboratories. Conclusion: We provide approaches that can produce high-quality epidemiologic and genomic data in multicenter studies of cancer in SSA.

Published
2018
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3. Centers for Mendelian Genomics: A decade of facilitating gene discovery

Author

Samantha M. Baxter, Jennifer E. Posey, Nicole J. Lake, Nara Sobreira, Jessica X. Chong, Steven Buyske, Elizabeth E. Blue, Lisa H. Chadwick, Zeynep H. Coban-Akdemir, Kimberly F. Doheny, Colleen P. Davis, Monkol Lek, Christopher Wellington, Shalini N. Jhangiani, Mark Gerstein, Richard A. Gibbs, Richard P. Lifton, Daniel G. MacArthur, Tara C. Matise, James R. Lupski, David Valle, Michael J. Bamshad, Ada Hamosh, Shrikant Mane, Deborah A. Nickerson, Heidi L. Rehm, Anne O’Donnell-Luria, Marcia Adams, François Aguet, Gulsen Akay, Peter Anderson, Corina Antonescu, Harindra M. Arachchi, Mehmed M. Atik, Christina A. Austin-Tse, Larry Babb, Tamara J. Bacus, Vahid Bahrambeigi, Suganthi Balasubramanian, Yavuz Bayram, Arthur L. Beaudet, Christine R. Beck, John W. Belmont, Jennifer E. Below, Kaya Bilguvar, Corinne D. Boehm, Eric Boerwinkle, Philip M. Boone, Sara J. Bowne, Harrison Brand, Kati J. Buckingham, Alicia B. Byrne, Daniel Calame, Ian M. Campbell, Xiaolong Cao, Claudia Carvalho, Varuna Chander, Jaime Chang, Katherine R. Chao, Ivan K. Chinn, Declan Clarke, Ryan L. Collins, Beryl Cummings, Zain Dardas, Moez Dawood, Kayla Delano, Stephanie P. DiTroia, Harshavardhan Doddapaneni, Haowei Du, Renqian Du, Ruizhi Duan, Mohammad Eldomery, Christine M. Eng, Eleina England, Emily Evangelista, Selin Everett, Jawid Fatih, Adam Felsenfeld, Laurent C. Francioli, Christian D. Frazar, Jack Fu, Emmanuel Gamarra, Tomasz Gambin, Weiniu Gan, Mira Gandhi, Vijay S. Ganesh, Kiran V. Garimella, Laura D. Gauthier, Danielle Giroux, Claudia Gonzaga-Jauregui, Julia K. Goodrich, William W. Gordon, Sean Griffith, Christopher M. Grochowski, Shen Gu, Sanna Gudmundsson, Stacey J. Hall, Adam Hansen, Tamar Harel, Arif O. Harmanci, Isabella Herman, Kurt Hetrick, Hadia Hijazi, Martha Horike-Pyne, Elvin Hsu, Jianhong Hu, Yongqing Huang, Jameson R. Hurless, Steve Jahl, Gail P. Jarvik, Yunyun Jiang, Eric Johanson, Angad Jolly, Ender Karaca, Michael Khayat, James Knight, J. Thomas Kolar, Sushant Kumar, Seema Lalani, Kristen M. Laricchia, Kathryn E. Larkin, Suzanne M. Leal, Gabrielle Lemire, Richard A. Lewis, He Li, Hua Ling, Rachel B. Lipson, Pengfei Liu, Alysia Kern Lovgren, Francesc López-Giráldez, Melissa P. MacMillan, Brian E. Mangilog, Stacy Mano, Dana Marafi, Beth Marosy, Jamie L. Marshall, Renan Martin, Colby T. Marvin, Michelle Mawhinney, Sean McGee, Daniel J. McGoldrick, Michelle Mehaffey, Betselote Mekonnen, Xiaolu Meng, Tadahiro Mitani, Christina Y. Miyake, David Mohr, Shaine Morris, Thomas E. Mullen, David R. Murdock, Mullai Murugan, Donna M. Muzny, Ben Myers, Juanita Neira, Kevin K. Nguyen, Patrick M. Nielsen, Natalie Nudelman, Emily O’Heir, Melanie C. O’Leary, Chrissie Ongaco, Jordan Orange, Ikeoluwa A. Osei-Owusu, Ingrid S. Paine, Lynn S. Pais, Justin Paschall, Karynne Patterson, Davut Pehlivan, Benjamin Pelle, Samantha Penney, Jorge Perez de Acha Chavez, Emma Pierce-Hoffman, Cecilia M. Poli, Jaya Punetha, Aparna Radhakrishnan, Matthew A. Richardson, Eliete Rodrigues, Gwendolin T. Roote, Jill A. Rosenfeld, Erica L. Ryke, Aniko Sabo, Alice Sanchez, Isabelle Schrauwen, Daryl A. Scott, Fritz Sedlazeck, Jillian Serrano, Chad A. Shaw, Tameka Shelford, Kathryn M. Shively, Moriel Singer-Berk, Joshua D. Smith, Hana Snow, Grace Snyder, Matthew Solomonson, Rachel G. Son, Xiaofei Song, Pawel Stankiewicz, Taylorlyn Stephan, V. Reid Sutton, Abigail Sveden, Diana Cornejo Sánchez, Monica Tackett, Michael Talkowski, Machiko S. Threlkeld, Grace Tiao, Miriam S. Udler, Laura Vail, Zaheer Valivullah, Elise Valkanas, Grace E. VanNoy, Qingbo S. Wang, Gao Wang, Lu Wang, Michael F. Wangler, Nicholas A. Watts, Ben Weisburd, Jeffrey M. Weiss, Marsha M. Wheeler, Janson J. White, Clara E. Williamson, Michael W. Wilson, Wojciech Wiszniewski, Marjorie A. Withers, Dane Witmer, Lauren Witzgall, Elizabeth Wohler, Monica H. Wojcik, Isaac Wong, Jordan C. Wood, Nan Wu, Jinchuan Xing, Yaping Yang, Qian Yi, Bo Yuan, Jordan E. Zeiger, Chaofan Zhang, Peng Zhang, Yan Zhang, Xiaohong Zhang, Yeting Zhang, Shifa Zhang, Huda Zoghbi, and Igna van den Veyver

Subjects
Phenotype, Exome Sequencing, Humans, Exome, Genomics, Article, Genetic Association Studies, Genetics (clinical)
Abstract

PURPOSE: Mendelian disease genomic research has undergone a massive transformation over the past decade. With increasing availability of exome and genome sequencing, the role of Mendelian research has expanded beyond data collection, sequencing, and analysis to worldwide data sharing and collaboration. METHODS: Over the past 10 years, the National Institutes of Health–supported Centers for Mendelian Genomics (CMGs) have played a major role in this research and clinical evolution. RESULTS: We highlight the cumulative gene discoveries facilitated by the program, biomedical research leveraged by the approach, and the larger impact on the research community. Beyond generating a list of gene-phenotype relationships and participating in widespread data sharing, the CMGs have created resources, tools, and training for the larger community to foster understanding of genes and genome variation. The CMGs have participated in a wide range of data sharing activities, including deposition of all eligible CMG data into the Analysis, Visualization, and Informatics Lab-space (AnVIL), sharing candidate genes through the Matchmaker Exchange and the CMG website, and sharing variants in Genotypes to Mendelian Phenotypes (Geno2MP) and VariantMatcher. CONCLUSION: The work is far from complete; strengthening communication between research and clinical realms, continued development and sharing of knowledge and tools, and improving access to richly characterized data sets are all required to diagnose the remaining molecularly undiagnosed patients.

Published
2022
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4. Supplementary Methods and Tables from The OncoArray Consortium: A Network for Understanding the Genetic Architecture of Common Cancers

Author

Douglas F. Easton, Jacques Simard, Stephen J. Chanock, Georgia Chenevix-Trench, Paul D.P. Pharoah, Antonis C. Antoniou, Daniela Seminara, Elizabeth Gillanders, Michael F. Seldin, Rosalind A. Eeles, Ulrike Peters, Ali Amin Al Olama, Jonathan Marchini, Rayjean J. Hung, Laura Ottini, Rita Schmutzler, Mads Thomassen, Kenneth Offit, Sue K. Park, John K. Field, Jack A. Taylor, Christopher K. Edlund, Tameka Shelford, Stephanie L. Schmit, Sylvie Laboissiere, Andrew Berchuck, Sune F. Nielsen, Marc T. Goodman, Deborah J. Thompson, Yongyong Shi, Hongbing Shen, Tracy A. O'Mara, Marjorie Riggan, Paul Brennan, Linda E. Kelemen, Sara Benlloch, Catherine M. Phelan, James D. McKay, Marcia Adams, Sara Lindström, Liesel FitzGerald, Peter Kraft, Zsofia Kote-Jarai, Katja Butterbach, Julie M. Cunningham, Judith Manz, Penny Soucy, Karoline Kuchenbaecker, Andrew Lee, Lesley McGuffog, Hua Ling, Belynda D. Hicks, Irene Brüske-Hohlfeld, Melanie Waldenberger, Angela Risch, Heike Bickeböller, David V. Conti, Graham G. Giles, Judith L. Forman, Fergus J. Couch, David E. Goldgar, Stephen Demetriades, Stefanie Nelson, David J. Van Den Berg, François Bacot, Daniel Vincent, Daniel Tessier, Craig Luccarini, Ahsan Kamal, Christopher A. Haiman, Charlisse Caga-Anan, Stig E. Bojesen, Dennis J. Hazelett, Gerhard A. Coetzee, Elizabeth Pugh, Jane Romm, Xiangjun Xiao, Yafang Li, Amanda B. Spurdle, Kimberly Doheny, Laura Fachal, Kyriaki Michailidou, Alison M. Dunning, Stephen B. Gruber, Thomas A. Sellers, David J. Hunter, Graham Casey, Simon A. Gayther, Fredrick R. Schumacher, Jinyoung Byun, Zhaoming Wang, Joe Dennis, and Christopher I. Amos

Abstract

Supplementary Methods and Tables

Published
2023
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5. Data from The OncoArray Consortium: A Network for Understanding the Genetic Architecture of Common Cancers

Author

Douglas F. Easton, Jacques Simard, Stephen J. Chanock, Georgia Chenevix-Trench, Paul D.P. Pharoah, Antonis C. Antoniou, Daniela Seminara, Elizabeth Gillanders, Michael F. Seldin, Rosalind A. Eeles, Ulrike Peters, Ali Amin Al Olama, Jonathan Marchini, Rayjean J. Hung, Laura Ottini, Rita Schmutzler, Mads Thomassen, Kenneth Offit, Sue K. Park, John K. Field, Jack A. Taylor, Christopher K. Edlund, Tameka Shelford, Stephanie L. Schmit, Sylvie Laboissiere, Andrew Berchuck, Sune F. Nielsen, Marc T. Goodman, Deborah J. Thompson, Yongyong Shi, Hongbing Shen, Tracy A. O'Mara, Marjorie Riggan, Paul Brennan, Linda E. Kelemen, Sara Benlloch, Catherine M. Phelan, James D. McKay, Marcia Adams, Sara Lindström, Liesel FitzGerald, Peter Kraft, Zsofia Kote-Jarai, Katja Butterbach, Julie M. Cunningham, Judith Manz, Penny Soucy, Karoline Kuchenbaecker, Andrew Lee, Lesley McGuffog, Hua Ling, Belynda D. Hicks, Irene Brüske-Hohlfeld, Melanie Waldenberger, Angela Risch, Heike Bickeböller, David V. Conti, Graham G. Giles, Judith L. Forman, Fergus J. Couch, David E. Goldgar, Stephen Demetriades, Stefanie Nelson, David J. Van Den Berg, François Bacot, Daniel Vincent, Daniel Tessier, Craig Luccarini, Ahsan Kamal, Christopher A. Haiman, Charlisse Caga-Anan, Stig E. Bojesen, Dennis J. Hazelett, Gerhard A. Coetzee, Elizabeth Pugh, Jane Romm, Xiangjun Xiao, Yafang Li, Amanda B. Spurdle, Kimberly Doheny, Laura Fachal, Kyriaki Michailidou, Alison M. Dunning, Stephen B. Gruber, Thomas A. Sellers, David J. Hunter, Graham Casey, Simon A. Gayther, Fredrick R. Schumacher, Jinyoung Byun, Zhaoming Wang, Joe Dennis, and Christopher I. Amos

Abstract

Background: Common cancers develop through a multistep process often including inherited susceptibility. Collaboration among multiple institutions, and funding from multiple sources, has allowed the development of an inexpensive genotyping microarray, the OncoArray. The array includes a genome-wide backbone, comprising 230,000 SNPs tagging most common genetic variants, together with dense mapping of known susceptibility regions, rare variants from sequencing experiments, pharmacogenetic markers, and cancer-related traits.Methods: The OncoArray can be genotyped using a novel technology developed by Illumina to facilitate efficient genotyping. The consortium developed standard approaches for selecting SNPs for study, for quality control of markers, and for ancestry analysis. The array was genotyped at selected sites and with prespecified replicate samples to permit evaluation of genotyping accuracy among centers and by ethnic background.Results: The OncoArray consortium genotyped 447,705 samples. A total of 494,763 SNPs passed quality control steps with a sample success rate of 97% of the samples. Participating sites performed ancestry analysis using a common set of markers and a scoring algorithm based on principal components analysis.Conclusions: Results from these analyses will enable researchers to identify new susceptibility loci, perform fine-mapping of new or known loci associated with either single or multiple cancers, assess the degree of overlap in cancer causation and pleiotropic effects of loci that have been identified for disease-specific risk, and jointly model genetic, environmental, and lifestyle-related exposures.Impact: Ongoing analyses will shed light on etiology and risk assessment for many types of cancer. Cancer Epidemiol Biomarkers Prev; 26(1); 126–35. ©2016 AACR.

Published
2023
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6. 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, Article, VLAG
Abstract

Colorectal cancer (CRC) is a leading cause of mortality worldwide. We conducted a genome-wide association study meta-analysis of 100,204 CRC cases and 154,587 controls of European and East Asian ancestry, identifying 205 independent risk associations, of which 50 were unreported. We performed integrative genomic, transcriptomic and methylomic analyses across large bowel mucosa and other tissues. Transcriptome- and methylome-wide association studies revealed an additional 53 risk associations. We identified 155 high confidence effector genes functionally linked to CRC risk, many of which had no previously established role in CRC. These have multiple different functions, and specifically indicate that variation in normal colorectal homeostasis, proliferation, cell adhesion, migration, immunity and microbial interactions determines CRC risk. Cross-tissue analyses indicated that over a third of effector genes most likely act outside the colonic mucosa. Our findings provide insights into colorectal oncogenesis, and highlight potential targets across tissues for new CRC treatment and chemoprevention strategies.

Published
2023
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7. 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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8. 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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9. Abstract LB090: Associations of somatically mutated genes and pathways with colorectal cancer specific survival in 4,500 colorectal cancer patients

Author

Quang M. Trinh, Amanda I. Phipps, Tameka Shelford, Syed H.E. Zaidi, Wei Sun, Ross L. Prentice, Stephen N. Thibodeau, Marc J. Gunter, Daniel D. Buchanan, Andrew T. Chan, Marios Giannakis, Li Hsu, Conghui Qu, Shuji Ogino, Peter T. Campbell, Sonja I. Berndt, David A. Drew, Ulrike Peters, Steven Gallinger, Andrea Gsur, Wen-Yi Huang, Paul J. Limburg, Victor Moreno, Robert S. Steinfelder, Kim F. Doheny, Tabitha A. Harrison, Michael Hoffmeister, Jane C. Figueiredo, and Polly A. Newcomb

Subjects
Oncology, Cancer Research, medicine.medical_specialty, business.industry, Colorectal cancer, Proportional hazards model, Hazard ratio, Cancer, Disease, medicine.disease, Statistical significance, Internal medicine, Medicine, Population study, business, Gene
Abstract

Colorectal cancer (CRC) is a heterogenous disease that develops through somatic mutations in driver genes, leading to activation of diverse neoplastic pathways. To systematically examine if somatically mutated genes and pathways impact survival, we sequenced tumor and normal DNA samples for 4,512 CRC cases using a targeted panel. We performed Cox regression to estimate hazard ratios (HR) and 95% confidence intervals (CIs) for associations of disease-specific (DS)-survival with somatically mutated genes and pathways, adjusting for age and sex, and stratifying baseline hazards by study population. We assessed statistical significance using Bonferroni p-value thresholds to account for multiple testing of 214 genes (2.34x10-4) and 6 key CRC pathways (8.3x10-3). We limited analyses to non-silent mutations. We observed that DS-survival was significantly more favorable among individuals with hypermutated (HM) tumors, primarily consisting of microsatellite unstable and POLE-mutated tumors, as compared to those with non-hypermutated (NHM) tumors (HR=0.4, 95% CI: 0.3-0.5, p=1.2x10-17). BRAF V600E mutations were associated with poorer survival (HR=2.0, 95% CI: 1.6-2.5, p=1.6x10-10). This association was more pronounced among NHM tumors (HR=2.3, 95% CI: 1.8-2.9, p=4.3x10-12). We identified suggestive associations (p-values < 5.0x10-3 in overall or stratified analyses) between DS-survival and mutations in B2M, TP53, and SMAD4. Mutations in B2M may provide more favorable prognosis for survival (HR=0.5, 95% CI: 0.3-0.8, p=4.4x10-3), with similar effect sizes in HM and NHM tumors. Poorer survival may be associated with mutations in TP53 (HR=1.2, 95% CI:1.2-1.4, p=9.3x10-4) and SMAD4 (HR=1.3, 95% CI:1.1-1.6, p=3.2x10-3) in NHM tumors. We further observed statistically significant associations between survival and three mutated pathways: TP53/ATM (HR=1.2, 95% CI:1.1-1.4, p=9.0x10-4), receptor tyrosine kinases (RTK) and RAS (HR=1.3, 95% CI:1.1-1.5, p=4.5x10-5), and TGF-beta (HR=1.3, 95% CI:1.1-1.5, p=2.9x10-4). Findings for TP53/ATM and RTK/RAS were primarily due to mutations in one gene within each pathway (TP53 and BRAF, respectively). However, the TGF-beta pathway finding, which was more pronounced in NHM tumors, included two genes with p-values less than 0.05 (SMAD4 p=3.2x10-3 and TGFBR2 p=0.01). Despite our large sample size, relatively few somatically mutated genes were significantly associated with DS-survival. It may be that pathway-level testing affords more power for analyses and that larger sample sizes are needed. It is of interest that non-silent mutations in B2M, whose product is a component of the class I major histocompatibility complex, was associated with improved DS-survival, though our finding was not statistically significant after multiple testing correction so further exploration and replication is needed. Citation Format: Tabitha A. Harrison, Syed H. Zaidi, Conghui Qu, Amanda I. Phipps, Robert S. Steinfelder, Quang M. Trinh, Sonja I. Berndt, Daniel D. Buchanan, Peter T. Campbell, Andrew T. Chan, Kim F. Doheny, David A. Drew, Jane C. Figueiredo, Steven J. Gallinger, Marios Giannakis, Andrea Gsur, Marc J. Gunter, Michael Hoffmeister, Wen-Yi Huang, Paul J. Limburg, Victor Moreno, Polly A. Newcomb, Shuji Ogino, Ross L. Prentice, Tameka Shelford, Wei Sun, Stephen N. Thibodeau, Li Hsu, Ulrike Peters. Associations of somatically mutated genes and pathways with colorectal cancer specific survival in 4,500 colorectal cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr LB090.

Published
2021
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10. Identification of 12 new susceptibility loci for different histotypes of epithelial ovarian cancer

Author

Eitan Friedman, Mattias Van Heetvelde, Jennifer B. Permuth, Joseph Vijai, Patricia A. Ganz, Jennifer A. Doherty, Argyrios Ziogas, Bernard Peissel, Edwin S. Iversen, Angela Brooks-Wilson, Ingo B. Runnebaum, Amanda B. Spurdle, Heli Nevanlinna, Kenneth Offit, Laura Papi, Georgia Chenevix-Trench, Saundra S. Buys, Martin Köbel, Fabienne Lesueur, Elizabeth W. Pugh, Joe Dennis, Sylvie Mazoyer, Diana Eccles, Shirley Hodgson, Jolanta Lissowska, Judy Garber, Pascal Pujol, Kristin K. Zorn, Orland Diez, Marcia Adams, Thomas Conner, Renée T. Fortner, Tjoung-Won Park-Simon, Vanesa García-Barberán, Kerstin Rhiem, Norbert Arnold, Karoline Kuchenbaecker, Susan M. Domchek, María Josefa Mosteiro García, Matthias W. Beckmann, Alex Henderson, Melissa C. Larson, Jane Romm, Anja Rudolph, Steven A. Narod, Mats Jernetz, Jolanta Kupryjanczyk, Natalia Bogdanova, Jacob Musinsky, Helga B. Salvesen, Jonathan Beesley, Paolo Peterlongo, Arif B. Ekici, Clarice R. Weinberg, Marion Piedmonte, Christian F. Singer, Robert L. Nussbaum, Katja K.H. Aben, Michael J. Birrer, Juul T. Wijnen, Elizabeth M. Poole, Phuong L. Mai, David J. Hunter, Tanja Pejovic, Athanassios Vratimos, Barbara Wappenschmidt, Nicolas Wentzensen, Marcus Q. Bernardini, Leigha Senter, Terence Cescon, Daniel W. Cramer, Silvia Tognazzo, Drakoulis Yannoukakos, Jacopo Azzollini, Ignace Vergote, Karen H. Lu, Gustavo C. Rodriguez, Julian Adlard, Tomasz Huzarski, Mark H. Greene, Susan L. Neuhausen, Marina Bermisheva, Alicja Wolk, Paulo C Lyra, Usha Menon, Ralf Bützow, Siddhartha Kar, Manuel R. Teixeira, Conxi Lázaro, Agnieszka Dansonka-Mieszkowska, Aleksandra Gentry-Maharaj, Zsofia K. Stadler, Melissa C. Southey, Ramunas Janavicius, Douglas F. Easton, Digna R. Velez Edwards, Jocelyne Chiquette, Karin Kast, Jonathan Tyrer, Georg Pfeiler, Tara M. Friebel, Bruno Buecher, Goska Leslie, Jackie Cook, Catherine M. Phelan, Steve Ellis, Estrid Høgdall, Beth Y. Karlan, Anthony J. Swerdlow, Sarah E. Ferguson, Rosalind Glasspool, Frans B. L. Hogervorst, Lotte Nedergaard, Britton Trabert, Jack A. Taylor, Irene L. Andrulis, Paolo Radice, Dennis J. Hazelett, Mads Thomassen, Dong Liang, Joseph H. Rothstein, Loren Lipworth, Melissa A. Merritt, Ana Vega, Petra H.M. Peeters, Claus Høgdall, Anna M. Piskorz, Bernardo Bonanni, Janet M. Lee, Malcolm C. Pike, Clemens Liebrich, Zachary C. Fogarty, Bent Ejlertsen, Yuan Chun Ding, Dieter Niederacher, Michael E. Carney, Dominique Stoppa-Lyonnet, Nadine Tung, Curtis Olswold, Ana Osorio, Fiona Bruinsma, Christine Walsh, Fabienne Prieur, Lara E. Sucheston-Campbell, Stephen B. Gruber, Maartje J. Hooning, George Fountzilas, Amanda Black, David E. Goldgar, Anna Jakubowska, Paul D.P. Pharoah, Angela R. Bradbury, Helene Holland, Ruth C. Travis, Susana Banerjee, Penelope M. Webb, Brooke L. Fridley, Clara Bodelon, Mary Anne Rossing, Yen Y. Tan, Rosa B. Barkardottir, Jong Won Lee, Stephen J. Chanock, Bruce Poppe, Sandra Fert Ferrer, Melissa Moffitt, Taymaa May, Gustavo Mendoza-Fandiño, Christopher A. Haiman, Alicia Beeghly-Fadiel, Rebecca Sutphen, Michelle A.T. Hildebrandt, Lambertus A. Kiemeney, Thilo Dörk, Douglas A. Levine, Gerasimos Aravantinos, Celeste Leigh Pearce, Sue K. Park, David Van Den Berg, Louise Izatt, Hannah P. Yang, Graham G. Giles, Linda S. Cook, John R. McLaughlin, Nick Orr, Weiva Sieh, Raymonda Varon-Mateeva, Marco Montagna, Honglin Song, Laura Ottini, Ruea-Yea Huang, Joanna Moes-Sosnowska, Anders Bojesen, David M. O'Malley, Andrew K. Godwin, Lucy Side, Sung-Won Kim, Lukasz Szafron, Christoph Engel, Harvey A. Risch, Alexander Hein, Penny Soucy, Elza Khusnutdinova, Ana Peixoto, Arto Leminen, Cora M. Aalfs, Matthias Dürst, Mary B. Daly, Patricia Rice, Nadeem Siddiqui, Dale P. Sandler, Ava Kwong, Madalene Earp, Marjorie J. Riggan, Inge Søkilde Pedersen, Susanne K. Kjaer, Mercedes Durán, Joellen M. Schildkraut, James D. Brenton, D. Gareth Evans, Liisa M. Pelttari, Kimberly F. Doheny, Karen Hosking, Miquel Angel Pujana, Salina B. Chan, Joan Brunet, Trinidad Caldés, Rosemarie Davidson, Jessica N. McAlpine, Jenny Lester, Niclas Håkansson, Kai-ren Ong, Ros Eeles, Francesmary Modugno, Martin Gore, Loic Le Marchand, Robert A. Vierkant, Wendy K. Chung, Christopher I. Amos, N. Charlotte Onland-Moret, Brita Arver, Marc Tischkowitz, Craig Luccarini, Daniel Barrowdale, Laima Tihomirova, Louise A. Brinton, Fergus J. Couch, Alfons Meindl, Nerea Larrañaga, Cristina Rodríguez-Antona, Alice S. Whittemore, Johanna I. Kiiski, Todd L. Edwards, Eric Hahnen, Grzegorz Sukiennicki, Els Van Nieuwenhuysen, Elizabeth J. van Rensburg, Michael Jones, Åke Borg, Edith Olah, Ute Hamann, Liv Cecilie Vestrheim Thomsen, Xiaoqing Chen, Ganna Chornokur, Minouk J. Schoemaker, Marc T. Goodman, Fanny Dao, Andrea Gehrig, Hagay Sobol, Nhu D. Le, Esther M. John, Adriaan Vanderstichele, Antonia Trichopoulou, Kunle Odunsi, Yukie Bean, David G. Huntsman, Lidia Pezzani, V. Wendy Setiawan, Marinus J. Blok, Yael Laitman, Mary Porteous, Patricia Harrington, Samantha Poblete, Shashikant Lele, Anne M. van Altena, Mingajeva Elvira, Lene Lundvall, Dominique Leroux, Annemarie H. van der Hout, Darya Prokofyeva, Debra Frost, Yoke-Eng Chiew, Gad Rennert, Stacey J. Winham, Muy-Kheng Tea, Kirsten B. Moysich, Angel Izquierdo, Anna H. Wu, Christine Rappaport-Fuerhauser, Peter Hillemanns, Rob B. van der Luijt, Gord Glendon, Jan Lubinński, Csilla Szabo, Gillian Mitchell, Andrea L. Richardson, Mark E. Robson, Roger L. Milne, Thomas Hansen, Francesca Damiola, Tameka Shelford, Natalia Antonenkova, Julie Lecarpentier, Paul A. James, Claudine Isaacs, Gianluca Severi, Maria A. Caligo, Teodora Goranova, Kate Lawrenson, Sandra Orsulic, Priyanka Sharma, Holly R. Harris, Peter A. Fasching, Christian Sutter, Torben A Kruse, Line Bjørge, Lesley McGuffog, Leon F.A.G. Massuger, Lynne R. Wilkens, Reidun K. Kopperud, Jillian Hung, Iain A. McNeish, Hanne Meijers-Heijboer, Uffe Birk Jensen, Diether Lambrechts, Johanna Rantala, Kelly-Anne Phillips, Michelle M.M. Woo, Kathryn L. Terry, Kathleen Claes, Ellen L. Goode, Olufunmilayo I. Olopade, Darcy L. Thull, Ailith Pirie, Sharon E. Johnatty, Soo Hwang Teo, Aimee A D'Aloisio, Evgeny N. Imyanitov, Domenico Palli, Andrew Berchuck, Banu Arun, Florentia Fostira, Jan Hauke, Jenny Chang-Claude, Pamela J. Thompson, Peter J. Hulick, Per Broberg, Arjen R. Mensenkamp, Xifeng Wu, Alicia A. Tone, Jacques Simard, Ursula Eilber, Jacek Gronwald, Kenneth Blankstein, James M. Flanagan, Alvaro N.A. Monteiro, Timea Pocza, Rita K. Schmutzler, Jeffrey N. Weitzel, Simon A. Gayther, William D. Foulkes, Valerie McGuire, Katherine L. Nathanson, Kevin H. Eng, Anna deFazio, Ian G. Campbell, Capucine Delnatte, Shan Wang-Gohrke, Jenna Lilyquist, Matti A. Rookus, Sakaeva Dina Damirovna, Laure Dossus, Simon G. Coetzee, Catherine J. Kennedy, Roberta B. Ness, James Paul, Andrew Lee, Linda E. Kelemen, Judith Balmaña, Anne-Marie Gerdes, Laure Barjhoux, Håkan Olsson, Lisa Walker, Doris Steinemann, Cecilia M. Dorfling, Julie M. Cunningham, Shelley S. Tworoger, Allan Jensen, Thomas A. Sellers, Javier Benitez, Anthony N. Karnezis, Hoda Anton-Culver, Carole Brewer, Siranoush Manoukian, Dorothea Wand, Ed Dicks, Antonis C. Antoniou, Amanda E. Toland, Anna Marie Mulligan, Päivi Kannisto, Rikki Cannioto, Bernd Dworniczak, Susan J. Ramus, Anna V. Tinker, Epidemiology and Data Science, Amsterdam Reproduction & Development (AR&D), CCA - Cancer biology and immunology, Amsterdam Neuroscience - Complex Trait Genetics, Human genetics, MUMC+: DA KG Lab Centraal Lab (9), RS: GROW - R4 - Reproductive and Perinatal Medicine, Government of Canada, Cancer Research Foundation, Canadian Institutes of Health Research, National Institutes of Health (US), Fonds de Recherche du Québec, Ministry of Health and Welfare (South Korea), Associazione Italiana per la Ricerca sul Cancro, Deutsche Krebshilfe, Genome Canada, Medical Oncology, Clinical Genetics, Human Genetics, ARD - Amsterdam Reproduction and Development, Centre Léon Bérard [Lyon], Service de Génétique Oncologique, Institut Curie [Paris], CRLCC René Gauducheau, Centre International de Recherche contre le Cancer - International Agency for Research on Cancer (CIRC - IARC), Organisation Mondiale de la Santé / World Health Organization Office (OMS / WHO), Centre Hospitalier Métropole Savoie [Chambéry], CHU Grenoble, Cancer et génome: Bioinformatique, biostatistiques et épidémiologie d'un système complexe, Institut Curie [Paris]-MINES ParisTech - École nationale supérieure des mines de Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM), MINES ParisTech - École nationale supérieure des mines de Paris, Université Paris sciences et lettres (PSL), Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), CHU Saint-Etienne, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Université Paris-Sud - Paris 11 - Faculté de médecine (UP11 UFR Médecine), Université Paris-Sud - Paris 11 (UP11), Institut Gustave Roussy (IGR), Université Paris-Saclay, Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), Tyrer, Jonathan [0000-0003-3724-4757], Dennis, Joe [0000-0003-4591-1214], Dicks, Ed [0000-0002-0617-0401], Lee, Andrew [0000-0003-0677-0252], Leslie, Goska [0000-0001-5756-6222], Brenton, James [0000-0002-5738-6683], Song, Honglin [0000-0001-5076-7371], Tischkowitz, Marc [0000-0002-7880-0628], Easton, Douglas [0000-0003-2444-3247], Antoniou, Antonis [0000-0001-9223-3116], Pharoah, Paul [0000-0001-8494-732X], and Apollo - University of Cambridge Repository

Subjects
0301 basic medicine, endocrine system diseases, Epidemiology, Càncer d'ovari, Genome-wide association study, Carcinoma, Ovarian Epithelial, Genome-wide association studies, susceptibility, Risk Factors, Genotype, Tumours of the digestive tract Radboud Institute for Molecular Life Sciences [Radboudumc 14], Medicine and Health Sciences, Neoplasms, Glandular and Epithelial, POPULATION, Genetics & Heredity, Genetics, Ovarian Neoplasms, RISK, education.field_of_study, Women's cancers Radboud Institute for Molecular Life Sciences [Radboudumc 17], cancer, ovary, BRCA1 Protein, COMMON VARIANTS, 11 Medical And Health Sciences, ASSOCIATION, female genital diseases and pregnancy complications, Women's cancers Radboud Institute for Health Sciences [Radboudumc 17], 3. Good health, Serous fluid, ovarian cancer, Urological cancers Radboud Institute for Health Sciences [Radboudumc 15], Female, Life Sciences & Biomedicine, epithelial ovarian cancer, BRCA1, BRCA2, Population, Telomere-Binding Proteins, [SDV.CAN]Life Sciences [q-bio]/Cancer, Locus (genetics), Biology, Polymorphism, Single Nucleotide, Article, 03 medical and health sciences, SDG 3 - Good Health and Well-being, Meta-Analysis as Topic, CLEAR-CELL CARCINOMA, Ovarian cancer, medicine, Journal Article, Humans, BREAST-CANCER, Genetic Predisposition to Disease, Allele, education, Genotyping, Alleles, METAANALYSIS, BRCA2 Protein, [SDV.GEN]Life Sciences [q-bio]/Genetics, Science & Technology, MUTATIONS, ENDOMETRIOSIS, Biology and Life Sciences, 06 Biological Sciences, medicine.disease, 030104 developmental biology, Genetic Loci, Mutation, TELOMERE LENGTH, Cancer research, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Developmental Biology, Genome-Wide Association Study
Abstract

The OCAC OncoArray genotyping project: et al., To identify common alleles associated with different histotypes of epithelial ovarian cancer (EOC), we pooled data from multiple genome-wide genotyping projects totaling 25,509 EOC cases and 40,941 controls. We identified nine new susceptibility loci for different EOC histotypes: six for serous EOC histotypes (3q28, 4q32.3, 8q21.11, 10q24.33, 18q11.2 and 22q12.1), two for mucinous EOC (3q22.3 and 9q31.1) and one for endometrioid EOC (5q12.3). We then performed meta-analysis on the results for high-grade serous ovarian cancer with the results from analysis of 31,448 BRCA1 and BRCA2 mutation carriers, including 3,887 mutation carriers with EOC. This identified three additional susceptibility loci at 2q13, 8q24.1 and 12q24.31. Integrated analyses of genes and regulatory biofeatures at each locus predicted candidate susceptibility genes, including OBFC1, a new candidate susceptibility gene for low-grade and borderline serous EOC., The OCAC OncoArray genotyping project was funded through grants from the US National Institutes of Health (CA1X01HG007491-01 (C.I.A.), U19-CA148112 (T.A.S.), R01-CA149429 (C.M.P.) and R01-CA058598 (M.T.G.)); Canadian Institutes of Health Research (MOP-86727 (L.E.K.)); and the Ovarian Cancer Research Fund (A.B.). Funding for the CIMBA OncoArray genotyping was provided by the Government of Canada through Genome Canada and the Canadian Institutes of Health Research, the Ministère de l’Économie, de la Science et de l’Innovation du Québec through Génome Québec, the Quebec Breast Cancer Foundation for the PERSPECTIVE project, the US National Institutes of Health (CA1X01HG007491-01 (C.I.A.)), the Odense University Hospital Research Foundation (M.T.), the National R&D Program for Cancer Control, Ministry of Health and Welfare, Republic of Korea (1420190 (S.K.P.)), the Italian Association for Cancer Research (IG16933 (L.O.)) and German Cancer Aid (110837 (R.K.S.).

Published
2017
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11. The OncoArray Consortium: a network for understanding the genetic architecture of common cancers

Author

Katja Butterbach, Daniel C. Tessier, Dennis J. Hazelett, Stephen J. Chanock, Paul Brennan, Zhaoming Wang, Marc T. Goodman, Ali Amin Al Olama, Daniela Seminara, Tracy A. O'Mara, Craig Luccarini, Lesley McGuffog, David Van Den Berg, Andy C. H. Lee, James McKay, Stephen B. Gruber, Sue K. Park, Jack A. Taylor, Graham G. Giles, Michael F. Seldin, Alison M. Dunning, Zsofia Kote-Jarai, Sara Lindström, David E. Goldgar, Irene Brüske-Hohlfeld, Stig E. Bojesen, Paul D.P. Pharoah, Jonathan Marchini, Rosalind A. Eeles, Karoline Kuchenbaecker, Laura Fachal, Penny Soucy, Rayjean J. Hung, Ahsan Kamal, Marjorie J. Riggan, Xiangjun Xiao, Fergus J. Couch, Francois Bacot, Georgia Chenevix-Trench, John K. Field, Amanda B. Spurdle, Christopher A. Haiman, Julie M. Cunningham, Andrew Berchuck, Fredrick R. Schumacher, Elizabeth M. Gillanders, Simon A. Gayther, Belynda Hicks, Laura Ottini, David J. Hunter, Peter Kraft, Charlisse Caga-Anan, Jane Romm, Sylvie Laboissiere, Heike Bickeböller, Catherine M. Phelan, Jacques Simard, Graham Casey, Stephanie L. Schmit, Yafang Li, Sune F. Nielsen, Thomas A. Sellers, Hua Ling, Christopher K. Edlund, Yongyong Shi, Liesel M. FitzGerald, Stefanie A. Nelson, Rita K. Schmutzler, Gerhard A. Coetzee, Linda E. Kelemen, Kimberly F. Doheny, Elizabeth W. Pugh, Antonis C. Antoniou, Melanie Waldenberger, Judith L. Forman, Angela Risch, Ulrike Peters, Joe Dennis, David V. Conti, Daniel Vincent, Stephen Demetriades, Jinyoung Byun, Sara Benlloch, Tameka Shelford, Hongbing Shen, Douglas F. Easton, Mads Thomassen, Marcia Adams, Christopher I. Amos, Kenneth Offit, Kyriaki Michailidou, Judith Manz, Deborah J. Thompson, Dennis, Joe [0000-0003-4591-1214], Dunning, Alison [0000-0001-6651-7166], Fachal Vilar, Laura [0000-0002-7256-9752], Lee, Andrew [0000-0003-0677-0252], Thompson, Deborah [0000-0003-1465-5799], Amin Al Olama, Ali [0000-0002-7178-3431], Antoniou, Antonis [0000-0001-9223-3116], Pharoah, Paul [0000-0001-8494-732X], Easton, Douglas [0000-0003-2444-3247], and Apollo - University of Cambridge Repository

Subjects
Male, 0301 basic medicine, epistasis, genetic epidemiology, Genotype, Epidemiology, Single-nucleotide polymorphism, Genome-wide association study, Biology, Polymorphism, Single Nucleotide, Risk Assessment, Article, 03 medical and health sciences, 0302 clinical medicine, Neoplasms, Genetic Predisposition to Disease/epidemiology, Genetic variation, Mendelian randomization, Prevalence, Humans, cancer, Genetic Predisposition to Disease, Selection, Genetic, Genotyping, Genetics, ancestry, Genetic Variation, Polymorphism, Single Nucleotide/genetics, Prognosis, Genetic architecture, 3. Good health, 030104 developmental biology, Genetic Variation/genetics, Oncology, 030220 oncology & carcinogenesis, OncoArray Consortium, genetic architecture, cancers, Genome-Wide Association Study/methods, Female, DNA microarray, Neoplasms/epidemiology, Genome-Wide Association Study, genetic susceptibility
Abstract

Background: Common cancers develop through a multistep process often including inherited susceptibility. Collaboration among multiple institutions, and funding from multiple sources, has allowed the development of an inexpensive genotyping microarray, the OncoArray. The array includes a genome-wide backbone, comprising 230,000 SNPs tagging most common genetic variants, together with dense mapping of known susceptibility regions, rare variants from sequencing experiments, pharmacogenetic markers and cancer related traits. Methods: The OncoArray can be genotyped using a novel technology developed by Illumina to facilitate efficient genotyping. The consortium developed standard approaches for selecting SNPs for study, for quality control of markers and for ancestry analysis. The array was genotyped at selected sites and with prespecified replicate samples to permit evaluation of genotyping accuracy among centers and by ethnic background. Results: The OncoArray consortium genotyped 447,705 samples. A total of 494,763 SNPs passed quality control steps with a sample success rate of 97% of the samples. Participating sites performed ancestry analysis using a common set of markers and a scoring algorithm based on principal components analysis. Conclusions: Results from these analyses will enable researchers to identify new susceptibility loci, perform fine mapping of new or known loci associated with either single or multiple cancers, assess the degree of overlap in cancer causation and pleiotropic effects of loci that have been identified for disease-specific risk, and jointly model genetic, environmental and lifestyle related exposures. Impact: Ongoing analyses will shed light on etiology and risk assessment for many types of cancer. TRICL (Transdisciplinary Research for Cancer of Lung) and International Lung Cancer Consortium (ILCCO): National Institute of Health U19 CA148127-01 (C.I. Amos, J. Byun, Y. Li, X. Xiao, J. L. Forman, A. Risch, H. Bickeböller, M. Waldenberger, I. Brüske, J. Manz, P. Brennan, R. Hung, H. Shen, Y. Shi, A. Kamal, C. I. Amos, J.K. Field), Canadian Cancer Society Research Institute (no. 020214, R. Hung). DRIVE (Discovery, Biology, and Risk of Inherited Variants in Breast Cancer): National Institute of Health U19 CA148065 (D.J. Hazelett, D. F. Easton, S. Lindström, P. Kraft, J. Dennis, A. Dunning, K. Michailidou, L. Fachal, S. Benlloch, J. Cunningham, K. Butterbach, K. Offit, R. Schmutzler, L. Ottini, D. Vincent). CORECT (ColoRectal Transdisciplinary Study): National Institute of Health U19 CA148107; R01 CA81488, P30 CA014089 (S. Gruber, U. Peters, G. Casey). ELLIPSE (ELLIPSE, Elucidating Loci in Prostate Cancer Susceptibility): This work was support by U19 CA148537(F. Schumacher, S.A. Gayther, S.L. Schmit, C.K. Edlund, D.J. Hazelett, G.A. Coetzee, C. Haiman, S. Demetriades, D. Van Den Berg). FOCI (Transdisciplinary Cancer Genetic Association and Interacting Studies): National Institutes of Health U19 CA148112- 01 (T.A. Sellers, C. Phelan), R01-CA122443(B. Hicks) ) P50-CA116201, CA192393 (F. Couch), P50-CA136393(J. Cunningham, F. Couch), OCAC - CA-149429 (C. Phelan). , P30-CA15083 (B. Hicks), Cancer Research UK (C490/A8339(A. Antoniou, P. Pharoah, A. Dunning), C490/A16561(P. Pharoah, A. Dunning), C490/A10119 (A. Dunning, P. Pharoah), C490/A10124 (A. Dunning, P. Pharoah)). ASTERISK: a Hospital Clinical Research Program (PHRC) and supported by the Regional Council of Pays de la Loire, the Groupement des Entreprises Françaises dans la Lutte contre le Cancer (GEFLUC), the Association Anne de Bretagne Génétique and the Ligue Régionale Contre le Cancer (LRCC) (F. Bacot). DACHS: German Research Council (Deutsche Downloaded from cebp.aacrjournals.org on October 31, 2016. © 2016 American Association for Cancer Research. Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on October 3, 2016; DOI: 10.1158/1055-9965.EPI-16-0106 Forschungsgemeinschaft, BR 1704/6-1, BR 1704/6-3, BR 1704/6-4, and CH 117/1-1, C.K. Edlund), and the German Federal Ministry of Education and Research (01KH0404 and 01ER0814). Prostate Lung Colon Ovarian Screening trial: Intramural Research Program of the Division of Cancer Epidemiology and Genetics and supported by contracts from the Division of Cancer Prevention, National Cancer Institute, NIH, DHHS. The GC-HBOC (German Consortium of Hereditary Breast and Ovarian Cancer) is supported by the German Cancer Aid (grant no 110837, coordinator: R. Schmutzler, Cologne). The PERSPECTIVE (J. Simard) project was supported by the Government of Canada through Genome Canada and the Canadian Institutes of Health Research (MOP-86727, L.E. Kelemen), the Ministère de l’Économie, Innovation et Exportation du Québec through Genome Québec, and thee Quebec Breast Cancer Foundation, including additional funding from the Canadian Breast Cancer Foundation and the National Cancer Institute USA through Breast Cancer Family Registry Cohort (#1UM1CA164920-01A1). European Union Framework Programme for Research and Innovation (MSCA-IF-2014-EF-656144)(L. Fachal). The Breast Cancer Research Foundation, P30 CA08748, Andrew Sabin Foundation (K. Offit). CIDR genotyping for the Oncoarray was conducted under contract 268201200008I to K.Doheny and through grant 1X01HG007491- 01 to C.I. Amos. This is the author accepted manuscript. The final version is available from American Association for Cancer Research via http://dx.doi.org/10.1158/1055-9965.EPI-16-0106

Published
2016
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