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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

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

Published
2024
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2. 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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4. Combining Asian and European genome-wide association studies of colorectal cancer improves risk prediction across racial and ethnic populations

Author

Minta Thomas, Yu-Ru Su, Elisabeth A. Rosenthal, Lori C. Sakoda, Stephanie L. Schmit, Maria N. Timofeeva, Zhishan Chen, Ceres Fernandez-Rozadilla, Philip J. Law, Neil Murphy, Robert Carreras-Torres, Virginia Diez-Obrero, Franzel J. B. van Duijnhoven, Shangqing Jiang, Aesun Shin, Alicja Wolk, Amanda I. Phipps, Andrea Burnett-Hartman, Andrea Gsur, Andrew T. Chan, Ann G. Zauber, Anna H. Wu, Annika Lindblom, Caroline Y. Um, Catherine M. Tangen, Chris Gignoux, Christina Newton, Christopher A. Haiman, Conghui Qu, D. Timothy Bishop, Daniel D. Buchanan, David R. Crosslin, David V. Conti, Dong-Hyun Kim, Elizabeth Hauser, Emily White, Erin Siegel, Fredrick R. Schumacher, Gad Rennert, Graham G. Giles, Heather Hampel, Hermann Brenner, Isao Oze, Jae Hwan Oh, Jeffrey K. Lee, Jennifer L. Schneider, Jenny Chang-Claude, Jeongseon Kim, Jeroen R. Huyghe, Jiayin Zheng, Jochen Hampe, Joel Greenson, John L. Hopper, Julie R. Palmer, Kala Visvanathan, Keitaro Matsuo, Koichi Matsuda, Keum Ji Jung, Li Li, Loic Le Marchand, Ludmila Vodickova, Luis Bujanda, Marc J. Gunter, Marco Matejcic, Mark A. Jenkins, Martha L. Slattery, Mauro D’Amato, Meilin Wang, Michael Hoffmeister, Michael O. Woods, Michelle Kim, Mingyang Song, Motoki Iwasaki, Mulong Du, Natalia Udaltsova, Norie Sawada, Pavel Vodicka, Peter T. Campbell, Polly A. Newcomb, Qiuyin Cai, Rachel Pearlman, Rish K. Pai, Robert E. Schoen, Robert S. Steinfelder, Robert W. Haile, Rosita Vandenputtelaar, Ross L. Prentice, Sébastien Küry, Sergi Castellví-Bel, Shoichiro Tsugane, Sonja I. Berndt, Soo Chin Lee, Stefanie Brezina, Stephanie J. Weinstein, Stephen J. Chanock, Sun Ha Jee, Sun-Seog Kweon, Susan Vadaparampil, Tabitha A. Harrison, Taiki Yamaji, Temitope O. Keku, Veronika Vymetalkova, Volker Arndt, Wei-Hua Jia, Xiao-Ou Shu, Yi Lin, Yoon-Ok Ahn, Zsofia K. Stadler, Bethany Van Guelpen, Cornelia M. Ulrich, Elizabeth A. Platz, John D. Potter, Christopher I. Li, Reinier Meester, Victor Moreno, Jane C. Figueiredo, Graham Casey, Iris Lansdorp Vogelaar, Malcolm G. Dunlop, Stephen B. Gruber, Richard B. Hayes, Paul D. P. Pharoah, Richard S. Houlston, Gail P. Jarvik, Ian P. Tomlinson, Wei Zheng, Douglas A. Corley, Ulrike Peters, and Li Hsu

Subjects
Science
Abstract

Abstract Polygenic risk scores (PRS) have great potential to guide precision colorectal cancer (CRC) prevention by identifying those at higher risk to undertake targeted screening. However, current PRS using European ancestry data have sub-optimal performance in non-European ancestry populations, limiting their utility among these populations. Towards addressing this deficiency, we expand PRS development for CRC by incorporating Asian ancestry data (21,731 cases; 47,444 controls) into European ancestry training datasets (78,473 cases; 107,143 controls). The AUC estimates (95% CI) of PRS are 0.63(0.62-0.64), 0.59(0.57-0.61), 0.62(0.60-0.63), and 0.65(0.63-0.66) in independent datasets including 1681-3651 cases and 8696-115,105 controls of Asian, Black/African American, Latinx/Hispanic, and non-Hispanic White, respectively. They are significantly better than the European-centric PRS in all four major US racial and ethnic groups (p-values

Published
2023
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7. Study protocol for a three-arm randomized controlled trial investigating the effectiveness, cost-utility, and physiological effects of a fully self-guided digital Acceptance and Commitment Therapy for Spanish patients with fibromyalgia

Author

Ana Gallego, Mayte Serrat, Estíbaliz Royuela-Colomer, Juan P Sanabria-Mazo, Xavier Borràs, Montserrat Esteve, Mar Grasa, Araceli Rosa, Antoni Rozadilla-Sacanell, Miriam Almirall, Francesco D’Amico, Yifei Dai, Michael J. Rosenbluth, Lance M. McCracken, Jaime Navarrete, Albert Feliu-Soler, and Juan V Luciano

Subjects
Computer applications to medicine. Medical informatics, R858-859.7
Abstract

Objective Fibromyalgia (FM) is a prevalent pain syndrome with significant healthcare and societal costs. The aim of the SMART-FM-SP study is to determine the effectiveness, cost-utility, and physiological effects in patients with FM of a digital intervention (STANZA®) currently marketed in the United States, which delivers smartphone-based, fully self-guided Acceptance and Commitment Therapy (Digital ACT) for treating FM-related symptoms. Methods A single-site, parallel-group, superiority, randomized controlled trial (RCT) will be conducted, including a total of 360 adults diagnosed with FM. Individuals will be randomly allocated (1:1:1) to treatment as usual (TAU), to TAU plus 12 weeks of treatment with Digital ACT, or to TAU plus 12 weeks of treatment with digital symptom tracking (i.e. FibroST). Participants will be assessed at baseline, post-treatment, and 6-month follow-up. An intention-to-treat analysis using linear mixed models will be computed to analyze the effects of Digital ACT on functional impairment (primary outcome), as measured by the Fibromyalgia Impact Questionnaire Revised at 6 months from the inception of the treatment. Secondary outcomes include impression of change, symptoms of distress, pain catastrophising, quality of life, cost-utility, and selected biomarkers (cortisol and cortisone, immune-inflammatory markers, and FKBP5 gene polymorphisms). The role of ACT-related processes of change will be tested with path analyses. Conclusions This study is the first RCT that tests Digital ACT for Spanish patients with FM. Results will be important not only for patients and clinicians, but also for policy makers by examining the cost-utility of the app in a public healthcare context.

Published
2024
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8. Combining Asian and European genome-wide association studies of colorectal cancer improves risk prediction across racial and ethnic populations

Author

Thomas, Minta, Su, Yu-Ru, Rosenthal, Elisabeth A., Sakoda, Lori C., Schmit, Stephanie L., Timofeeva, Maria N., Chen, Zhishan, Fernandez-Rozadilla, Ceres, Law, Philip J., Murphy, Neil, Carreras-Torres, Robert, Diez-Obrero, Virginia, van Duijnhoven, Franzel J. B., Jiang, Shangqing, Shin, Aesun, Wolk, Alicja, Phipps, Amanda I., Burnett-Hartman, Andrea, Gsur, Andrea, Chan, Andrew T., Zauber, Ann G., Wu, Anna H., Lindblom, Annika, Um, Caroline Y., Tangen, Catherine M., Gignoux, Chris, Newton, Christina, Haiman, Christopher A., Qu, Conghui, Bishop, D. Timothy, Buchanan, Daniel D., Crosslin, David R., Conti, David V., Kim, Dong-Hyun, Hauser, Elizabeth, White, Emily, Siegel, Erin, Schumacher, Fredrick R., Rennert, Gad, Giles, Graham G., Hampel, Heather, Brenner, Hermann, Oze, Isao, Oh, Jae Hwan, Lee, Jeffrey K., Schneider, Jennifer L., Chang-Claude, Jenny, Kim, Jeongseon, Huyghe, Jeroen R., Zheng, Jiayin, Hampe, Jochen, Greenson, Joel, Hopper, John L., Palmer, Julie R., Visvanathan, Kala, Matsuo, Keitaro, Matsuda, Koichi, Jung, Keum Ji, Li, Li, Le Marchand, Loic, Vodickova, Ludmila, Bujanda, Luis, Gunter, Marc J., Matejcic, Marco, Jenkins, Mark A., Slattery, Martha L., D’Amato, Mauro, Wang, Meilin, Hoffmeister, Michael, Woods, Michael O., Kim, Michelle, Song, Mingyang, Iwasaki, Motoki, Du, Mulong, Udaltsova, Natalia, Sawada, Norie, Vodicka, Pavel, Campbell, Peter T., Newcomb, Polly A., Cai, Qiuyin, Pearlman, Rachel, Pai, Rish K., Schoen, Robert E., Steinfelder, Robert S., Haile, Robert W., Vandenputtelaar, Rosita, Prentice, Ross L., Küry, Sébastien, Castellví-Bel, Sergi, Tsugane, Shoichiro, Berndt, Sonja I., Lee, Soo Chin, Brezina, Stefanie, Weinstein, Stephanie J., Chanock, Stephen J., Jee, Sun Ha, Kweon, Sun-Seog, Vadaparampil, Susan, Harrison, Tabitha A., Yamaji, Taiki, Keku, Temitope O., Vymetalkova, Veronika, Arndt, Volker, Jia, Wei-Hua, Shu, Xiao-Ou, Lin, Yi, Ahn, Yoon-Ok, Stadler, Zsofia K., Van Guelpen, Bethany, Ulrich, Cornelia M., Platz, Elizabeth A., Potter, John D., Li, Christopher I., Meester, Reinier, Moreno, Victor, Figueiredo, Jane C., Casey, Graham, Lansdorp Vogelaar, Iris, Dunlop, Malcolm G., Gruber, Stephen B., Hayes, Richard B., Pharoah, Paul D. P., Houlston, Richard S., Jarvik, Gail P., Tomlinson, Ian P., Zheng, Wei, Corley, Douglas A., Peters, Ulrike, and Hsu, Li

Published
2023
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10. Deciphering colorectal cancer genetics through multi-omic analysis of 100,204 cases and 154,587 controls of European and east Asian ancestries

Author

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

Published
2023
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11. BMPR2 as a Novel Predisposition Gene for Hereditary Colorectal Polyposis

Author

Bonjoch, Laia, Fernandez-Rozadilla, Ceres, Alvarez-Barona, Miriam, Lopez-Novo, Anael, Herrera-Pariente, Cristina, Amigo, Jorge, Bujanda, Luis, Remedios, David, Dacal, Andrés, Cubiella, Joaquín, Balaguer, Francesc, Fernández-Bañares, Fernando, Carracedo, Angel, Jover, Rodrigo, Castellvi-Bel, Sergi, and Ruiz-Ponte, Clara

Published
2023
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12. NAD pool as an antitumor target against cancer stem cells in head and neck cancer

Author

Lola E. Navas, Elena Blanco-Alcaina, Elisa Suarez-Martinez, Eva M. Verdugo-Sivianes, Asuncion Espinosa-Sanchez, Laura Sanchez-Diaz, Eduardo Dominguez-Medina, Ceres Fernandez-Rozadilla, Angel Carracedo, Lindsay E. Wu, and Amancio Carnero

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

Summary Head and neck squamous cell carcinoma (HNSCC) is a heterogeneous group of tumors that affect different anatomical locations. Despite this heterogeneity, HNSCC treatment depends on the anatomical location, TNM stage and resectability of the tumor. Classical chemotherapy is based on platinum-derived drugs (cisplatin, carboplatin and oxaliplatin), taxanes (docetaxel, paclitaxel) and 5-fluorouracil1. Despite advances in HNSCC treatment, the rate of tumor recurrence and patient mortality remain high. Therefore, the search for new prognostic identifiers and treatments targeting therapy-resistant tumor cells is vital. Our work demonstrates that there are different subgroups with high phenotypic plasticity within the CSC population in HNSCC. CD10, CD184, and CD166 may identify some of these CSC subpopulations with NAMPT as a common metabolic gene for the resilient cells of these subpopulations. We observed that NAMPT reduction causes a decrease in tumorigenic and stemness properties, migration capacity and CSC phenotype through NAD pool depletion. However, NAMPT-inhibited cells can acquire resistance by activating the NAPRT enzyme of the Preiss-Handler pathway. We observed that coadministration of the NAMPT inhibitor with the NAPRT inhibitor cooperated inhibiting tumor growth. The use of an NAPRT inhibitor as an adjuvant improved NAMPT inhibitor efficacy and reduced the dose and toxicity of these inhibitors. Therefore, it seems that the reduction in the NAD pool could have efficacy in tumor therapy. This was confirmed by in vitro assays supplying the cells with products of inhibited enzymes (NA, NMN or NAD) and restoring their tumorigenic and stemness properties. In conclusion, the coinhibition of NAMPT and NAPRT improved the efficacy of antitumor treatment, indicating that the reduction in the NAD pool is important to prevent tumor growth.

Published
2023
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15. The uppermost Cretaceous continental deposits at the southern end of Patagonia, the Chorrillo Formation case study (Austral-Magallanes Basin): Sedimentology, fossil content and regional implications

Author

Moyano-Paz, D., Rozadilla, S., Agnolín, F., Vera, E., Coronel, M.D., Varela, A.N., Gómez-Dacal, A.R., Aranciaga-Rolando, A.M., D'Angelo, J., Pérez-Loinaze, V., Richiano, S., Chimento, N., Motta, M.J., Sterli, J., Manabe, M., Tsuihiji, T., Isasi, M.P., Poiré, D.G., and Novas, F.E.

Published
2022
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17. 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

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

Published
2023
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19. Contributors

Author

Aguilar, José Francisco Noguera, primary, Alhayek-Aí, Mohammed, additional, Alonso Aguirre, Pedro A., additional, Álvarez-Chaver, Paula, additional, Alvarez-Gonzalez, Sara, additional, Álvarez-Santullano, Lucía, additional, Alvariño, Javier Castro, additional, Amigo, Jorge, additional, Antón Aparicio, Luis M., additional, Aptsiauri, Natalia, additional, Ares, María Sánchez, additional, Balea, Begoña Campos, additional, Balo, Paula Vieiro, additional, Barcia, Lucía, additional, Bou, Germán, additional, Barreiro, Vanesa Balboa, additional, Bendayán, Isaac Martínez, additional, Bernal, Mónica, additional, Briones, Pedro Carpintero, additional, Brozos-Vázquez, Elena, additional, Bueno, Begoña Bravo, additional, Burundarena, Alba, additional, Caamaño, Antonio Gómez, additional, Calviño, José Manuel Mera, additional, Calvo, Marcos, additional, Candamio-Folgar, Sonia, additional, Cardelle-Cobas, Alejandra, additional, Carracedo, Ángel, additional, Carrasco, Ainhoa, additional, Castro, Álvaro Gómez, additional, Castro, Ana María Carballo, additional, Cepeda, Alberto, additional, Cepeda-Emiliani, Alfonso, additional, Concha, Ángel, additional, Conde, Benito González, additional, Cordero, Oscar J., additional, Cortés, Alberto Centeno, additional, Cotoré, Jesús Paredes, additional, Crespo, Patricia Calvo, additional, de Castro, Alain García, additional, De Chiara, Loretta, additional, de la Ballina González, Enrique González, additional, de Llano, Sofía Rodríguez Martínez, additional, Deben, Manuel Núñez, additional, del Carmen Corujeira Rivera, M., additional, Díaz, Cristina Méndez, additional, Díaz, Sonia Pértega, additional, Diéguez, Leticia García, additional, D'Jesús, Antonio Rodríguez, additional, Dourado, Ramón Vázquez, additional, Dovigo, Alba Gómez, additional, Fajardo, Paloma Sosa, additional, Fernández, Nereida Fernández, additional, Fernández, Rafaela Soler, additional, Fernández, Rosalía, additional, Fernández, Sergio Manuel Estévez, additional, Fernandez-Lozano, Carlos, additional, Fernández-Rozadilla, Ceres, additional, Ferreiro, Raquel Sardina, additional, Ferreiro, Silvia Varela, additional, Figueiras, Roberto García, additional, Figueroa, Angélica, additional, Fontoira, Lydia Fraga, additional, Franco, Carlos M.N, additional, Gallardo-Gómez, María, additional, García, Concepción Crespo, additional, García, Esther Rodríguez, additional, García-López, Alba, additional, Garrido, Federico, additional, González, Javier Aguirrezabalaga, additional, González-Carreró, Joaquín, additional, Gonzalez-Rivas, Diego, additional, Graña-Suárez, Begoña, additional, Hernández, Vicent, additional, Higuero, Paula Peleteiro, additional, Iglesias, Héctor Lázare, additional, Lago, Orlando Fernández, additional, Lamas, Alexandre, additional, Liñares-Blanco, Jose, additional, Llanas, María Jose Martinez-Sapiña, additional, López, Fernando Fernández, additional, López, José Ramón Antúnez, additional, López-López, Rafael, additional, López-Novo, Anael, additional, Lorenzo, Carmen Álvarez, additional, Loureiro, Miguel Pereira, additional, Macenlle García, Ramiro Manuel, additional, Maldonado, Shirly Margarita Nieves, additional, Marcos, Sara Seijas, additional, Marqués, Eva Martí, additional, Martín, Cristina González, additional, Martínez, Arantza Germade, additional, Martínez Lago, Nieves, additional, Martínez-Bernal, Gala, additional, Martínez-Pérez, Julia, additional, Mato-Abad, Virginia, additional, Méndez, Silvia Louzao, additional, Montalvo, Manuel Bustamante, additional, Mosquera, Beatriz Romero, additional, Muñoz, Catuxa Celeiro, additional, Munteanu, Cristian R., additional, Nine, Ángel Concheiro, additional, Novoa, Alejandra García, additional, Oreiro, Martina Lema, additional, Osuna, Francisco Ruíz-Cabello, additional, Otero, María, additional, Otero Muinelo, Susana A., additional, Parada, Pilar Díaz, additional, Paredes Cotoré, Jesús P., additional, Pazos, Alejandro, additional, Pazos García, Alejandro, additional, Pazos García, Carla, additional, Pedreira, Nieves, additional, Pillado, María Teresa Seoane, additional, Piñeiro, Susana López, additional, Poza, Margarita, additional, Purriños, Natalia Cal, additional, Queipo, Francisco, additional, Regal, Patricia, additional, Reinquet, Fernando Zelaya, additional, Rey, María Teresa Vázquez, additional, Rivas, Andrés Dacal, additional, Rocha, José Luis Ulla, additional, Rodríguez, Alejandro Ledo, additional, Rodríguez, Francisco Javier González, additional, Rodríguez, Gerardo Baños, additional, Rodríguez, María Teresa García, additional, Rodríguez, Máximo Fraga, additional, Rojas, Miriam, additional, Rosés, Leopoldo López, additional, Rúa, Marta Covela, additional, Ruiz-Bañobre, Juan, additional, Ruiz-Ponte, Clara, additional, Saavedra, Francisco Javier Maestro, additional, Sacristán Santos, Víctor, additional, Said-Criado, Ismael, additional, Sánchez, Aliuska Duardo, additional, Santamaría, Paloma González, additional, Sardenberg, Rodrigo A.S., additional, Sieira, Antonio Jurjo, additional, Silva, Paulino Pais, additional, Suarez, Rosa Fungueiriño, additional, Taboada, Tatiana María Civeira, additional, Trillo, Adriana Barreiro, additional, Trillo, Rosa, additional, Vázquez-Tunas, M. Lidia, additional, Turnes, Alfonso Martínez, additional, Valladares, Begoña Taboada, additional, Valladares-Ayerbes, Manuel, additional, Varela, Vanesa Val, additional, Varela-Calviño, Rubén, additional, Vázquez, Beatriz I., additional, Vázquez, Carla Blanco, additional, Vázquez, Juan Turnes, additional, Vázquez, Pablo Parada, additional, Vázquez, Vanesa Vilanova, additional, Vázquez-Naya, José M., additional, Vázquez-Rivera, Francisca, additional, Veiga, Alberto, additional, Vidal-Ínsua, Yolanda, additional, Vilas, Alba María Arceo, additional, and Worner, Ignacio Couto, additional

Published
2022
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21. New transitional fossil from late Jurassic of Chile sheds light on the origin of modern crocodiles

Author

Fernando E. Novas, Federico L. Agnolin, Gabriel L. Lio, Sebastián Rozadilla, Manuel Suárez, Rita de la Cruz, Ismar de Souza Carvalho, David Rubilar-Rogers, and Marcelo P. Isasi

Subjects
Medicine, Science
Abstract

Abstract We describe the basal mesoeucrocodylian Burkesuchus mallingrandensis nov. gen. et sp., from the Upper Jurassic (Tithonian) Toqui Formation of southern Chile. The new taxon constitutes one of the few records of non-pelagic Jurassic crocodyliforms for the entire South American continent. Burkesuchus was found on the same levels that yielded titanosauriform and diplodocoid sauropods and the herbivore theropod Chilesaurus diegosuarezi, thus expanding the taxonomic composition of currently poorly known Jurassic reptilian faunas from Patagonia. Burkesuchus was a small-sized crocodyliform (estimated length 70 cm), with a cranium that is dorsoventrally depressed and transversely wide posteriorly and distinguished by a posteroventrally flexed wing-like squamosal. A well-defined longitudinal groove runs along the lateral edge of the postorbital and squamosal, indicative of a anteroposteriorly extensive upper earlid. Phylogenetic analysis supports Burkesuchus as a basal member of Mesoeucrocodylia. This new discovery expands the meagre record of non-pelagic representatives of this clade for the Jurassic Period, and together with Batrachomimus, from Upper Jurassic beds of Brazil, supports the idea that South America represented a cradle for the evolution of derived crocodyliforms during the Late Jurassic.

Published
2021
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22. Fine-mapping analysis including over 254 000 East Asian and European descendants identifies 136 putative colorectal cancer susceptibility genes

Author

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

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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23. Study protocol for a three-arm randomized controlled trial investigating the effectiveness, cost-utility, and physiological effects of a fully self-guided digital Acceptance and Commitment Therapy for Spanish patients with fibromyalgia

Author

Gallego, Ana, Serrat, Mayte, Royuela-Colomer, Estibaliz, Sanabria-Mazo, Juan P., Borras, Xavier, Esteve, Montserrat, Grasa, Mar, Rosa, Araceli, Rozadilla-Sacanell, Antoni, Almirall, Miriam, D'Amico, Francesco, Dai, Yifei, Rosenbluth, Michael J., McCracken, Lance, Navarrete, Jaime, Feliu-Soler, Albert, Luciano, Juan, V, Gallego, Ana, Serrat, Mayte, Royuela-Colomer, Estibaliz, Sanabria-Mazo, Juan P., Borras, Xavier, Esteve, Montserrat, Grasa, Mar, Rosa, Araceli, Rozadilla-Sacanell, Antoni, Almirall, Miriam, D'Amico, Francesco, Dai, Yifei, Rosenbluth, Michael J., McCracken, Lance, Navarrete, Jaime, Feliu-Soler, Albert, and Luciano, Juan, V

Abstract

Objective: Fibromyalgia (FM) is a prevalent pain syndrome with significant healthcare and societal costs. The aim of the SMART-FM-SP study is to determine the effectiveness, cost-utility, and physiological effects in patients with FM of a digital intervention (STANZA (R)) currently marketed in the United States, which delivers smartphone-based, fully self-guided Acceptance and Commitment Therapy (Digital ACT) for treating FM-related symptoms. Methods: A single-site, parallel-group, superiority, randomized controlled trial (RCT) will be conducted, including a total of 360 adults diagnosed with FM. Individuals will be randomly allocated (1:1:1) to treatment as usual (TAU), to TAU plus 12 weeks of treatment with Digital ACT, or to TAU plus 12 weeks of treatment with digital symptom tracking (i.e. FibroST). Participants will be assessed at baseline, post-treatment, and 6-month follow-up. An intention-to-treat analysis using linear mixed models will be computed to analyze the effects of Digital ACT on functional impairment (primary outcome), as measured by the Fibromyalgia Impact Questionnaire Revised at 6 months from the inception of the treatment. Secondary outcomes include impression of change, symptoms of distress, pain catastrophising, quality of life, cost-utility, and selected biomarkers (cortisol and cortisone, immune-inflammatory markers, and FKBP5 gene polymorphisms). The role of ACT-related processes of change will be tested with path analyses. Conclusions: This study is the first RCT that tests Digital ACT for Spanish patients with FM. Results will be important not only for patients and clinicians, but also for policy makers by examining the cost-utility of the app in a public healthcare context.

Published
2024
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24. Exome sequencing of early-onset patients supports genetic heterogeneity in colorectal cancer

Author

C. Fernández-Rozadilla, M. Álvarez-Barona, I. Quintana, A. López-Novo, J. Amigo, J. M. Cameselle-Teijeiro, E. Roman, D. Gonzalez, X. Llor, L. Bujanda, X. Bessa, R. Jover, F. Balaguer, A. Castells, S. Castellví-Bel, G. Capellá, A. Carracedo, L. Valle, and Clara Ruiz-Ponte

Subjects
Medicine, Science
Abstract

Abstract Colorectal cancer (CRC) is a complex disease that can be caused by a spectrum of genetic variants ranging from low to high penetrance changes, that interact with the environment to determine which individuals will develop the disease. In this study, we sequenced 20 early-onset CRC patients to discover novel genetic variants that could be linked to the prompt disease development. Eight genes, CHAD, CHD1L, ERCC6, IGTB7, PTPN13, SPATA20, TDG and TGS1, were selected and re-sequenced in a further 304 early onset CRC patients to search for rare, high-impact variants. Although we found a recurring truncating variant in the TDG gene shared by two independent patients, the results obtained did not help consolidate any of the candidates as promising CRC predisposing genes. However, we found that potential risk alleles in our extended list of candidate variants have a tendency to appear at higher numbers in younger cases. This supports the idea that CRC onset may be oligogenic in nature and may show molecular heterogeneity. Further, larger and robust studies are thus needed to unravel the genetics behind early-onset CRC development, coupled with novel functional analyses and omic approaches that may offer complementary insight.

Published
2021
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27. Study protocol for a three-arm randomized controlled trial investigating the effectiveness, cost-utility, and physiological effects of a fully self-guided digital Acceptance and Commitment Therapy for Spanish patients with fibromyalgia

Author

Gallego, Ana, primary, Serrat, Mayte, additional, Royuela-Colomer, Estíbaliz, additional, Sanabria-Mazo, Juan P, additional, Borràs, Xavier, additional, Esteve, Montserrat, additional, Grasa, Mar, additional, Rosa, Araceli, additional, Rozadilla-Sacanell, Antoni, additional, Almirall, Miriam, additional, D’Amico, Francesco, additional, Dai, Yifei, additional, Rosenbluth, Michael J., additional, McCracken, Lance M., additional, Navarrete, Jaime, additional, Feliu-Soler, Albert, additional, and Luciano, Juan V, additional

Published
2024
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28. Study protocol for a randomised, double-blinded, placebo-controlled phase III trial examining the add-on efficacy, cost–utility and neurobiological effects of low-dose naltrexone (LDN) in patients with fibromyalgia (INNOVA study)

Author

Carlos Suso-Ribera, Azucena García-Palacios, Juan P Sanabria-Mazo, Ariadna Colomer-Carbonell, Francesco D'Amico, Michael Maes, Xavier Borràs, Albert Feliu-Soler, Juan V Luciano, Jordi Muchart, Josep Munuera, Halbert Hernández-Negrín, Jarred W Younger, and Antoni Rozadilla-Sacanell

Subjects
Medicine
Published
2022
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33. Fossil Vertebrates From The Cerro Fortaleza Formation (Upper Cretaceous), Santa Cruz Province, Argentina

Author

Agnolín, Federico L., primary, Herrera, Gerardo Álvarez, additional, Rolando, Mauro Aranciaga, additional, Motta, Matías, additional, Rozadilla, Sebastián, additional, Verdiquio, Lucía, additional, D’Angelo, Julia S., additional, Moyano-Paz, Damián, additional, Varela, Augusto N., additional, Sterli, Juliana, additional, Bogan, Sergio, additional, Miner, Santiago, additional, Moreno, Ana, additional, Muñoz, Gonzalo, additional, Isasi, Marcelo P., additional, and Novas, Fernando E., additional

Published
2023
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34. Association analyses identify 31 new risk loci for colorectal cancer susceptibility

Author

Philip J. Law, Maria Timofeeva, Ceres Fernandez-Rozadilla, Peter Broderick, James Studd, Juan Fernandez-Tajes, Susan Farrington, Victoria Svinti, Claire Palles, Giulia Orlando, Amit Sud, Amy Holroyd, Steven Penegar, Evropi Theodoratou, Peter Vaughan-Shaw, Harry Campbell, Lina Zgaga, Caroline Hayward, Archie Campbell, Sarah Harris, Ian J. Deary, John Starr, Laura Gatcombe, Maria Pinna, Sarah Briggs, Lynn Martin, Emma Jaeger, Archana Sharma-Oates, James East, Simon Leedham, Roland Arnold, Elaine Johnstone, Haitao Wang, David Kerr, Rachel Kerr, Tim Maughan, Richard Kaplan, Nada Al-Tassan, Kimmo Palin, Ulrika A. Hänninen, Tatiana Cajuso, Tomas Tanskanen, Johanna Kondelin, Eevi Kaasinen, Antti-Pekka Sarin, Johan G. Eriksson, Harri Rissanen, Paul Knekt, Eero Pukkala, Pekka Jousilahti, Veikko Salomaa, Samuli Ripatti, Aarno Palotie, Laura Renkonen-Sinisalo, Anna Lepistö, Jan Böhm, Jukka-Pekka Mecklin, Daniel D. Buchanan, Aung-Ko Win, John Hopper, Mark E. Jenkins, Noralane M. Lindor, Polly A. Newcomb, Steven Gallinger, David Duggan, Graham Casey, Per Hoffmann, Markus M. Nöthen, Karl-Heinz Jöckel, Douglas F. Easton, Paul D. P. Pharoah, Julian Peto, Federico Canzian, Anthony Swerdlow, Rosalind A. Eeles, Zsofia Kote-Jarai, Kenneth Muir, Nora Pashayan, The PRACTICAL consortium, Andrea Harkin, Karen Allan, John McQueen, James Paul, Timothy Iveson, Mark Saunders, Katja Butterbach, Jenny Chang-Claude, Michael Hoffmeister, Hermann Brenner, Iva Kirac, Petar Matošević, Philipp Hofer, Stefanie Brezina, Andrea Gsur, Jeremy P. Cheadle, Lauri A. Aaltonen, Ian Tomlinson, Richard S. Houlston, and Malcolm G. Dunlop

Subjects
Science
Abstract

In colorectal cancer (CRC), finding loci associated with risk may give insight into disease aetiology. Here, the authors report a genome-wide association analysis in Europeans of 34,627 CRC cases and 71,379 controls, and find 31 new risk loci and 17 new risk SNPs at previously reported loci.

Published
2019
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35. Patterns of genetic differentiation and the footprints of historical migrations in the Iberian Peninsula

Author

Clare Bycroft, Ceres Fernandez-Rozadilla, Clara Ruiz-Ponte, Inés Quintela, Ángel Carracedo, Peter Donnelly, and Simon Myers

Subjects
Science
Abstract

The Iberian Peninsula has a complex history. Here, the authors analyse the genetic structure of the modern Iberian population at fine scale, revealing historical population movements associated with the time of Muslim rule.

Published
2019
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36. Comments on the Morphology of Basal Paravian Shoulder Girdle: New Data Based on Unenlagiid Theropods and Paleognath Birds

Author

Fernando E. Novas, Matías J. Motta, Federico L. Agnolín, Sebastián Rozadilla, Gastón E. Lo Coco, and Federico Brissón Egli

Subjects
Archaeopteryx, hypothetical stages, flight origins, pectoral girdle, Ostrom, Science
Abstract

In 1976 John Ostrom published an enlightening paper about the anatomical transformations in the shoulder girdle and forelimb elements along the origin of birds. Most of his ideas were based on comparing Archaeopteryx lithographica with the extant New World vulture Cathartes aura. Ostrom offered innovative ideas about range of movements and function of wing elements in the basal bird Archaeopteryx. Further, he explored anatomical transformations that may have occurred at early stages of the evolution of flight and established several hypothetical steps toward the acquisition of flapping flight in modern birds. Since then, however, our understanding of paravian diversity and anatomy has increased dramatically. Based on novel information derived from recent experiments, and currently available anatomical evidence of basal paravians, the present paper aims to review some important topics on pectoral girdle anatomy related to flight origins. Further, a brief analysis of pectoral girdle osteology and myology of the extant paleognath Rhea americana is also included with the aim to test whether Ostrom’s ideas still remain valid under this new context, based on available phylogenetic and anatomical frameworks.

Published
2021
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37. Anxiety, Depression, and Asthma Control: Changes After Standardized Treatment

Author

González, F. Callejas, López, J. Jiménez, Riaza, M. Martínez, Orenes, M. Moscardó, Montaño, P. Prieto, Toro, M. Torrecillas, Balaguer, C. Andreu, Girones, M. Antón, Martinez, C. Baeza, Martín, I. Flores, Delgado, P. Gonzalez, Calahorro, M. Martos, Carrasco, G. Mediero, Pacheco, R. Rodríguez, Tomás, V. Vilella, Godoy, M. Mota, Yébenes, J. Zapata, Balza De Vallejo, O. Villarreal, Fernandez, J. Alvarez, Gonzalez, T. Bazus, De Las Pozas, G. Castaño, Donado, C. Diaz, Angulo, S. Díaz, Ortiz, G. Gala, Mañana, B. Requejo, Gonzalez, R. Blanco, Nieves, E. Gómez, Torrado, J. Marin, Culla, M. Dordal, Pla, J. Juanola, Bellfill, R. Lleonart, Velasco, J. Martos, Nogues, E. Pinto, Ortun, M. Rivera, Aguñin, P. Rubinstein, Farre, N. Subira, Combas, J. Valldeperas, Zubeldia, I. Ansotegui, Hortigüela, G. Bernaola, Ayuso, J. Ciruelos, Álvarez, G. González, Peña, M. Herrerias, Castro, A. Lahuerta, Llorente, P. Losada, Martinez, P. Marin, Malanda, N. Marina, Gonzalez, F. Garcia, Miguel, T. Peña, Hernandez, M., Timon, S. Jimenez, Carreño, S. Porcel, Olbah, M. Alwakil, Muñoz, A. Arnedillo, Mohedad, J. Chamorro, Fernandez, D. Gutierrez, Camacho, A. Letran, Lopez, C. Merinas, Gonzalez, M. Millan, Bernal, S. Niño, Pellon, L. Fernandez, Miguel, E. Morchon, Portal, F. Ortiz, Rodríguez, A. Suárez, Alapont, M. Modesto, Raducan, I., Segarra, M. Salvador, Bonilla, P. Galindo, Calderon, P. Mata, Rodriguez, M. Mena, Martinez, R. Lama, Pérez, M. Martín, Villarejo, M. Morales, Aparicio, M. Blanco, Muíño Joga, M. Do, Garcia-Boente, L. Fontan, Paz, V. García, Barcala, F. Gonzalez, Orjales, R. Nuñez, Castedo, C. Rabade, Diaz, M. Rico, Fernandez, A. Moreno, Español, S. Aparicio, San Francisco, A. Ruiz, Navarrete, B. Alcázar, Gomez De Cadiz, L. Cassini, Rodriguez, M. Escribano, Lopez, J. Florido, Jiménez, M. Lara, Caballero, J. Lopez, Ceres, M. Martínez, Costoya, R. Mayorgas, García, C. Morales, Vilchez, M. Rojas, Ortiz, A. Romero, Mazuecos, J. Beitia, Castro, A. Vega, Arenaza, B. Labeguerie, Mendizabal, S. Lizarza, Sampedro, I. Perez, Vazquez, L. Valverde, De Sus, J. Cegoñino, Villa, J. Compaired, Pargada, D. Ferrer, Jarque, J. Herrero, Patiño, M. Chacon, Gomila, A. Fuster, Pastrie, F. Nicolau, Lopez, J. Almagro, Martinez, P. Benito, Ruiz De Lobera, A. Velez, Gonzalez, F. Carballada, Carral, C. Perez, Racamonde, A. Veres, Del Pino, M. Cervera, Sacanell, J. Rozadilla, García, I. Ali, Mejias, Y. Anta, Bausela, B. Añíbarro, Cozar, M. Arroyo, Sanz, P. Barranco, Bobolea, I., Fernandez, A. Bueso, De Santiago Delgado, E., Campos, R. Diaz, Uña, J. Donado, Vila, A. Feliu, Cano, M. Gandolfo, De Pedro, J. Garcia, Galicia, M. Garcimartin, De Olano, D. González, Barbudo, B. Huertas, Viña, A. López, Peña, A. Losada, Martin, G. Minguez, De Francisco, A. Montoro, Borque, R. Moreno, Moro, M., Prieto, M. Ramirez, Frutos, M. Reche, Jimenez, B. Rodriguez, Rodríguez, M., Ribate, D. Romero, Perez, F. Ruano, Hornillos, J. Ruiz, López, P. Sánchez, Martinez, F. Sola, Garrido-Lestache, J. Subiza, Gambasica, Z. Vasquez, Albelda, C. Vila, Ramirez, J. Alcazar, De Luiz Martínez, G., Núñez, I. García, De Luna, F. Linde, Sáenz De Tejada, E. Ortega, Galo, A. Padilla, Martinez, R. Rodriguez, Esojo, M. Soria, Espinosa, R. Andujar, Inglés, M. Avilés, Mora, R. Bernabeu, Campos, M. Franco, Arellano, M. Peña, Puebla, M. Alvarez, Figueroa, B. García, Fernández, S. Garrido, Rivera, J. Olaguibel, Purroy, A. Tabar, Garazo, B. Presedo, Losada, S. Varela, Villamuza, Y. García, Bonny, J. Cumplido, Sintes, R. Alvarez, Landin, J. Castro, Paz, A. Cobas, Abelaira, M. Corbacho, Rio, F. Iglesias, Sanmartín, A. Pallarés, Picans, I., Moreira, A. Regueiro, Romera, R. Tejedor, Aznar, J. Igea, Bellido, F. Muñoz, Hernandez, M. Rodriguez, Perez, R. González, Flores, H. Izaguirre, Gutierrez, F. Alvarez, Cimbollek, S., De Luque Piñana, V., Gallardo, J. Medina, Garcia, V. Moreno, Cuevas, J. Orta, Crespo, Y. Puente, Enriquez, J. Quiralte, Dominguez, P. Serrano, Elias, Ò. Sotorra, Pamplona, M. Muñoz, Lara, M. Jimenez, De Gregorio, A. Moral, Martin, M. Alvariño, Canelles, M. Ballester, Baixauli, E. Burches, Serra, P. Catalán, Gregori, M. Climent, Rodriguez, P. Cordero, De Las Marinas Alvarez, M., Palacios, M. Díaz, El-Qutob López, D., Giner, J. Greses, Lara, S. Herrera, Martínez, G. Jorro, Santafé, J. Liñana, Bayo, A. Lloris, Moragon, E. Martinez, Sancho, I. Molero, Lacomba, J. Montoro, Sendra, E. Naval, Seisdedos, L. Navarro, Bertol, B. Orosa, Iniesta, A. Robles, Cubillan, J. Ruiz, Sánchez-Toril López, F., Vinuesa, A. Saura, Gomez, A. Alonso, De Frutos Arribas, J., Fernandez, E. Macias, Alonso, A. Sanchez, Sanz, C. Colás, Fuentes, M. Domínguez, Sotillos, M. Garcés, Arazuri, N. Segura, Sastre, Joaquín, Crespo, Astrid, Fernandez-Sanchez, Antonio, Rial, Manuel, and Plaza, Vicente

Published
2018
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38. Tumor Profiling at the Service of Cancer Therapy

Author

Ceres Fernandez-Rozadilla, Ana Rita Simões, Matilde E. Lleonart, Amancio Carnero, and Ángel Carracedo

Subjects
cancer treatment, omics, profiling, immunotherapy, personalized medicine, precision oncology, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Cancer treatment options have evolved significantly in the past few years. From the initial surgical procedures, to the latest next-generation technologies, we are now in the position to analyze and understand tumors in a one-by-one basis and use that to our advantage to provide with individualized treatment options that may increase patient survival. In this review, we will focus on how tumor profiling has evolved over the past decades to deliver more efficient and personalized treatment options, and how novel technologies can help us envisage the future of precision oncology toward a better management and, ultimately, increased survival.

Published
2021
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39. A colorectal cancer genome-wide association study in a Spanish cohort identifies two variants associated with colorectal cancer risk at 1p33 and 8p12

Author

Fernandez-Rozadilla, Ceres, Cazier, Jean-Baptiste, Tomlinson, Ian P, Carvajal-Carmona, Luis G, Palles, Claire, Lamas, María J, Baiget, Montserrat, López-Fernández, Luis A, Brea-Fernández, Alejandro, Abulí, Anna, Bujanda, Luis, Clofent, Juan, Gonzalez, Dolors, Xicola, Rosa, Andreu, Montserrat, Bessa, Xavier, Jover, Rodrigo, Llor, Xavier, The EPICOLON Consortium, Moreno, Víctor, Castells, Antoni, Carracedo, Ángel, Castellvi-Bel, Sergi, and Ruiz-Ponte, Clara

Subjects
Cancer, Prevention, Digestive Diseases, Colo-Rectal Cancer, Human Genome, Genetics, Aetiology, 2.1 Biological and endogenous factors, Aged, Aged, 80 and over, Chromosomes, Human, Pair 1, Chromosomes, Human, Pair 8, Cohort Studies, Colorectal Neoplasms, Dual-Specificity Phosphatases, Female, Genetic Loci, Genome, Human, Genome-Wide Association Study, Genotype, Humans, Male, Middle Aged, Mitogen-Activated Protein Kinase Phosphatases, Odds Ratio, Polymorphism, Single Nucleotide, Principal Component Analysis, Risk Factors, Spain, White People, GWAS, SNPs, Colorectal cancer, Spanish cohort, 1p33, 8p12, EPICOLON Consortium, Biological Sciences, Information and Computing Sciences, Medical and Health Sciences, Bioinformatics
Abstract

BackgroundColorectal cancer (CRC) is a disease of complex aetiology, with much of the expected inherited risk being due to several common low risk variants. Genome-Wide Association Studies (GWAS) have identified 20 CRC risk variants. Nevertheless, these have only been able to explain part of the missing heritability. Moreover, these signals have only been inspected in populations of Northern European origin.ResultsThus, we followed the same approach in a Spanish cohort of 881 cases and 667 controls. Sixty-four variants at 24 loci were found to be associated with CRC at p-values

Published
2013

40. Refinement of the associations between risk of colorectal cancer and polymorphisms on chromosomes 1q41 and 12q13.13

Author

Spain, Sarah L, Carvajal-Carmona, Luis G, Howarth, Kimberley M, Jones, Angela M, Su, Zhan, Cazier, Jean-Baptiste, Williams, Jennet, Aaltonen, Lauri A, Pharoah, Paul, Kerr, David J, Cheadle, Jeremy, Li, Li, Casey, Graham, Vodicka, Pavel, Sieber, Oliver, Lipton, Lara, Gibbs, Peter, Martin, Nicholas G, Montgomery, Grant W, Young, Joanne, Baird, Paul N, Morreau, Hans, van Wezel, Tom, Ruiz-Ponte, Clara, Fernandez-Rozadilla, Ceres, Carracedo, Angel, Castells, Antoni, Castellvi-Bel, Sergi, Dunlop, Malcolm, Houlston, Richard S, and Tomlinson, Ian PM

Subjects
Genetics, Colo-Rectal Cancer, Aging, Digestive Diseases, Human Genome, Biotechnology, Cancer, Aetiology, 2.1 Biological and endogenous factors, Chromosome Mapping, Chromosomes, Human, Pair 1, Chromosomes, Human, Pair 12, Colorectal Neoplasms, Computational Biology, Genetic Predisposition to Disease, Genome-Wide Association Study, Genotyping Techniques, Haplotypes, Humans, Logistic Models, Polymorphism, Single Nucleotide, Software, Biological Sciences, Medical and Health Sciences, Genetics & Heredity
Abstract

In genome-wide association studies (GWASs) of colorectal cancer, we have identified two genomic regions in which pairs of tagging-single nucleotide polymorphisms (tagSNPs) are associated with disease; these comprise chromosomes 1q41 (rs6691170, rs6687758) and 12q13.13 (rs7163702, rs11169552). We investigated these regions further, aiming to determine whether they contain more than one independent association signal and/or to identify the SNPs most strongly associated with disease. Genotyping of additional sample sets at the original tagSNPs showed that, for both regions, the two tagSNPs were unlikely to identify a single haplotype on which the functional variation lay. Conversely, one of the pair of SNPs did not fully capture the association signal in each region. We therefore undertook more detailed analyses, using imputation, logistic regression, genealogical analysis using the GENECLUSTER program and haplotype analysis. In the 1q41 region, the SNP rs11118883 emerged as a strong candidate based on all these analyses, sufficient to account for the signals at both rs6691170 and rs6687758. rs11118883 lies within a region with strong evidence of transcriptional regulatory activity and has been associated with expression of PDGFRB mRNA. For 12q13.13, a complex situation was found: SNP rs7972465 showed stronger association than either rs11169552 or rs7136702, and GENECLUSTER found no good evidence for a two-SNP model. However, logistic regression and haplotype analyses supported a two-SNP model, in which a signal at the SNP rs706793 was added to that at rs11169552. Post-GWAS fine-mapping studies are challenging, but the use of multiple tools can assist in identifying candidate functional variants in at least some cases.

Published
2012

41. Development of a panel of genome-wide ancestry informative markers to study admixture throughout the Americas.

Author

Galanter, Joshua Mark, Fernandez-Lopez, Juan Carlos, Gignoux, Christopher R, Barnholtz-Sloan, Jill, Fernandez-Rozadilla, Ceres, Via, Marc, Hidalgo-Miranda, Alfredo, Contreras, Alejandra V, Figueroa, Laura Uribe, Raska, Paola, Jimenez-Sanchez, Gerardo, Zolezzi, Irma Silva, Torres, Maria, Ponte, Clara Ruiz, Ruiz, Yarimar, Salas, Antonio, Nguyen, Elizabeth, Eng, Celeste, Borjas, Lisbeth, Zabala, William, Barreto, Guillermo, González, Fernando Rondón, Ibarra, Adriana, Taboada, Patricia, Porras, Liliana, Moreno, Fabián, Bigham, Abigail, Gutierrez, Gerardo, Brutsaert, Tom, León-Velarde, Fabiola, Moore, Lorna G, Vargas, Enrique, Cruz, Miguel, Escobedo, Jorge, Rodriguez-Santana, José, Rodriguez-Cintrón, William, Chapela, Rocio, Ford, Jean G, Bustamante, Carlos, Seminara, Daniela, Shriver, Mark, Ziv, Elad, Burchard, Esteban Gonzalez, Haile, Robert, Parra, Esteban, Carracedo, Angel, and LACE Consortium

Subjects
LACE Consortium, Humans, Genetic Markers, Population Dynamics, Genome, Human, African Continental Ancestry Group, American Native Continental Ancestry Group, European Continental Ancestry Group, Latin America, Genome, Human, Genetics, Developmental Biology
Abstract

Most individuals throughout the Americas are admixed descendants of Native American, European, and African ancestors. Complex historical factors have resulted in varying proportions of ancestral contributions between individuals within and among ethnic groups. We developed a panel of 446 ancestry informative markers (AIMs) optimized to estimate ancestral proportions in individuals and populations throughout Latin America. We used genome-wide data from 953 individuals from diverse African, European, and Native American populations to select AIMs optimized for each of the three main continental populations that form the basis of modern Latin American populations. We selected markers on the basis of locus-specific branch length to be informative, well distributed throughout the genome, capable of being genotyped on widely available commercial platforms, and applicable throughout the Americas by minimizing within-continent heterogeneity. We then validated the panel in samples from four admixed populations by comparing ancestry estimates based on the AIMs panel to estimates based on genome-wide association study (GWAS) data. The panel provided balanced discriminatory power among the three ancestral populations and accurate estimates of individual ancestry proportions (R² > 0.9 for ancestral components with significant between-subject variance). Finally, we genotyped samples from 18 populations from Latin America using the AIMs panel and estimated variability in ancestry within and between these populations. This panel and its reference genotype information will be useful resources to explore population history of admixture in Latin America and to correct for the potential effects of population stratification in admixed samples in the region.

Published
2012

42. Case-control study for colorectal cancer genetic susceptibility in EPICOLON: previously identified variants and mucins

Author

Abulí, Anna, Fernández-Rozadilla, Ceres, Alonso-Espinaco, Virginia, Muñoz, Jenifer, Gonzalo, Victoria, Bessa, Xavier, González, Dolors, Clofent, Joan, Cubiella, Joaquin, Morillas, Juan D, Rigau, Joaquim, Latorre, Mercedes, Fernández-Bañares, Fernando, Peña, Elena, Riestra, Sabino, Payá, Artemio, Jover, Rodrigo, Xicola, Rosa M, Llor, Xavier, Carvajal-Carmona, Luis, Villanueva, Cristina M, Moreno, Victor, Piqué, Josep M, Carracedo, Angel, Castells, Antoni, Andreu, Montserrat, Ruiz-Ponte, Clara, Castellví-Bel, Sergi, and for the Gastrointestinal Oncology Group of the Spanish Gastroenterological Association

Subjects
Prevention, Cancer, Clinical Research, Genetics, Colo-Rectal Cancer, Digestive Diseases, 2.1 Biological and endogenous factors, Aetiology, Case-Control Studies, Colonic Neoplasms, Genetic Predisposition to Disease, Humans, Mucins, N-Acetylgalactosaminyltransferases, Polymorphism, Single Nucleotide, Prospective Studies, Spain, Colorectal Neoplasms, Single Nucleotide Polymorphism, Genetic Association Studies, Gastrointestinal Oncology Group of the Spanish Gastroenterological Association, Oncology and Carcinogenesis, Public Health and Health Services, Oncology & Carcinogenesis
Abstract

BackgroundColorectal cancer (CRC) is the second leading cause of cancer death in developed countries. Familial aggregation in CRC is also important outside syndromic forms and, in this case, a polygenic model with several common low-penetrance alleles contributing to CRC genetic predisposition could be hypothesized. Mucins and GALNTs (N-acetylgalactosaminyltransferase) are interesting candidates for CRC genetic susceptibility and have not been previously evaluated. We present results for ten genetic variants linked to CRC risk in previous studies (previously identified category) and 18 selected variants from the mucin gene family in a case-control association study from the Spanish EPICOLON consortium.MethodsCRC cases and matched controls were from EPICOLON, a prospective, multicenter, nationwide Spanish initiative, comprised of two independent stages. Stage 1 corresponded to 515 CRC cases and 515 controls, whereas stage 2 consisted of 901 CRC cases and 909 controls. Also, an independent cohort of 549 CRC cases and 599 controls outside EPICOLON was available for additional replication. Genotyping was performed for ten previously identified SNPs in ADH1C, APC, CCDN1, IL6, IL8, IRS1, MTHFR, PPARG, VDR and ARL11, and 18 selected variants in the mucin gene family.ResultsNone of the 28 SNPs analyzed in our study was found to be associated with CRC risk. Although four SNPs were significant with a P-value < 0.05 in EPICOLON stage 1 [rs698 in ADH1C (OR = 1.63, 95% CI = 1.06-2.50, P-value = 0.02, recessive), rs1800795 in IL6 (OR = 1.62, 95% CI = 1.10-2.37, P-value = 0.01, recessive), rs3803185 in ARL11 (OR = 1.58, 95% CI = 1.17-2.15, P-value = 0.007, codominant), and rs2102302 in GALNTL2 (OR = 1.20, 95% CI = 1.00-1.44, P-value = 0.04, log-additive 0, 1, 2 alleles], only rs3803185 achieved statistical significance in EPICOLON stage 2 (OR = 1.34, 95% CI = 1.06-1.69, P-value = 0.01, recessive). In the joint analysis for both stages, results were only significant for rs3803185 (OR = 1.12, 95% CI = 1.00-1.25, P-value = 0.04, log-additive 0, 1, 2 alleles) and borderline significant for rs698 and rs2102302. The rs3803185 variant was not significantly associated with CRC risk in an external cohort (MCC-Spain), but it still showed some borderline significance in the pooled analysis of both cohorts (OR = 1.08, 95% CI = 0.98-1.18, P-value = 0.09, log-additive 0, 1, 2 alleles).ConclusionsARL11, ADH1C, GALNTL2 and IL6 genetic variants may have an effect on CRC risk. Further validation and meta-analyses should be undertaken in larger CRC studies.

Published
2011

43. A two-phase case–control study for colorectal cancer genetic susceptibility: candidate genes from chromosomal regions 9q22 and 3q22

Author

Abulí, A, Fernández-Rozadilla, C, Giráldez, MD, Muñoz, J, Gonzalo, V, Bessa, X, Bujanda, L, Reñé, JM, Lanas, A, García, AM, Saló, J, Argüello, L, Vilella, À, Carreño, R, Jover, R, Xicola, RM, Llor, X, Carvajal-Carmona, L, Tomlinson, IPM, Kerr, DJ, Houlston, RS, Piqué, JM, Carracedo, A, Castells, A, Andreu, M, Ruiz-Ponte, C, Castellví-Bel, S, and for the Gastrointestinal Oncology Group of the Spanish Gastroenterological Association

Subjects
Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Cancer, Prevention, Digestive Diseases, Colo-Rectal Cancer, Genetics, Aetiology, 2.1 Biological and endogenous factors, Aged, Antigens, CD, Carrier Proteins, Case-Control Studies, Chromosomes, Human, Pair 3, Chromosomes, Human, Pair 9, Colorectal Neoplasms, DNA-Binding Proteins, GPI-Linked Proteins, Genetic Association Studies, Genetic Predisposition to Disease, Humans, Male, Nuclear Proteins, Polymorphism, Single Nucleotide, Semaphorins, colorectal neoplasm, genetic predisposition to disease, single-nucleotide polymorphism, genetic association study, Gastrointestinal Oncology Group of the Spanish Gastroenterological Association, Public Health and Health Services, Oncology & Carcinogenesis, Oncology and carcinogenesis
Abstract

BackgroundColorectal cancer (CRC) is the second cause of cancer-related death in the Western world. Much of the CRC genetic risk remains unidentified and may be attributable to a large number of common, low-penetrance genetic variants. Genetic linkage studies in CRC families have reported additional association with regions 9q22-31, 3q21-24, 7q31, 11q, 14q and 22q. There are several plausible candidate genes for CRC susceptibility within the aforementioned linkage regions including PTCH1, XPA and TGFBR1 in 9q22-31, and EPHB1 and MRAS in 3q21-q24.MethodsCRC cases and matched controls were from EPICOLON, a prospective, multicentre, nationwide Spanish initiative, composed of two independent phases. Phase 1 corresponded to 515 CRC cases and 515 controls, whereas phase 2 consisted of 901 CRC cases and 909 controls. Genotyping was performed for 172 single-nucleotide polymorphisms (SNPs) in 84 genes located within regions 9q22-31 and 3q21-q24.ResultsNone of the 172 SNPs analysed in our study could be formally associated with CRC risk. However, rs1444601 (TOPBP1) and rs13088006 (CDV3) in region 3q22 showed interesting results and may have an effect on CRC risk.ConclusionsTOPBP1 and CDV3 genetic variants on region 3q22 may modulate CRC risk. Further validation and meta-analysis should be undertaken in larger CRC cohorts.

Published
2011

44. Multiple common susceptibility variants near BMP pathway loci GREM1, BMP4, and BMP2 explain part of the missing heritability of colorectal cancer.

Author

Tomlinson, Ian PM, Carvajal-Carmona, Luis G, Dobbins, Sara E, Tenesa, Albert, Jones, Angela M, Howarth, Kimberley, Palles, Claire, Broderick, Peter, Jaeger, Emma EM, Farrington, Susan, Lewis, Annabelle, Prendergast, James GD, Pittman, Alan M, Theodoratou, Evropi, Olver, Bianca, Walker, Marion, Penegar, Steven, Barclay, Ella, Whiffin, Nicola, Martin, Lynn, Ballereau, Stephane, Lloyd, Amy, Gorman, Maggie, Lubbe, Steven, COGENT Consortium, CORGI Collaborators, EPICOLON Consortium, Howie, Bryan, Marchini, Jonathan, Ruiz-Ponte, Clara, Fernandez-Rozadilla, Ceres, Castells, Antoni, Carracedo, Angel, Castellvi-Bel, Sergi, Duggan, David, Conti, David, Cazier, Jean-Baptiste, Campbell, Harry, Sieber, Oliver, Lipton, Lara, Gibbs, Peter, Martin, Nicholas G, Montgomery, Grant W, Young, Joanne, Baird, Paul N, Gallinger, Steven, Newcomb, Polly, Hopper, John, Jenkins, Mark A, Aaltonen, Lauri A, Kerr, David J, Cheadle, Jeremy, Pharoah, Paul, Casey, Graham, Houlston, Richard S, and Dunlop, Malcolm G

Subjects
COGENT Consortium, CORGI Collaborators, EPICOLON Consortium, Humans, Colorectal Neoplasms, Genetic Predisposition to Disease, Intercellular Signaling Peptides and Proteins, Case-Control Studies, Signal Transduction, Gene Frequency, Quantitative Trait, Heritable, Polymorphism, Single Nucleotide, Aged, Middle Aged, Male, Genetic Variation, Genome-Wide Association Study, Bone Morphogenetic Protein 2, Bone Morphogenetic Protein 4, Polymorphism, Single Nucleotide, Quantitative Trait, Heritable, Genetics, Developmental Biology
Abstract

Genome-wide association studies (GWAS) have identified 14 tagging single nucleotide polymorphisms (tagSNPs) that are associated with the risk of colorectal cancer (CRC), and several of these tagSNPs are near bone morphogenetic protein (BMP) pathway loci. The penalty of multiple testing implicit in GWAS increases the attraction of complementary approaches for disease gene discovery, including candidate gene- or pathway-based analyses. The strongest candidate loci for additional predisposition SNPs are arguably those already known both to have functional relevance and to be involved in disease risk. To investigate this proposition, we searched for novel CRC susceptibility variants close to the BMP pathway genes GREM1 (15q13.3), BMP4 (14q22.2), and BMP2 (20p12.3) using sample sets totalling 24,910 CRC cases and 26,275 controls. We identified new, independent CRC predisposition SNPs close to BMP4 (rs1957636, P = 3.93×10(-10)) and BMP2 (rs4813802, P = 4.65×10(-11)). Near GREM1, we found using fine-mapping that the previously-identified association between tagSNP rs4779584 and CRC actually resulted from two independent signals represented by rs16969681 (P = 5.33×10(-8)) and rs11632715 (P = 2.30×10(-10)). As low-penetrance predisposition variants become harder to identify-owing to small effect sizes and/or low risk allele frequencies-approaches based on informed candidate gene selection may become increasingly attractive. Our data emphasise that genetic fine-mapping studies can deconvolute associations that have arisen owing to independent correlation of a tagSNP with more than one functional SNP, thus explaining some of the apparently missing heritability of common diseases.

Published
2011

45. HoSeIn: A Workflow for Integrating Various Homology Search Results from Metagenomic and Metatranscriptomic Sequence Datasets

Author

Gaston Rozadilla, Jorgelina Moreiras Clemente, and Christina McCarthy

Subjects
Biology (General), QH301-705.5
Abstract

Data generated by metagenomic and metatranscriptomic experiments is both enormous and inherently noisy. When using taxonomy-dependent alignment-based methods to classify and label reads, the first step consists in performing homology searches against sequence databases. To obtain the most information from the samples, nucleotide sequences are usually compared to various databases (nucleotide and protein) using local sequence aligners such as BLASTN and BLASTX. Nevertheless, the analysis and integration of these results can be problematic because the outputs from these searches usually show inconsistencies, which can be notorious when working with RNA-seq. Moreover, and to the best of our knowledge, existing tools do not criss-cross and integrate information from the different homology searches, but provide the results of each analysis separately. We developed the HoSeIn workflow to intersect the information from these homology searches, and then determine the taxonomic and functional profile of the sample using this integrated information. The workflow is based on the assumption that the sequences that correspond to a certain taxon are composed of:1) sequences that were assigned to the same taxon by both homology searches;2) sequences that were assigned to that taxon by one of the homology searches but returned no hits in the other one.

Published
2020
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46. Agua no potable para consumo en la Horticultura de La Plata (Buenos Aires). Causas, consecuencias y alternativas

Author

Matias Garcia, Gastón Rozadilla, and Leonardo Cano

Subjects
calidad del agua, horticultores, contaminación, Technology, Science
Abstract

En la región periurbana de La Plata se destaca la producción de hortalizas frescas llevada a cabo por pequeños agricultores familiares. En el marco de las problemáticas de hábitat y salud, se observa una serie de sintomatologías que afectan tanto a los productores/trabajadores y sus familias -principalmente los chicos que allí habitan- como así también a los consumidores de los productos hortícolas. Estas sintomatologías tienen como origen principal la utilización de agua no potable. El trabajo se propone determinar el tipo y magnitud de la contaminación del agua, identificar los causales del mismo y evaluar alternativas que resuelvan el presente inconveniente. Los resultados indican que una problemática compleja como la planteada, requiere que las soluciones tecnológicas sean acompañadas de acciones políticas que modifiquen condiciones estructurales de la vida de los productores en el cinturón hortícola platense.

Published
2020
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47. Genetic variation at 11q23.1 confers colorectal cancer risk by dysregulation of colonic tuft cell transcriptional activatorPOU2AF2

Author

Rajasekaran, V, primary, Harris, B. T, additional, Osborn, R. T, additional, Smillie, C, additional, Donnelly, K, additional, Bacou, M, additional, Esiri-Bloom, E, additional, Ooi, L.Y, additional, Allan, M, additional, Walker, M, additional, Reid, S, additional, Meynert, A, additional, Grimes, G, additional, Blackmur, J. P, additional, Vaughan-Shaw, P. G, additional, Law, P. J, additional, Fernandez-Rozadilla, C, additional, Tomlinson, I. P, additional, Houlston, R, additional, Myant, K. B, additional, Din, F. V, additional, Dunlop, M. G., additional, and Farrington, S. M, additional

Published
2023
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49. Deciphering colorectal cancer genetics through multi-omic analysis of 100,204 cases and 154,587 controls of European and east Asian ancestries

Author

Fernandez-Rozadilla, C, Timofeeva, M, Chen, Z, Law, P, Thomas, M, Bien, S, Diez-Obrero, V, Li, L, Fernandez-Tajes, J, Palles, C, Sherwood, K, Harris, S, Svinti, V, McDonnell, K, Farrington, S, Studd, J, Vaughan-Shaw, P, Shu, X-O, Long, J, Cai, Q, Guo, X, Lu, Y, Scacheri, P, Huyghe, J, Harrison, T, Shibata, D, Haiman, C, Devall, M, Schumacher, F, Melas, M, Rennert, G, Obon-Santacana, M, Martin-Sanchez, V, Moratalla-Navarro, F, Oh, JH, Kim, J, Jee, SH, Jung, KJ, Kweon, S-S, Shin, M-H, Shin, A, Ahn, Y-O, Kim, D-H, Oze, I, Wen, W, Matsuo, K, Matsuda, K, Tanikawa, C, Ren, Z, Gao, Y-T, Jia, W-H, Potter, J, Jenkins, M, Win, AK, Pai, R, Figueiredo, J, Haile, R, Gallinger, S, Woods, M, Newcomb, P, Cheadle, J, Kaplan, R, Maughan, T, Kerr, R, Kerr, D, Kirac, I, Boehm, J, Mecklin, L-P, Jousilahti, P, Knekt, P, Aaltonen, L, Rissanen, H, Pukkala, E, Eriksson, J, Cajuso, T, Hanninen, U, Kondelin, J, Palin, K, Tanskanen, T, Renkonen-Sinisalo, L, Zanke, B, Mannisto, S, Albanes, D, Weinstein, S, Ruiz-Narvaez, E, Palmer, J, Buchanan, D, Platz, E, Visvanathan, K, Ulrich, C, Siegel, E, Brezina, S, Gsur, A, Campbell, P, Chang-Claude, J, Hoffmeister, M, Brenner, H, Slattery, M, Tsilidis, K, Schulze, M, Gunter, M, Murphy, N, Castells, A, Castellvi-Bel, S, Moreira, L, Arndt, V, Shcherbina, A, Stern, M, Pardamean, B, Bishop, T, Giles, G, Southey, M, Idos, G, Abu-Ful, Z, Greenson, J, Shulman, K, Lejbkowicz, F, Offit, K, Su, Y-R, Steinfelder, R, Keku, T, van Guelpen, B, Hudson, T, Hampel, H, Pearlman, R, Berndt, S, Hayes, R, Martinez, ME, Thomas, S, Corley, D, Pharoah, P, Larsson, S, Yen, Y, Lenz, H-J, White, E, Doheny, K, Pugh, E, Shelford, T, Chan, A, Cruz-Correa, M, Lindblom, A, Joshi, A, Schafmayer, C, Kundaje, A, Nickerson, D, Schoen, R, Hampe, J, Stadler, Z, Vodicka, P, Vodickova, L, Vymetalkova, V, Papadopoulos, N, Edlund, C, Gauderman, W, Thomas, D, Toland, A, Markowitz, S, Kim, A, Gruber, S, van Duijnhoven, F, Feskens, E, Sakoda, L, Gago-Dominguez, M, Wolk, A, Naccarati, A, Pardini, B, FitzGerald, L, Lee, SC, Ogino, S, Kooperberg, C, Li, C, Lin, Y, Prentice, R, Qu, C, Bezieau, S, Tangen, C, Mardis, E, Yamaji, T, Sawada, N, Iwasaki, M, Le Marchand, L, Wu, A, McNeil, C, Coetzee, G, Hayward, C, Deary, I, Theodoratou, E, Reid, S, Walker, M, Ooi, LY, Moreno, V, Casey, G, Tomlinson, I, Zheng, W, Dunlop, M, Houlston, R, Peters, U, Fernandez-Rozadilla, C, Timofeeva, M, Chen, Z, Law, P, Thomas, M, Bien, S, Diez-Obrero, V, Li, L, Fernandez-Tajes, J, Palles, C, Sherwood, K, Harris, S, Svinti, V, McDonnell, K, Farrington, S, Studd, J, Vaughan-Shaw, P, Shu, X-O, Long, J, Cai, Q, Guo, X, Lu, Y, Scacheri, P, Huyghe, J, Harrison, T, Shibata, D, Haiman, C, Devall, M, Schumacher, F, Melas, M, Rennert, G, Obon-Santacana, M, Martin-Sanchez, V, Moratalla-Navarro, F, Oh, JH, Kim, J, Jee, SH, Jung, KJ, Kweon, S-S, Shin, M-H, Shin, A, Ahn, Y-O, Kim, D-H, Oze, I, Wen, W, Matsuo, K, Matsuda, K, Tanikawa, C, Ren, Z, Gao, Y-T, Jia, W-H, Potter, J, Jenkins, M, Win, AK, Pai, R, Figueiredo, J, Haile, R, Gallinger, S, Woods, M, Newcomb, P, Cheadle, J, Kaplan, R, Maughan, T, Kerr, R, Kerr, D, Kirac, I, Boehm, J, Mecklin, L-P, Jousilahti, P, Knekt, P, Aaltonen, L, Rissanen, H, Pukkala, E, Eriksson, J, Cajuso, T, Hanninen, U, Kondelin, J, Palin, K, Tanskanen, T, Renkonen-Sinisalo, L, Zanke, B, Mannisto, S, Albanes, D, Weinstein, S, Ruiz-Narvaez, E, Palmer, J, Buchanan, D, Platz, E, Visvanathan, K, Ulrich, C, Siegel, E, Brezina, S, Gsur, A, Campbell, P, Chang-Claude, J, Hoffmeister, M, Brenner, H, Slattery, M, Tsilidis, K, Schulze, M, Gunter, M, Murphy, N, Castells, A, Castellvi-Bel, S, Moreira, L, Arndt, V, Shcherbina, A, Stern, M, Pardamean, B, Bishop, T, Giles, G, Southey, M, Idos, G, Abu-Ful, Z, Greenson, J, Shulman, K, Lejbkowicz, F, Offit, K, Su, Y-R, Steinfelder, R, Keku, T, van Guelpen, B, Hudson, T, Hampel, H, Pearlman, R, Berndt, S, Hayes, R, Martinez, ME, Thomas, S, Corley, D, Pharoah, P, Larsson, S, Yen, Y, Lenz, H-J, White, E, Doheny, K, Pugh, E, Shelford, T, Chan, A, Cruz-Correa, M, Lindblom, A, Joshi, A, Schafmayer, C, Kundaje, A, Nickerson, D, Schoen, R, Hampe, J, Stadler, Z, Vodicka, P, Vodickova, L, Vymetalkova, V, Papadopoulos, N, Edlund, C, Gauderman, W, Thomas, D, Toland, A, Markowitz, S, Kim, A, Gruber, S, van Duijnhoven, F, Feskens, E, Sakoda, L, Gago-Dominguez, M, Wolk, A, Naccarati, A, Pardini, B, FitzGerald, L, Lee, SC, Ogino, S, Kooperberg, C, Li, C, Lin, Y, Prentice, R, Qu, C, Bezieau, S, Tangen, C, Mardis, E, Yamaji, T, Sawada, N, Iwasaki, M, Le Marchand, L, Wu, A, McNeil, C, Coetzee, G, Hayward, C, Deary, I, Theodoratou, E, Reid, S, Walker, M, Ooi, LY, Moreno, V, Casey, G, Tomlinson, I, Zheng, W, Dunlop, M, Houlston, R, and Peters, U

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. Crosstissue analyses indicated that over a third of effector genes most probably 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

50. Novel approaches for the discovery of pharmacogenetic biomarkers of chemotoxicity in patients with colorectal cancer

Author

Fernández Rozadilla, Ceres, Carracedo Álvarez, Ángel, Universidade de Santiago de Compostela. Escola de Doutoramento Internacional (EDIUS), Universidade de Santiago de Compostela. Programa de Doutoramento en Medicina Molecular, Simões, Ana Rita Santos, Fernández Rozadilla, Ceres, Carracedo Álvarez, Ángel, Universidade de Santiago de Compostela. Escola de Doutoramento Internacional (EDIUS), Universidade de Santiago de Compostela. Programa de Doutoramento en Medicina Molecular, and Simões, Ana Rita Santos

Abstract

Colorectal cancer (CRC) is often linked to adverse drug reactions (ADRs), which can be severe or even fatal. To address this issue, pharmacogenetic studies have emerged to help personalise treatments based on molecular information. However, these have been limited by a lack of standardized data, the complexity of ADR phenotyping and the need for novel strategies and functional assays. Therefore, the aim of this project was to find and validate new CRC chemotoxicity biomarkers, using state-of-the-art approaches. We have conducted different omic analyses to identify low to highpenetrance variants and performed in vitro assays on a variant of interest. Our work successfully identified several candidate toxicity variants/genes that might be influencing the development of ADRs in CRC patients.

Published
2023

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