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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. On the informative value of community‐based indoor radon values in relation to lung cancer

Author: Albert Rosenberger, Heike Bickeböller, David C. Christiani, Geoffrey Liu, Matthew B. Schabath, Luisa F. Duarte, Loic Le Marchand, Christopher Haiman, Teresa Landi, Dario Consonni, John K. Field, Michael P. A. Davies, Demetrios Albanes, Adonina Tardón, Guillermo Fernández‐Tardón, Gad Rennert, Christopher I. Amos, and Rayjean J. Hung
Subjects: histological subtypes, lung cancer, radiation, smoking, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract: Abstract Background Radon is a radioactive gas and a major risk factor for lung cancer (LC). Methods We investigated the dose–response relationship between radon and LC risk in the International Lung Cancer Consortium with 8927 cases and 5562 controls from Europe, North America, and Israel, conducted between 1992 and 2016. Spatial indoor radon exposure in the residential area (sIR) obtained from national surveys was linked to the participants' residential geolocation. Parametric linear and spline functions were fitted within a logistic regression framework. Results We observed a non‐linear spatial‐dose response relationship for sIR
Published: 2024
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3. Genome-wide interaction study of dietary intake of fibre, fruits, and vegetables with risk of colorectal cancerResearch in context

Author: Nikos Papadimitriou, Andre Kim, Eric S. Kawaguchi, John Morrison, Virginia Diez-Obrero, Demetrius Albanes, Sonja I. Berndt, Stéphane Bézieau, Stephanie A. Bien, D Timothy Bishop, Emmanouil Bouras, Hermann Brenner, Daniel D. Buchanan, Peter T. Campbell, Robert Carreras-Torres, Andrew T. Chan, Jenny Chang-Claude, David V. Conti, Matthew A. Devall, Niki Dimou, David A. Drew, Stephen B. Gruber, Tabitha A. Harrison, Michael Hoffmeister, Jeroen R. Huyghe, Amit D. Joshi, Temitope O. Keku, Anshul Kundaje, Sébastien Küry, Loic Le Marchand, Juan Pablo Lewinger, Li Li, Brigid M. Lynch, Victor Moreno, Christina C. Newton, Mireia Obón-Santacana, Jennifer Ose, Andrew J. Pellatt, Anita R. Peoples, Elizabeth A. Platz, Conghui Qu, Gad Rennert, Edward Ruiz-Narvaez, Anna Shcherbina, Mariana C. Stern, Yu-Ru Su, Duncan C. Thomas, Claire E. Thomas, Yu Tian, Konstantinos K. Tsilidis, Cornelia M. Ulrich, Caroline Y. Um, Kala Visvanathan, Jun Wang, Emily White, Michael O. Woods, Stephanie L. Schmit, Finlay Macrae, John D. Potter, John L. Hopper, Ulrike Peters, Neil Murphy, Li Hsu, Marc J. Gunter, and W. James Gauderman
Subjects: Diet, Fibre, Gene-environment interaction, Colorectal cancer, GWAS, Medicine, Medicine (General), R5-920
Abstract: Summary: Background: Consumption of fibre, fruits and vegetables have been linked with lower colorectal cancer (CRC) risk. A genome-wide gene-environment (G × E) analysis was performed to test whether genetic variants modify these associations. Methods: A pooled sample of 45 studies including up to 69,734 participants (cases: 29,896; controls: 39,838) of European ancestry were included. To identify G × E interactions, we used the traditional 1--degree-of-freedom (DF) G × E test and to improve power a 2-step procedure and a 3DF joint test that investigates the association between a genetic variant and dietary exposure, CRC risk and G × E interaction simultaneously. Findings: The 3-DF joint test revealed two significant loci with p-value
Published: 2024
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4. Impact of individual level uncertainty of lung cancer polygenic risk score (PRS) on risk stratification

Author: Xinan Wang, Ziwei Zhang, Yi Ding, Tony Chen, Lorelei Mucci, Demetrios Albanes, Maria Teresa Landi, Neil E. Caporaso, Stephen Lam, Adonina Tardon, Chu Chen, Stig E. Bojesen, Mattias Johansson, Angela Risch, Heike Bickeböller, H-Erich Wichmann, Gadi Rennert, Susanne Arnold, Paul Brennan, James D. McKay, John K. Field, Sanjay S. Shete, Loic Le Marchand, Geoffrey Liu, Angeline S. Andrew, Lambertus A. Kiemeney, Shan Zienolddiny-Narui, Annelie Behndig, Mikael Johansson, Angie Cox, Philip Lazarus, Matthew B. Schabath, Melinda C. Aldrich, Rayjean J. Hung, Christopher I. Amos, Xihong Lin, and David C. Christiani
Subjects: Non-small cell lung cancer (NSCLC), Polygenic risk score (PRSs), Cancer control, Population science, Genetic epidemiology, Medicine, Genetics, QH426-470
Abstract: Abstract Background Although polygenic risk score (PRS) has emerged as a promising tool for predicting cancer risk from genome-wide association studies (GWAS), the individual-level accuracy of lung cancer PRS and the extent to which its impact on subsequent clinical applications remains largely unexplored. Methods Lung cancer PRSs and confidence/credible interval (CI) were constructed using two statistical approaches for each individual: (1) the weighted sum of 16 GWAS-derived significant SNP loci and the CI through the bootstrapping method (PRS-16-CV) and (2) LDpred2 and the CI through posteriors sampling (PRS-Bayes), among 17,166 lung cancer cases and 12,894 controls with European ancestry from the International Lung Cancer Consortium. Individuals were classified into different genetic risk subgroups based on the relationship between their own PRS mean/PRS CI and the population level threshold. Results Considerable variances in PRS point estimates at the individual level were observed for both methods, with an average standard deviation (s.d.) of 0.12 for PRS-16-CV and a much larger s.d. of 0.88 for PRS-Bayes. Using PRS-16-CV, only 25.0% of individuals with PRS point estimates in the lowest decile of PRS and 16.8% in the highest decile have their entire 95% CI fully contained in the lowest and highest decile, respectively, while PRS-Bayes was unable to find any eligible individuals. Only 19% of the individuals were concordantly identified as having high genetic risk (> 90th percentile) using the two PRS estimators. An increased relative risk of lung cancer comparing the highest PRS percentile to the lowest was observed when taking the CI into account (OR = 2.73, 95% CI: 2.12–3.50, P-value = 4.13 × 10−15) compared to using PRS-16-CV mean (OR = 2.23, 95% CI: 1.99–2.49, P-value = 5.70 × 10−46). Improved risk prediction performance with higher AUC was consistently observed in individuals identified by PRS-16-CV CI, and the best performance was achieved by incorporating age, gender, and detailed smoking pack-years (AUC: 0.73, 95% CI = 0.72–0.74). Conclusions Lung cancer PRS estimates using different methods have modest correlations at the individual level, highlighting the importance of considering individual-level uncertainty when evaluating the practical utility of PRS.
Published: 2024
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5. Body size and risk of colorectal cancer molecular defined subtypes and pathways: Mendelian randomization analysesResearch in context

Author: Nikos Papadimitriou, Conghui Qu, Tabitha A. Harrison, Alaina M. Bever, Richard M. Martin, Konstantinos K. Tsilidis, Polly A. Newcomb, Stephen N. Thibodeau, Christina C. Newton, Caroline Y. Um, Mireia Obón-Santacana, Victor Moreno, Hermann Brenner, Marko Mandic, Jenny Chang-Claude, Michael Hoffmeister, Andrew J. Pellatt, Robert E. Schoen, Sophia Harlid, Shuji Ogino, Tomotaka Ugai, Daniel D. Buchanan, Brigid M. Lynch, Stephen B. Gruber, Yin Cao, Li Hsu, Jeroen R. Huyghe, Yi Lin, Robert S. Steinfelder, Wei Sun, Bethany Van Guelpen, Syed H. Zaidi, Amanda E. Toland, Sonja I. Berndt, Wen-Yi Huang, Elom K. Aglago, David A. Drew, Amy J. French, Peter Georgeson, Marios Giannakis, Meredith Hullar, Johnathan A. Nowak, Claire E. Thomas, Loic Le Marchand, Iona Cheng, Steven Gallinger, Mark A. Jenkins, Marc J. Gunter, Peter T. Campbell, Ulrike Peters, Mingyang Song, Amanda I. Phipps, and Neil Murphy
Subjects: Obesity, Colorectal cancer, Mendelian randomization, Molecular subtypes, Medicine, Medicine (General), R5-920
Abstract: Summary: Background: Obesity has been positively associated with most molecular subtypes of colorectal cancer (CRC); however, the magnitude and the causality of these associations is uncertain. Methods: We used Mendelian randomization (MR) to examine potential causal relationships between body size traits (body mass index [BMI], waist circumference, and body fat percentage) with risks of Jass classification types and individual subtypes of CRC (microsatellite instability [MSI] status, CpG island methylator phenotype [CIMP] status, BRAF and KRAS mutations). Summary data on tumour markers were obtained from two genetic consortia (CCFR, GECCO). Findings: A 1-standard deviation (SD:5.1 kg/m2) increment in BMI levels was found to increase risks of Jass type 1MSI-high,CIMP-high,BRAF-mutated,KRAS-wildtype (odds ratio [OR]: 2.14, 95% confidence interval [CI]: 1.46, 3.13; p-value = 9 × 10−5) and Jass type 2non-MSI-high,CIMP-high,BRAF-mutated,KRAS-wildtype CRC (OR: 2.20, 95% CI: 1.26, 3.86; p-value = 0.005). The magnitude of these associations was stronger compared with Jass type 4non-MSI-high,CIMP-low/negative,BRAF-wildtype,KRAS-wildtype CRC (p-differences: 0.03 and 0.04, respectively). A 1-SD (SD:13.4 cm) increment in waist circumference increased risk of Jass type 3non-MSI-high,CIMP-low/negative,BRAF-wildtype,KRAS-mutated (OR 1.73, 95% CI: 1.34, 2.25; p-value = 9 × 10−5) that was stronger compared with Jass type 4 CRC (p-difference: 0.03). A higher body fat percentage (SD:8.5%) increased risk of Jass type 1 CRC (OR: 2.59, 95% CI: 1.49, 4.48; p-value = 0.001), which was greater than Jass type 4 CRC (p-difference: 0.03). Interpretation: Body size was more strongly linked to the serrated (Jass types 1 and 2) and alternate (Jass type 3) pathways of colorectal carcinogenesis in comparison to the traditional pathway (Jass type 4). Funding: Cancer Research UK, National Institute for Health Research, Medical Research Council, National Institutes of Health, National Cancer Institute, American Institute for Cancer Research, Brigham and Women's Hospital, Prevent Cancer Foundation, Victorian Cancer Agency, Swedish Research Council, Swedish Cancer Society, Region Västerbotten, Knut and Alice Wallenberg Foundation, Lion’s Cancer Research Foundation, Insamlingsstiftelsen, Umeå University. Full funding details are provided in acknowledgements.
Published: 2024
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6. 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. Association of the CHEK2 c.1100delC variant, radiotherapy, and systemic treatment with contralateral breast cancer risk and breast cancer‐specific survival

Author: Anna Morra, Maartje A. C. Schreurs, Irene L. Andrulis, Hoda Anton‐Culver, Annelie Augustinsson, Matthias W. Beckmann, Sabine Behrens, Stig E. Bojesen, Manjeet K. Bolla, Hiltrud Brauch, Annegien Broeks, Saundra S. Buys, Nicola J. Camp, Jose E. Castelao, Melissa H. Cessna, Jenny Chang‐Claude, Wendy K. Chung, NBCS Collaborators, Sarah V. Colonna, Fergus J. Couch, Angela Cox, Simon S. Cross, Kamila Czene, Mary B. Daly, Joe Dennis, Peter Devilee, Thilo Dörk, Alison M. Dunning, Miriam Dwek, Douglas F. Easton, Diana M. Eccles, Mikael Eriksson, D. Gareth Evans, Peter A. Fasching, Tanja N. Fehm, Jonine D. Figueroa, Henrik Flyger, Marike Gabrielson, Manuela Gago‐Dominguez, Montserrat García‐Closas, José A. García‐Sáenz, Jeanine Genkinger, Felix Grassmann, Melanie Gündert, Eric Hahnen, Christopher A. Haiman, Ute Hamann, Patricia A. Harrington, Jaana M. Hartikainen, Reiner Hoppe, John L. Hopper, Richard S. Houlston, Anthony Howell, ABCTB Investigators, kConFab Investigators, Anna Jakubowska, Wolfgang Janni, Helena Jernström, Esther M. John, Nichola Johnson, Michael E. Jones, Vessela N. Kristensen, Allison W. Kurian, Diether Lambrechts, Loic Le Marchand, Annika Lindblom, Jan Lubiński, Michael P. Lux, Arto Mannermaa, Dimitrios Mavroudis, Anna Marie Mulligan, Taru A. Muranen, Heli Nevanlinna, Ines Nevelsteen, Patrick Neven, William G. Newman, Nadia Obi, Kenneth Offit, Andrew F. Olshan, Tjoung‐Won Park‐Simon, Alpa V. Patel, Paolo Peterlongo, Kelly‐Anne Phillips, Dijana Plaseska‐Karanfilska, Eric C. Polley, Nadege Presneau, Katri Pylkäs, Brigitte Rack, Paolo Radice, Muhammad U. Rashid, Valerie Rhenius, Mark Robson, Atocha Romero, Emmanouil Saloustros, Elinor J. Sawyer, Rita K. Schmutzler, Sabine Schuetze, Christopher Scott, Mitul Shah, Snezhana Smichkoska, Melissa C. Southey, William J. Tapper, Lauren R. Teras, Rob A. E. M. Tollenaar, Katarzyna Tomczyk, Ian Tomlinson, Melissa A. Troester, Celine M. Vachon, Elke M. vanVeen, Qin Wang, Camilla Wendt, Hans Wildiers, Robert Winqvist, Argyrios Ziogas, Per Hall, Paul D. P. Pharoah, Muriel A. Adank, Antoinette Hollestelle, Marjanka K. Schmidt, and Maartje J. Hooning
Subjects: CHEK2 c.1100delC germline genetic variant, contralateral breast cancer risk, radiotherapy, survival, systemic treatment, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract: Abstract Background Breast cancer (BC) patients with a germline CHEK2 c.1100delC variant have an increased risk of contralateral BC (CBC) and worse BC‐specific survival (BCSS) compared to non‐carriers. Aim To assessed the associations of CHEK2 c.1100delC, radiotherapy, and systemic treatment with CBC risk and BCSS. Methods Analyses were based on 82,701 women diagnosed with a first primary invasive BC including 963 CHEK2 c.1100delC carriers; median follow‐up was 9.1 years. Differential associations with treatment by CHEK2 c.1100delC status were tested by including interaction terms in a multivariable Cox regression model. A multi‐state model was used for further insight into the relation between CHEK2 c.1100delC status, treatment, CBC risk and death. Results There was no evidence for differential associations of therapy with CBC risk by CHEK2 c.1100delC status. The strongest association with reduced CBC risk was observed for the combination of chemotherapy and endocrine therapy [HR (95% CI): 0.66 (0.55–0.78)]. No association was observed with radiotherapy. Results from the multi‐state model showed shorter BCSS for CHEK2 c.1100delC carriers versus non‐carriers also after accounting for CBC occurrence [HR (95% CI): 1.30 (1.09–1.56)]. Conclusion Systemic therapy was associated with reduced CBC risk irrespective of CHEK2 c.1100delC status. Moreover, CHEK2 c.1100delC carriers had shorter BCSS, which appears not to be fully explained by their CBC risk.
Published: 2023
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8. A genome-wide gene-environment interaction study of breast cancer risk for women of European ancestry

Author: Pooja Middha, Xiaoliang Wang, Sabine Behrens, Manjeet K. Bolla, Qin Wang, Joe Dennis, Kyriaki Michailidou, Thomas U. Ahearn, Irene L. Andrulis, Hoda Anton-Culver, Volker Arndt, Kristan J. Aronson, Paul L. Auer, Annelie Augustinsson, Thaïs Baert, Laura E. Beane Freeman, Heiko Becher, Matthias W. Beckmann, Javier Benitez, Stig E. Bojesen, Hiltrud Brauch, Hermann Brenner, Angela Brooks-Wilson, Daniele Campa, Federico Canzian, Angel Carracedo, Jose E. Castelao, Stephen J. Chanock, Georgia Chenevix-Trench, CTS Consortium, Emilie Cordina-Duverger, Fergus J. Couch, Angela Cox, Simon S. Cross, Kamila Czene, Laure Dossus, Pierre-Antoine Dugué, A. Heather Eliassen, Mikael Eriksson, D. Gareth Evans, Peter A. Fasching, Jonine D. Figueroa, Olivia Fletcher, Henrik Flyger, Marike Gabrielson, Manuela Gago-Dominguez, Graham G. Giles, Anna González-Neira, Felix Grassmann, Anne Grundy, Pascal Guénel, Christopher A. Haiman, Niclas Håkansson, Per Hall, Ute Hamann, Susan E. Hankinson, Elaine F. Harkness, Bernd Holleczek, Reiner Hoppe, John L. Hopper, Richard S. Houlston, Anthony Howell, David J. Hunter, Christian Ingvar, ABCTB Investigators, kConFab Investigators, Karolin Isaksson, Helena Jernström, Esther M. John, Michael E. Jones, Rudolf Kaaks, Renske Keeman, Cari M. Kitahara, Yon-Dschun Ko, Stella Koutros, Allison W. Kurian, James V. Lacey, Diether Lambrechts, Nicole L. Larson, Susanna Larsson, Loic Le Marchand, Flavio Lejbkowicz, Shuai Li, Martha Linet, Jolanta Lissowska, Maria Elena Martinez, Tabea Maurer, Anna Marie Mulligan, Claire Mulot, Rachel A. Murphy, William G. Newman, Sune F. Nielsen, Børge G. Nordestgaard, Aaron Norman, Katie M. O’Brien, Janet E. Olson, Alpa V. Patel, Ross Prentice, Erika Rees-Punia, Gad Rennert, Valerie Rhenius, Kathryn J. Ruddy, Dale P. Sandler, Christopher G. Scott, Mitul Shah, Xiao-Ou Shu, Ann Smeets, Melissa C. Southey, Jennifer Stone, Rulla M. Tamimi, Jack A. Taylor, Lauren R. Teras, Katarzyna Tomczyk, Melissa A. Troester, Thérèse Truong, Celine M. Vachon, Sophia S. Wang, Clarice R. Weinberg, Hans Wildiers, Walter Willett, Stacey J. Winham, Alicja Wolk, Xiaohong R. Yang, M. Pilar Zamora, Wei Zheng, Argyrios Ziogas, Alison M. Dunning, Paul D. P. Pharoah, Montserrat García-Closas, Marjanka K. Schmidt, Peter Kraft, Roger L. Milne, Sara Lindström, Douglas F. Easton, and Jenny Chang-Claude
Subjects: Breast cancer, Gene-environment interactions, Genetic epidemiology, European ancestry, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract: Abstract Background Genome-wide studies of gene–environment interactions (G×E) may identify variants associated with disease risk in conjunction with lifestyle/environmental exposures. We conducted a genome-wide G×E analysis of ~ 7.6 million common variants and seven lifestyle/environmental risk factors for breast cancer risk overall and for estrogen receptor positive (ER +) breast cancer. Methods Analyses were conducted using 72,285 breast cancer cases and 80,354 controls of European ancestry from the Breast Cancer Association Consortium. Gene–environment interactions were evaluated using standard unconditional logistic regression models and likelihood ratio tests for breast cancer risk overall and for ER + breast cancer. Bayesian False Discovery Probability was employed to assess the noteworthiness of each SNP-risk factor pairs. Results Assuming a 1 × 10–5 prior probability of a true association for each SNP-risk factor pairs and a Bayesian False Discovery Probability
Published: 2023
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9. Association between circulating inflammatory markers and adult cancer risk: a Mendelian randomization analysisResearch in context

Author: James Yarmolinsky, Jamie W. Robinson, Daniela Mariosa, Ville Karhunen, Jian Huang, Niki Dimou, Neil Murphy, Kimberley Burrows, Emmanouil Bouras, Karl Smith-Byrne, Sarah J. Lewis, Tessel E. Galesloot, Lambertus A. Kiemeney, Sita Vermeulen, Paul Martin, Demetrius Albanes, Lifang Hou, Polly A. Newcomb, Emily White, Alicja Wolk, Anna H. Wu, Loïc Le Marchand, Amanda I. Phipps, Daniel D. Buchanan, Sizheng Steven Zhao, Dipender Gill, Stephen J. Chanock, Mark P. Purdue, George Davey Smith, Paul Brennan, Karl-Heinz Herzig, Marjo-Riitta Järvelin, Chris I. Amos, Rayjean J. Hung, Abbas Dehghan, Mattias Johansson, Marc J. Gunter, Kostas K. Tsilidis, Richard M. Martin, Maria Teresa Landi, Victoria Stevens, Ying Wang, Demetrios Albanes, Neil Caporaso, Christopher I. Amos, Sanjay Shete, Heike Bickeböller, Angela Risch, Richard Houlston, Stephen Lam, Adonina Tardon, Chu Chen, Stig E. Bojesen, H-Erich Wichmann, David Christiani, Gadi Rennert, Susanne Arnold, John K. Field, Loic Le Marchand, Olle Melander, Hans Brunnström, Geoffrey Liu, Angeline Andrew, Hongbing Shen, Shan Zienolddiny, Kjell Grankvist, Mikael Johansson, M. Dawn Teare, Yun-Chul Hong, Jian-Min Yuan, Philip Lazarus, Matthew B. Schabath, Melinda C. Aldrich, Rosalind A. Eeles, Christopher A. Haiman, Zsofia Kote-Jarai, Fredrick R. Schumacher, Sara Benlloch, Ali Amin Al Olama, Kenneth R. Muir, Sonja I. Berndt, David V. Conti, Fredrik Wiklund, Stephen Chanock, Catherine M. Tangen, Jyotsna Batra, Judith A. Clements, Henrik Grönberg, Nora Pashayan, Johanna Schleutker, Stephanie J. Weinstein, Catharine M.L. West, Lorelei A. Mucci, Géraldine Cancel-Tassin, Stella Koutros, Karina Dalsgaard Sørensen, Eli Marie Grindedal, David E. Neal, Freddie C. Hamdy, Jenny L. Donovan, Ruth C. Travis, Robert J. Hamilton, Sue Ann Ingles, Barry S. Rosenstein, Yong-Jie Lu, Graham G. Giles, Robert J. MacInnis, Adam S. Kibel, Ana Vega, Manolis Kogevinas, Kathryn L. Penney, Jong Y. Park, Janet L. Stanfrod, Cezary Cybulski, Børge G. Nordestgaard, Sune F. Nielsen, Hermann Brenner, Christiane Maier, Christopher J. Logothetis, Esther M. John, Manuel R. Teixeira, Susan L. Neuhausen, Kim De Ruyck, Azad Razack, Lisa F. Newcomb, Davor Lessel, Radka Kaneva, Nawaid Usmani, Frank Claessens, Paul A. Townsend, Jose Esteban Castelao, Monique J. Roobol, Florence Menegaux, Kay-Tee Khaw, Lisa Cannon-Albright, Hardev Pandha, Stephen N. Thibodeau, David J. Hunter, Peter Kraft, William J. Blot, and Elio Riboli
Subjects: Inflammation, Cancer, Mendelian randomization, Genetic epidemiology, Medicine, Medicine (General), R5-920
Abstract: Summary: Background: Tumour-promoting inflammation is a “hallmark” of cancer and conventional epidemiological studies have reported links between various inflammatory markers and cancer risk. The causal nature of these relationships and, thus, the suitability of these markers as intervention targets for cancer prevention is unclear. Methods: We meta-analysed 6 genome-wide association studies of circulating inflammatory markers comprising 59,969 participants of European ancestry. We then used combined cis-Mendelian randomization and colocalisation analysis to evaluate the causal role of 66 circulating inflammatory markers in risk of 30 adult cancers in 338,294 cancer cases and up to 1,238,345 controls. Genetic instruments for inflammatory markers were constructed using genome-wide significant (P 70% was employed to indicate support for shared causal variants across inflammatory markers and cancer outcomes. Findings were replicated in the FinnGen study and then pooled using meta-analysis. Findings: We found strong evidence to support an association of genetically-proxied circulating pro-adrenomedullin concentrations with increased breast cancer risk (OR: 1.19, 95% CI: 1.10–1.29, q-value = 0.033, PPH4 = 84.3%) and suggestive evidence to support associations of interleukin-23 receptor concentrations with increased pancreatic cancer risk (OR: 1.42, 95% CI: 1.20–1.69, q-value = 0.055, PPH4 = 73.9%), prothrombin concentrations with decreased basal cell carcinoma risk (OR: 0.66, 95% CI: 0.53–0.81, q-value = 0.067, PPH4 = 81.8%), and interleukin-1 receptor-like 1 concentrations with decreased triple-negative breast cancer risk (OR: 0.92, 95% CI: 0.88–0.97, q-value = 0.15, PPH4 = 85.6%). These findings were replicated in pooled analyses with the FinnGen study. Though suggestive evidence was found to support an association of macrophage migration inhibitory factor concentrations with increased bladder cancer risk (OR: 2.46, 95% CI: 1.48–4.10, q-value = 0.072, PPH4 = 76.1%), this finding was not replicated when pooled with the FinnGen study. For 22 of 30 cancer outcomes examined, there was little evidence (q-value ≥0.20) that any of the 66 circulating inflammatory markers examined were associated with cancer risk. Interpretation: Our comprehensive joint Mendelian randomization and colocalisation analysis of the role of circulating inflammatory markers in cancer risk identified potential roles for 4 circulating inflammatory markers in risk of 4 site-specific cancers. Contrary to reports from some prior conventional epidemiological studies, we found little evidence of association of circulating inflammatory markers with the majority of site-specific cancers evaluated. Funding: Cancer Research UK (C68933/A28534, C18281/A29019, PPRCPJT∖100005), World Cancer Research Fund (IIG_FULL_2020_022), National Institute for Health Research (NIHR202411, BRC-1215-20011), Medical Research Council (MC_UU_00011/1, MC_UU_00011/3, MC_UU_00011/6, and MC_UU_00011/4), Academy of Finland Project 326291, European Union's Horizon 2020 grant agreement no. 848158 (EarlyCause), French National Cancer Institute (INCa SHSESP20, 2020-076), Versus Arthritis (21173, 21754, 21755), National Institutes of Health (U19 CA203654), National Cancer Institute (U19CA203654).
Published: 2024
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10. Impact of weight loss on cancer-related proteins in serum: results from a cluster randomised controlled trial of individuals with type 2 diabetesResearch in context

Author: Caroline J. Bull, Emma Hazelwood, Danny N. Legge, Laura J. Corbin, Tom G. Richardson, Matthew Lee, James Yarmolinsky, Karl Smith-Byrne, David A. Hughes, Mattias Johansson, Ulrike Peters, Sonja I. Berndt, Hermann Brenner, Andrea Burnett-Hartman, Iona Cheng, Sun-Seog Kweon, Loic Le Marchand, Li Li, Polly A. Newcomb, Rachel Pearlman, Alex McConnachie, Paul Welsh, Roy Taylor, Mike E.J. Lean, Naveed Sattar, Neil Murphy, Marc J. Gunter, Nicholas J. Timpson, and Emma E. Vincent
Subjects: Weight loss, DiRECT, Diabetes, Obesity, Cancer, Mendelian randomization, Medicine, Medicine (General), R5-920
Abstract: Summary: Background: Type 2 diabetes is associated with higher risk of several cancer types. However, the biological intermediates driving this relationship are not fully understood. As novel interventions for treating and managing type 2 diabetes become increasingly available, whether they also disrupt the pathways leading to increased cancer risk is currently unknown. We investigated the effect of a type 2 diabetes intervention, in the form of intentional weight loss, on circulating proteins associated with cancer risk to gain insight into potential mechanisms linking type 2 diabetes and adiposity with cancer development. Methods: Fasting serum samples from participants with diabetes enrolled in the Diabetes Remission Clinical Trial (DiRECT) receiving the Counterweight-Plus weight-loss programme (intervention, N = 117, mean weight-loss 10 kg, 46% diabetes remission) or best-practice care by guidelines (control, N = 143, mean weight-loss 1 kg, 4% diabetes remission) were subject to proteomic analysis using the Olink Oncology-II platform (48% of participants were female; 52% male). To identify proteins which may be altered by the weight-loss intervention, the difference in protein levels between groups at baseline and 1 year was examined using linear regression. Mendelian randomization (MR) was performed to extend these results to evaluate cancer risk and elucidate possible biological mechanisms linking type 2 diabetes and cancer development. MR analyses were conducted using independent datasets, including large cancer meta-analyses, UK Biobank, and FinnGen, to estimate potential causal relationships between proteins modified during intentional weight loss and the risk of colorectal, breast, endometrial, gallbladder, liver, and pancreatic cancers. Findings: Nine proteins were modified by the intervention: glycoprotein Nmb; furin; Wnt inhibitory factor 1; toll-like receptor 3; pancreatic prohormone; erb-b2 receptor tyrosine kinase 2; hepatocyte growth factor; endothelial cell specific molecule 1 and Ret proto-oncogene (Holm corrected P-value
Published: 2024
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11. Identifying metabolic features of colorectal cancer liability using Mendelian randomization

Author: Caroline Bull, Emma Hazelwood, Joshua A Bell, Vanessa Tan, Andrei-Emil Constantinescu, Carolina Borges, Danny Legge, Kimberley Burrows, Jeroen R Huyghe, Hermann Brenner, Sergi Castellvi-Bel, Andrew T Chan, Sun-Seog Kweon, Loic Le Marchand, Li Li, Iona Cheng, Rish K Pai, Jane C Figueiredo, Neil Murphy, Marc J Gunter, Nicholas J Timpson, and Emma E Vincent
Subjects: Mendelian randomization, obesity, colorectal cancer, metabolomics, Medicine, Science, Biology (General), QH301-705.5
Abstract: Background: Recognizing the early signs of cancer risk is vital for informing prevention, early detection, and survival. Methods: To investigate whether changes in circulating metabolites characterize the early stages of colorectal cancer (CRC) development, we examined the associations between a genetic risk score (GRS) associated with CRC liability (72 single-nucleotide polymorphisms) and 231 circulating metabolites measured by nuclear magnetic resonance spectroscopy in the Avon Longitudinal Study of Parents and Children (N = 6221). Linear regression models were applied to examine the associations between genetic liability to CRC and circulating metabolites measured in the same individuals at age 8 y, 16 y, 18 y, and 25 y. Results: The GRS for CRC was associated with up to 28% of the circulating metabolites at FDR-P < 0.05 across all time points, particularly with higher fatty acids and very-low- and low-density lipoprotein subclass lipids. Two-sample reverse Mendelian randomization (MR) analyses investigating CRC liability (52,775 cases, 45,940 controls) and metabolites measured in a random subset of UK Biobank participants (N = 118,466, median age 58 y) revealed broadly consistent effect estimates with the GRS analysis. In conventional (forward) MR analyses, genetically predicted polyunsaturated fatty acid concentrations were most strongly associated with higher CRC risk. Conclusions: These analyses suggest that higher genetic liability to CRC can cause early alterations in systemic metabolism and suggest that fatty acids may play an important role in CRC development. Funding: This work was supported by the Elizabeth Blackwell Institute for Health Research, University of Bristol, the Wellcome Trust, the Medical Research Council, Diabetes UK, the University of Bristol NIHR Biomedical Research Centre, and Cancer Research UK. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. This work used the computational facilities of the Advanced Computing Research Centre, University of Bristol - http://www.bristol.ac.uk/acrc/.
Published: 2023
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12. Genome-wide association study of lung adenocarcinoma in East Asia and comparison with a European population

Author: Jianxin Shi, Kouya Shiraishi, Jiyeon Choi, Keitaro Matsuo, Tzu-Yu Chen, Juncheng Dai, Rayjean J. Hung, Kexin Chen, Xiao-Ou Shu, Young Tae Kim, Maria Teresa Landi, Dongxin Lin, Wei Zheng, Zhihua Yin, Baosen Zhou, Bao Song, Jiucun Wang, Wei Jie Seow, Lei Song, I-Shou Chang, Wei Hu, Li-Hsin Chien, Qiuyin Cai, Yun-Chul Hong, Hee Nam Kim, Yi-Long Wu, Maria Pik Wong, Brian Douglas Richardson, Karen M. Funderburk, Shilan Li, Tongwu Zhang, Charles Breeze, Zhaoming Wang, Batel Blechter, Bryan A. Bassig, Jin Hee Kim, Demetrius Albanes, Jason Y. Y. Wong, Min-Ho Shin, Lap Ping Chung, Yang Yang, She-Juan An, Hong Zheng, Yasushi Yatabe, Xu-Chao Zhang, Young-Chul Kim, Neil E. Caporaso, Jiang Chang, James Chung Man Ho, Michiaki Kubo, Yataro Daigo, Minsun Song, Yukihide Momozawa, Yoichiro Kamatani, Masashi Kobayashi, Kenichi Okubo, Takayuki Honda, Dean H. Hosgood, Hideo Kunitoh, Harsh Patel, Shun-ichi Watanabe, Yohei Miyagi, Haruhiko Nakayama, Shingo Matsumoto, Hidehito Horinouchi, Masahiro Tsuboi, Ryuji Hamamoto, Koichi Goto, Yuichiro Ohe, Atsushi Takahashi, Akiteru Goto, Yoshihiro Minamiya, Megumi Hara, Yuichiro Nishida, Kenji Takeuchi, Kenji Wakai, Koichi Matsuda, Yoshinori Murakami, Kimihiro Shimizu, Hiroyuki Suzuki, Motonobu Saito, Yoichi Ohtaki, Kazumi Tanaka, Tangchun Wu, Fusheng Wei, Hongji Dai, Mitchell J. Machiela, Jian Su, Yeul Hong Kim, In-Jae Oh, Victor Ho Fun Lee, Gee-Chen Chang, Ying-Huang Tsai, Kuan-Yu Chen, Ming-Shyan Huang, Wu-Chou Su, Yuh-Min Chen, Adeline Seow, Jae Yong Park, Sun-Seog Kweon, Kun-Chieh Chen, Yu-Tang Gao, Biyun Qian, Chen Wu, Daru Lu, Jianjun Liu, Ann G. Schwartz, Richard Houlston, Margaret R. Spitz, Ivan P. Gorlov, Xifeng Wu, Ping Yang, Stephen Lam, Adonina Tardon, Chu Chen, Stig E. Bojesen, Mattias Johansson, Angela Risch, Heike Bickeböller, Bu-Tian Ji, H-Erich Wichmann, David C. Christiani, Gadi Rennert, Susanne Arnold, Paul Brennan, James McKay, John K. Field, Sanjay S. Shete, Loic Le Marchand, Geoffrey Liu, Angeline Andrew, Lambertus A. Kiemeney, Shan Zienolddiny-Narui, Kjell Grankvist, Mikael Johansson, Angela Cox, Fiona Taylor, Jian-Min Yuan, Philip Lazarus, Matthew B. Schabath, Melinda C. Aldrich, Hyo-Sung Jeon, Shih Sheng Jiang, Jae Sook Sung, Chung-Hsing Chen, Chin-Fu Hsiao, Yoo Jin Jung, Huan Guo, Zhibin Hu, Laurie Burdett, Meredith Yeager, Amy Hutchinson, Belynda Hicks, Jia Liu, Bin Zhu, Sonja I. Berndt, Wei Wu, Junwen Wang, Yuqing Li, Jin Eun Choi, Kyong Hwa Park, Sook Whan Sung, Li Liu, Chang Hyun Kang, Wen-Chang Wang, Jun Xu, Peng Guan, Wen Tan, Chong-Jen Yu, Gong Yang, Alan Dart Loon Sihoe, Ying Chen, Yi Young Choi, Jun Suk Kim, Ho-Il Yoon, In Kyu Park, Ping Xu, Qincheng He, Chih-Liang Wang, Hsiao-Han Hung, Roel C. H. Vermeulen, Iona Cheng, Junjie Wu, Wei-Yen Lim, Fang-Yu Tsai, John K. C. Chan, Jihua Li, Hongyan Chen, Hsien-Chih Lin, Li Jin, Jie Liu, Norie Sawada, Taiki Yamaji, Kathleen Wyatt, Shengchao A. Li, Hongxia Ma, Meng Zhu, Zhehai Wang, Sensen Cheng, Xuelian Li, Yangwu Ren, Ann Chao, Motoki Iwasaki, Junjie Zhu, Gening Jiang, Ke Fei, Guoping Wu, Chih-Yi Chen, Chien-Jen Chen, Pan-Chyr Yang, Jinming Yu, Victoria L. Stevens, Joseph F. Fraumeni, Nilanjan Chatterjee, Olga Y. Gorlova, Chao Agnes Hsiung, Christopher I. Amos, Hongbing Shen, Stephen J. Chanock, Nathaniel Rothman, Takashi Kohno, and Qing Lan
Subjects: Science
Abstract: Abstract Lung adenocarcinoma is the most common type of lung cancer. Known risk variants explain only a small fraction of lung adenocarcinoma heritability. Here, we conducted a two-stage genome-wide association study of lung adenocarcinoma of East Asian ancestry (21,658 cases and 150,676 controls; 54.5% never-smokers) and identified 12 novel susceptibility variants, bringing the total number to 28 at 25 independent loci. Transcriptome-wide association analyses together with colocalization studies using a Taiwanese lung expression quantitative trait loci dataset (n = 115) identified novel candidate genes, including FADS1 at 11q12 and ELF5 at 11p13. In a multi-ancestry meta-analysis of East Asian and European studies, four loci were identified at 2p11, 4q32, 16q23, and 18q12. At the same time, most of our findings in East Asian populations showed no evidence of association in European populations. In our studies drawn from East Asian populations, a polygenic risk score based on the 25 loci had a stronger association in never-smokers vs. individuals with a history of smoking (Pinteraction = 0.0058). These findings provide new insights into the etiology of lung adenocarcinoma in individuals from East Asian populations, which could be important in developing translational applications.
Published: 2023
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13. Aggregation tests identify new gene associations with breast cancer in populations with diverse ancestry

Author: Stefanie H. Mueller, Alvina G. Lai, Maria Valkovskaya, Kyriaki Michailidou, Manjeet K. Bolla, Qin Wang, Joe Dennis, Michael Lush, Zomoruda Abu-Ful, Thomas U. Ahearn, Irene L. Andrulis, Hoda Anton-Culver, Natalia N. Antonenkova, Volker Arndt, Kristan J. Aronson, Annelie Augustinsson, Thais Baert, Laura E. Beane Freeman, Matthias W. Beckmann, Sabine Behrens, Javier Benitez, Marina Bermisheva, Carl Blomqvist, Natalia V. Bogdanova, Stig E. Bojesen, Bernardo Bonanni, Hermann Brenner, Sara Y. Brucker, Saundra S. Buys, Jose E. Castelao, Tsun L. Chan, Jenny Chang-Claude, Stephen J. Chanock, Ji-Yeob Choi, Wendy K. Chung, NBCS Collaborators, Sarah V. Colonna, CTS Consortium, Sten Cornelissen, Fergus J. Couch, Kamila Czene, Mary B. Daly, Peter Devilee, Thilo Dörk, Laure Dossus, Miriam Dwek, Diana M. Eccles, Arif B. Ekici, A. Heather Eliassen, Christoph Engel, D. Gareth Evans, Peter A. Fasching, Olivia Fletcher, Henrik Flyger, Manuela Gago-Dominguez, Yu-Tang Gao, Montserrat García-Closas, José A. García-Sáenz, Jeanine Genkinger, Aleksandra Gentry-Maharaj, Felix Grassmann, Pascal Guénel, Melanie Gündert, Lothar Haeberle, Eric Hahnen, Christopher A. Haiman, Niclas Håkansson, Per Hall, Elaine F. Harkness, Patricia A. Harrington, Jaana M. Hartikainen, Mikael Hartman, Alexander Hein, Weang-Kee Ho, Maartje J. Hooning, Reiner Hoppe, John L. Hopper, Richard S. Houlston, Anthony Howell, David J. Hunter, Dezheng Huo, ABCTB Investigators, Hidemi Ito, Motoki Iwasaki, Anna Jakubowska, Wolfgang Janni, Esther M. John, Michael E. Jones, Audrey Jung, Rudolf Kaaks, Daehee Kang, Elza K. Khusnutdinova, Sung-Won Kim, Cari M. Kitahara, Stella Koutros, Peter Kraft, Vessela N. Kristensen, Katerina Kubelka-Sabit, Allison W. Kurian, Ava Kwong, James V. Lacey, Diether Lambrechts, Loic Le Marchand, Jingmei Li, Martha Linet, Wing-Yee Lo, Jirong Long, Artitaya Lophatananon, Arto Mannermaa, Mehdi Manoochehri, Sara Margolin, Keitaro Matsuo, Dimitrios Mavroudis, Usha Menon, Kenneth Muir, Rachel A. Murphy, Heli Nevanlinna, William G. Newman, Dieter Niederacher, Katie M. O’Brien, Nadia Obi, Kenneth Offit, Olufunmilayo I. Olopade, Andrew F. Olshan, Håkan Olsson, Sue K. Park, Alpa V. Patel, Achal Patel, Charles M. Perou, Julian Peto, Paul D. P. Pharoah, Dijana Plaseska-Karanfilska, Nadege Presneau, Brigitte Rack, Paolo Radice, Dhanya Ramachandran, Muhammad U. Rashid, Gad Rennert, Atocha Romero, Kathryn J. Ruddy, Matthias Ruebner, Emmanouil Saloustros, Dale P. Sandler, Elinor J. Sawyer, Marjanka K. Schmidt, Rita K. Schmutzler, Michael O. Schneider, Christopher Scott, Mitul Shah, Priyanka Sharma, Chen-Yang Shen, Xiao-Ou Shu, Jacques Simard, Harald Surowy, Rulla M. Tamimi, William J. Tapper, Jack A. Taylor, Soo Hwang Teo, Lauren R. Teras, Amanda E. Toland, Rob A. E. M. Tollenaar, Diana Torres, Gabriela Torres-Mejía, Melissa A. Troester, Thérèse Truong, Celine M. Vachon, Joseph Vijai, Clarice R. Weinberg, Camilla Wendt, Robert Winqvist, Alicja Wolk, Anna H. Wu, Taiki Yamaji, Xiaohong R. Yang, Jyh-Cherng Yu, Wei Zheng, Argyrios Ziogas, Elad Ziv, Alison M. Dunning, Douglas F. Easton, Harry Hemingway, Ute Hamann, and Karoline B. Kuchenbaecker
Subjects: Breast cancer susceptibility, Diverse ancestry, Rare variants, Gene regulation, Genome-wide association study, Medicine, Genetics, QH426-470
Abstract: Abstract Background Low-frequency variants play an important role in breast cancer (BC) susceptibility. Gene-based methods can increase power by combining multiple variants in the same gene and help identify target genes. Methods We evaluated the potential of gene-based aggregation in the Breast Cancer Association Consortium cohorts including 83,471 cases and 59,199 controls. Low-frequency variants were aggregated for individual genes’ coding and regulatory regions. Association results in European ancestry samples were compared to single-marker association results in the same cohort. Gene-based associations were also combined in meta-analysis across individuals with European, Asian, African, and Latin American and Hispanic ancestry. Results In European ancestry samples, 14 genes were significantly associated (q
Published: 2023
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14. Separating the effects of early and later life adiposity on colorectal cancer risk: a Mendelian randomization study

Author: Nikos Papadimitriou, Caroline J. Bull, Mazda Jenab, David J. Hughes, Joshua A. Bell, Eleanor Sanderson, Nicholas J. Timpson, George Davey Smith, Demetrius Albanes, Peter T. Campbell, Sébastien Küry, Loic Le Marchand, Cornelia M. Ulrich, Kala Visvanathan, Jane C. Figueiredo, Polly A. Newcomb, Rish K. Pai, Ulrike Peters, Kostas K. Tsilidis, Jolanda M. A. Boer, Emma E. Vincent, Daniela Mariosa, Marc J. Gunter, Tom G. Richardson, and Neil Murphy
Subjects: Obesity, Colorectal cancer, Mendelian randomization, Adult, Early life, Medicine
Abstract: Abstract Background Observational studies have linked childhood obesity with elevated risk of colorectal cancer; however, it is unclear if this association is causal or independent from the effects of obesity in adulthood on colorectal cancer risk. Methods We conducted Mendelian randomization (MR) analyses to investigate potential causal relationships between self-perceived body size (thinner, plumper, or about average) in early life (age 10) and measured body mass index in adulthood (mean age 56.5) with risk of colorectal cancer. The total and independent effects of body size exposures were estimated using univariable and multivariable MR, respectively. Summary data were obtained from a genome-wide association study of 453,169 participants in UK Biobank for body size and from a genome-wide association study meta-analysis of three colorectal cancer consortia of 125,478 participants. Results Genetically predicted early life body size was estimated to increase odds of colorectal cancer (odds ratio [OR] per category change: 1.12, 95% confidence interval [CI]: 0.98–1.27), with stronger results for colon cancer (OR: 1.16, 95% CI: 1.00–1.35), and distal colon cancer (OR: 1.25, 95% CI: 1.04–1.51). After accounting for adult body size using multivariable MR, effect estimates for early life body size were attenuated towards the null for colorectal cancer (OR: 0.97, 95% CI: 0.77–1.22) and colon cancer (OR: 0.97, 95% CI: 0.76–1.25), while the estimate for distal colon cancer was of similar magnitude but more imprecise (OR: 1.27, 95% CI: 0.90–1.77). Genetically predicted adult life body size was estimated to increase odds of colorectal (OR: 1.27, 95% CI: 1.03, 1.57), colon (OR: 1.32, 95% CI: 1.05, 1.67), and proximal colon (OR: 1.57, 95% CI: 1.21, 2.05). Conclusions Our findings suggest that the positive association between early life body size and colorectal cancer risk is likely due to large body size retainment into adulthood.
Published: 2023
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15. Interactions between folate intake and genetic predictors of gene expression levels associated with colorectal cancer risk

Author: Cameron B. Haas, Yu-Ru Su, Paneen Petersen, Xiaoliang Wang, Stephanie A. Bien, Yi Lin, Demetrius Albanes, Stephanie J. Weinstein, Mark A. Jenkins, Jane C. Figueiredo, Polly A. Newcomb, Graham Casey, Loic Le Marchand, Peter T. Campbell, Victor Moreno, John D. Potter, Lori C. Sakoda, Martha L. Slattery, Andrew T. Chan, Li Li, Graham G. Giles, Roger L. Milne, Stephen B. Gruber, Gad Rennert, Michael O. Woods, Steven J. Gallinger, Sonja Berndt, Richard B. Hayes, Wen-Yi Huang, Alicja Wolk, Emily White, Hongmei Nan, Rami Nassir, Noralane M. Lindor, Juan P. Lewinger, Andre E. Kim, David Conti, W. James Gauderman, Daniel D. Buchanan, Ulrike Peters, and Li Hsu
Subjects: Medicine, Science
Abstract: Abstract Observational studies have shown higher folate consumption to be associated with lower risk of colorectal cancer (CRC). Understanding whether and how genetic risk factors interact with folate could further elucidate the underlying mechanism. Aggregating functionally relevant genetic variants in set-based variant testing has higher power to detect gene–environment (G × E) interactions and may provide information on the underlying biological pathway. We investigated interactions between folate consumption and predicted gene expression on colorectal cancer risk across the genome. We used variant weights from the PrediXcan models of colon tissue-specific gene expression as a priori variant information for a set-based G × E approach. We harmonized total folate intake (mcg/day) based on dietary intake and supplemental use across cohort and case–control studies and calculated sex and study specific quantiles. Analyses were performed using a mixed effects score tests for interactions between folate and genetically predicted expression of 4839 genes with available genetically predicted expression. We pooled results across 23 studies for a total of 13,498 cases with colorectal tumors and 13,918 controls of European ancestry. We used a false discovery rate of 0.2 to identify genes with suggestive evidence of an interaction. We found suggestive evidence of interaction with folate intake on CRC risk for genes including glutathione S-Transferase Alpha 1 (GSTA1; p = 4.3E−4), Tonsuko Like, DNA Repair Protein (TONSL; p = 4.3E−4), and Aspartylglucosaminidase (AGA: p = 4.5E−4). We identified three genes involved in preventing or repairing DNA damage that may interact with folate consumption to alter CRC risk. Glutathione is an antioxidant, preventing cellular damage and is a downstream metabolite of homocysteine and metabolized by GSTA1. TONSL is part of a complex that functions in the recovery of double strand breaks and AGA plays a role in lysosomal breakdown of glycoprotein.
Published: 2022
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16. The impact of COVID-19 on cancer screening and treatment in older adults: The Multiethnic Cohort Study

Author: Victoria P Mak, Kami White, Lynne R Wilkens, Iona Cheng, Christopher A Haiman, and Loic Le Marchand
Subjects: COVID-19, health-related behaviors, cancer screening, lifestyle factors, multiethnic cohort, Medicine, Science, Biology (General), QH301-705.5
Abstract: Background: The Coronavirus Disease of 2019 (COVID-19) has impacted the health and day-to-day life of individuals, especially the elderly and people with certain pre-existing medical conditions, including cancer. The purpose of this study was to investigate how COVID-19 impacted access to cancer screenings and treatment, by studying the participants in the Multiethnic Cohort (MEC) study. Methods: The MEC has been following over 215,000 residents of Hawai‘i and Los Angeles for the development of cancer and other chronic diseases since 1993–1996. It includes men and women of five racial and ethnic groups: African American, Japanese American, Latino, Native Hawaiian, and White. In 2020, surviving participants were sent an invitation to complete an online survey on the impact of COVID-19 on their daily life activities, including adherence to cancer screening and treatment. Approximately 7,000 MEC participants responded. A cross-sectional analysis was performed to investigate the relationships between the postponement of regular health care visits and cancer screening procedures or treatment with race and ethnicity, age, education, and comorbidity. Results: Women with more education, women with lung disease, COPD, or asthma, and women and men diagnosed with cancer in the past 5 years were more likely to postpone any cancer screening test/procedure due to the COVID-19 pandemic. Groups less likely to postpone cancer screening included older women compared to younger women and Japanese American men and women compared to White men and women. Conclusions: This study revealed specific associations of race/ethnicity, age, education level, and comorbidities with the cancer-related screening and healthcare of MEC participants during the COVID-19 pandemic. Increased monitoring of patients in high-risk groups for cancer and other diseases is of the utmost importance as the chance of undiagnosed cases or poor prognosis is increased as a result of delayed screening and treatment. Funding: This research was partially supported by the Omidyar 'Ohana Foundation and grant U01 CA164973 from the National Cancer Institute.
Published: 2023
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17. The association between genetically elevated polyunsaturated fatty acids and risk of cancerResearch in context

Author: Philip C. Haycock, Maria Carolina Borges, Kimberley Burrows, Rozenn N. Lemaitre, Stephen Burgess, Nikhil K. Khankari, Konstantinos K. Tsilidis, Tom R. Gaunt, Gibran Hemani, Jie Zheng, Therese Truong, Brenda M. Birmann, Tracy OMara, Amanda B. Spurdle, Mark M. Iles, Matthew H. Law, Susan L. Slager, Fatemeh Saberi Hosnijeh, Daniela Mariosa, Michelle Cotterchio, James R. Cerhan, Ulrike Peters, Stefan Enroth, Puya Gharahkhani, Loic Le Marchand, Ann C. Williams, Robert C. Block, Christopher I. Amos, Rayjean J. Hung, Wei Zheng, Marc J. Gunter, George Davey Smith, Caroline Relton, Richard M. Martin, Nathan Tintle, Terri Rice, Iona Cheng, Mark Jenkins, Steve Gallinger, Alex J. Cornish, Amit Sud, Jayaram Vijayakrishnan, Margaret Wrensch, Mattias Johansson, Aaron D. Norman, Alison Klein, Alyssa Clay-Gilmour, Andre Franke, Andres V. Ardisson Korat, Bill Wheeler, Björn Nilsson, Caren Smith, Chew-Kiat Heng, Ci Song, David Riadi, Elizabeth B. Claus, Eva Ellinghaus, Evgenia Ostroumova, Hosnijeh, Florent de Vathaire, Giovanni Cugliari, Giuseppe Matullo, Irene Oi-Lin Ng, Jeanette E. Passow, Jia Nee Foo, Jiali Han, Jianjun Liu, Jill Barnholtz-Sloan, Joellen M. Schildkraut, John Maris, Joseph L. Wiemels, Kari Hemminki, Keming Yang, Lambertus A. Kiemeney, Lang Wu, Laufey Amundadottir, Marc-Henri Stern, Marie-Christine Boutron, Mark Martin Iles, Mark P. Purdue, Martin Stanulla, Melissa Bondy, Mia Gaudet, Lenha Mobuchon, Nicola J. Camp, Pak Chung Sham, Pascal Guénel, Paul Brennan, Philip R. Taylor, Quinn Ostrom, Rachael Stolzenberg-Solomon, Rajkumar Dorajoo, Richard Houlston, Robert B. Jenkins, Sharon Diskin, Sonja I. Berndt, Spiridon Tsavachidis, Stephen J. Channock, Tabitha Harrison, Tessel Galesloot, Ulf Gyllensten, Vijai Joseph, Y. Shi, Wenjian Yang, Yi Lin, and Stephen K. Van Den Eeden
Subjects: Mendelian randomization, Cancer risk, Polyunsaturated fatty acids, Omega 3, Omega 6, Delta-5 desaturase, Medicine, Medicine (General), R5-920
Abstract: Summary: Background: The causal relevance of polyunsaturated fatty acids (PUFAs) for risk of site-specific cancers remains uncertain. Methods: Using a Mendelian randomization (MR) framework, we assessed the causal relevance of PUFAs for risk of cancer in European and East Asian ancestry individuals. We defined the primary exposure as PUFA desaturase activity, proxied by rs174546 at the FADS locus. Secondary exposures were defined as omega 3 and omega 6 PUFAs that could be proxied by genetic polymorphisms outside the FADS region. Our study used summary genetic data on 10 PUFAs and 67 cancers, corresponding to 562,871 cases and 1,619,465 controls, collected by the Fatty Acids in Cancer Mendelian Randomization Collaboration. We estimated odds ratios (ORs) for cancer per standard deviation increase in genetically proxied PUFA exposures. Findings: Genetically elevated PUFA desaturase activity was associated (P
Published: 2023
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18. Genome-wide interaction analysis of menopausal hormone therapy use and breast cancer risk among 62,370 women

Author: Xiaoliang Wang, Pooja Middha Kapoor, Paul L. Auer, Joe Dennis, Alison M. Dunning, Qin Wang, Michael Lush, Kyriaki Michailidou, Manjeet K. Bolla, Kristan J. Aronson, Rachel A. Murphy, Angela Brooks-Wilson, Derrick G. Lee, Emilie Cordina-Duverger, Pascal Guénel, Thérèse Truong, Claire Mulot, Lauren R. Teras, Alpa V. Patel, Laure Dossus, Rudolf Kaaks, Reiner Hoppe, Wing-Yee Lo, Thomas Brüning, Ute Hamann, Kamila Czene, Marike Gabrielson, Per Hall, Mikael Eriksson, Audrey Jung, Heiko Becher, Fergus J. Couch, Nicole L. Larson, Janet E. Olson, Kathryn J. Ruddy, Graham G. Giles, Robert J. MacInnis, Melissa C. Southey, Loic Le Marchand, Lynne R. Wilkens, Christopher A. Haiman, Håkan Olsson, Annelie Augustinsson, Ute Krüger, Philippe Wagner, Christopher Scott, Stacey J. Winham, Celine M. Vachon, Charles M. Perou, Andrew F. Olshan, Melissa A. Troester, David J. Hunter, Heather A. Eliassen, Rulla M. Tamimi, Kristen Brantley, Irene L. Andrulis, Jonine Figueroa, Stephen J. Chanock, Thomas U. Ahearn, Montserrat García-Closas, Gareth D. Evans, William G. Newman, Elke M. van Veen, Anthony Howell, Alicja Wolk, Niclas Håkansson, Hoda Anton-Culver, Argyrios Ziogas, Michael E. Jones, Nick Orr, Minouk J. Schoemaker, Anthony J. Swerdlow, Cari M. Kitahara, Martha Linet, Ross L. Prentice, Douglas F. Easton, Roger L. Milne, Peter Kraft, Jenny Chang-Claude, and Sara Lindström
Subjects: Medicine, Science
Abstract: Abstract Use of menopausal hormone therapy (MHT) is associated with increased risk for breast cancer. However, the relevant mechanisms and its interaction with genetic variants are not fully understood. We conducted a genome-wide interaction analysis between MHT use and genetic variants for breast cancer risk in 27,585 cases and 34,785 controls from 26 observational studies. All women were post-menopausal and of European ancestry. Multivariable logistic regression models were used to test for multiplicative interactions between genetic variants and current MHT use. We considered interaction p-values
Published: 2022
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19. Gene–gene interaction of AhRwith and within the Wntcascade affects susceptibility to lung cancer

Author: Albert Rosenberger, Nils Muttray, Rayjean J. Hung, David C. Christiani, Neil E. Caporaso, Geoffrey Liu, Stig E. Bojesen, Loic Le Marchand, Demetrios Albanes, Melinda C. Aldrich, Adonina Tardon, Guillermo Fernández-Tardón, Gad Rennert, John K. Field, Michael P. A. Davies, Triantafillos Liloglou, Lambertus A. Kiemeney, Philip Lazarus, Bernadette Wendel, Aage Haugen, Shanbeh Zienolddiny, Stephen Lam, Matthew B. Schabath, Angeline S. Andrew, Eric J. Duell, Susanne M. Arnold, Gary E. Goodman, Chu Chen, Jennifer A. Doherty, Fiona Taylor, Angela Cox, Penella J. Woll, Angela Risch, Thomas R. Muley, Mikael Johansson, Paul Brennan, Maria Teresa Landi, Sanjay S. Shete, Christopher I. Amos, Heike Bickeböller, and The INTEGRAL-ILCCO Consortium
Subjects: Susceptibility, Association, Gene–gene integration, Prediction, Polygenic risk score, Decision trees, Medicine
Abstract: Abstract Background Aberrant Wnt signalling, regulating cell development and stemness, influences the development of many cancer types. The Aryl hydrocarbon receptor (AhR) mediates tumorigenesis of environmental pollutants. Complex interaction patterns of genes assigned to AhR/Wnt-signalling were recently associated with lung cancer susceptibility. Aim To assess the association and predictive ability of AhR/Wnt-genes with lung cancer in cases and controls of European descent. Methods Odds ratios (OR) were estimated for genomic variants assigned to the Wnt agonist and the antagonistic genes DKK2, DKK3, DKK4, FRZB, SFRP4 and Axin2. Logistic regression models with variable selection were trained, validated and tested to predict lung cancer, at which other previously identified SNPs that have been robustly associated with lung cancer risk could also enter the model. Furthermore, decision trees were created to investigate variant × variant interaction. All analyses were performed for overall lung cancer and for subgroups. Results No genome-wide significant association of AhR/Wnt-genes with overall lung cancer was observed, but within the subgroups of ever smokers (e.g., maker rs2722278 SFRP4; OR = 1.20; 95% CI 1.13–1.27; p = 5.6 × 10–10) and never smokers (e.g., maker rs1133683 Axin2; OR = 1.27; 95% CI 1.19–1.35; p = 1.0 × 10–12). Although predictability is poor, AhR/Wnt-variants are unexpectedly overrepresented in optimized prediction scores for overall lung cancer and for small cell lung cancer. Remarkably, the score for never-smokers contained solely two AhR/Wnt-variants. The optimal decision tree for never smokers consists of 7 AhR/Wnt-variants and only two lung cancer variants. Conclusions The role of variants belonging to Wnt/AhR-pathways in lung cancer susceptibility may be underrated in main-effects association analysis. Complex interaction patterns in individuals of European descent have moderate predictive capacity for lung cancer or subgroups thereof, especially in never smokers.
Published: 2022
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20. Association of Genetic Risk Score With NAFLD in An Ethnically Diverse Cohort

Author: Jun Wang, David V. Conti, David Bogumil, Xin Sheng, Mazen Noureddin, Lynne R. Wilkens, Loic Le Marchand, Hugo R. Rosen, Christopher A. Haiman, and Veronica Wendy Setiawan
Subjects: Diseases of the digestive system. Gastroenterology, RC799-869
Abstract: Most genetic studies of nonalcoholic fatty liver disease (NAFLD) have been conducted in Whites. In this large and ethnically diverse cohort, we assessed the transportability of previously identified genetic variants for NAFLD, built a genetic risk score (GRS), and examined its association with NAFLD risk in multiple ethnic groups. Thirty previously identified genome‐wide association studies (GWAS) variants (P
Published: 2021
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21. Germline variants and breast cancer survival in patients with distant metastases at primary breast cancer diagnosis

Author: Maria Escala-Garcia, Sander Canisius, Renske Keeman, Jonathan Beesley, Hoda Anton-Culver, Volker Arndt, Annelie Augustinsson, Heiko Becher, Matthias W. Beckmann, Sabine Behrens, Marina Bermisheva, Stig E. Bojesen, Manjeet K. Bolla, Hermann Brenner, Federico Canzian, Jose E. Castelao, Jenny Chang-Claude, Stephen J. Chanock, Fergus J. Couch, Kamila Czene, Mary B. Daly, Joe Dennis, Peter Devilee, Thilo Dörk, Alison M. Dunning, Douglas F. Easton, Arif B. Ekici, A. Heather Eliassen, Peter A. Fasching, Henrik Flyger, Manuela Gago-Dominguez, Montserrat García-Closas, José A. García-Sáenz, Jürgen Geisler, Graham G. Giles, Mervi Grip, Melanie Gündert, Eric Hahnen, Christopher A. Haiman, Niclas Håkansson, Per Hall, Ute Hamann, Jaana M. Hartikainen, Bernadette A. M. Heemskerk-Gerritsen, Antoinette Hollestelle, Reiner Hoppe, John L. Hopper, David J. Hunter, William Jacot, Anna Jakubowska, Esther M. John, Audrey Y. Jung, Rudolf Kaaks, Elza Khusnutdinova, Linetta B. Koppert, Peter Kraft, Vessela N. Kristensen, Allison W. Kurian, Diether Lambrechts, Loic Le Marchand, Annika Lindblom, Robert N. Luben, Jan Lubiński, Arto Mannermaa, Mehdi Manoochehri, Sara Margolin, Dimitrios Mavroudis, Taru A. Muranen, Heli Nevanlinna, Andrew F. Olshan, Håkan Olsson, Tjoung-Won Park-Simon, Alpa V. Patel, Paolo Peterlongo, Paul D. P. Pharoah, Kevin Punie, Paolo Radice, Gad Rennert, Hedy S. Rennert, Atocha Romero, Rebecca Roylance, Thomas Rüdiger, Matthias Ruebner, Emmanouil Saloustros, Elinor J. Sawyer, Rita K. Schmutzler, Minouk J. Schoemaker, Christopher Scott, Melissa C. Southey, Harald Surowy, Anthony J. Swerdlow, Rulla M. Tamimi, Lauren R. Teras, Emilie Thomas, Ian Tomlinson, Melissa A. Troester, Celine M. Vachon, Qin Wang, Robert Winqvist, Alicja Wolk, Argyrios Ziogas, kConFab/AOCS Investigators, Kyriaki Michailidou, Georgia Chenevix-Trench, Thomas Bachelot, and Marjanka K. Schmidt
Subjects: Medicine, Science
Abstract: Abstract Breast cancer metastasis accounts for most of the deaths from breast cancer. Identification of germline variants associated with survival in aggressive types of breast cancer may inform understanding of breast cancer progression and assist treatment. In this analysis, we studied the associations between germline variants and breast cancer survival for patients with distant metastases at primary breast cancer diagnosis. We used data from the Breast Cancer Association Consortium (BCAC) including 1062 women of European ancestry with metastatic breast cancer, 606 of whom died of breast cancer. We identified two germline variants on chromosome 1, rs138569520 and rs146023652, significantly associated with breast cancer-specific survival (P = 3.19 × 10−8 and 4.42 × 10−8). In silico analysis suggested a potential regulatory effect of the variants on the nearby target genes SDE2 and H3F3A. However, the variants showed no evidence of association in a smaller replication dataset. The validation dataset was obtained from the SNPs to Risk of Metastasis (StoRM) study and included 293 patients with metastatic primary breast cancer at diagnosis. Ultimately, larger replication studies are needed to confirm the identified associations.
Published: 2021
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22. Association of germline genetic variants with breast cancer-specific survival in patient subgroups defined by clinic-pathological variables related to tumor biology and type of systemic treatment

Author: Anna Morra, Maria Escala-Garcia, Jonathan Beesley, Renske Keeman, Sander Canisius, Thomas U. Ahearn, Irene L. Andrulis, Hoda Anton-Culver, Volker Arndt, Paul L. Auer, Annelie Augustinsson, Laura E. Beane Freeman, Heiko Becher, Matthias W. Beckmann, Sabine Behrens, Stig E. Bojesen, Manjeet K. Bolla, Hermann Brenner, Thomas Brüning, Saundra S. Buys, Bette Caan, Daniele Campa, Federico Canzian, Jose E. Castelao, Jenny Chang-Claude, Stephen J. Chanock, Ting-Yuan David Cheng, Christine L. Clarke, NBCS Collaborators, Sarah V. Colonna, Fergus J. Couch, Angela Cox, Simon S. Cross, Kamila Czene, Mary B. Daly, Joe Dennis, Thilo Dörk, Laure Dossus, Alison M. Dunning, Miriam Dwek, Diana M. Eccles, Arif B. Ekici, A. Heather Eliassen, Mikael Eriksson, D. Gareth Evans, Peter A. Fasching, Henrik Flyger, Lin Fritschi, Manuela Gago-Dominguez, José A. García-Sáenz, Graham G. Giles, Mervi Grip, Pascal Guénel, Melanie Gündert, Eric Hahnen, Christopher A. Haiman, Niclas Håkansson, Per Hall, Ute Hamann, Steven N. Hart, Jaana M. Hartikainen, Arndt Hartmann, Wei He, Maartje J. Hooning, Reiner Hoppe, John L. Hopper, Anthony Howell, David J. Hunter, ABCTB Investigators, kConFab Investigators, Agnes Jager, Anna Jakubowska, Wolfgang Janni, Esther M. John, Audrey Y. Jung, Rudolf Kaaks, Machteld Keupers, Cari M. Kitahara, Stella Koutros, Peter Kraft, Vessela N. Kristensen, Allison W. Kurian, James V. Lacey, Diether Lambrechts, Loic Le Marchand, Annika Lindblom, Martha Linet, Robert N. Luben, Jan Lubiński, Michael Lush, Arto Mannermaa, Mehdi Manoochehri, Sara Margolin, John W. M. Martens, Maria Elena Martinez, Dimitrios Mavroudis, Kyriaki Michailidou, Roger L. Milne, Anna Marie Mulligan, Taru A. Muranen, Heli Nevanlinna, William G. Newman, Sune F. Nielsen, Børge G. Nordestgaard, Andrew F. Olshan, Håkan Olsson, Nick Orr, Tjoung-Won Park-Simon, Alpa V. Patel, Bernard Peissel, Paolo Peterlongo, Dijana Plaseska-Karanfilska, Karolina Prajzendanc, Ross Prentice, Nadege Presneau, Brigitte Rack, Gad Rennert, Hedy S. Rennert, Valerie Rhenius, Atocha Romero, Rebecca Roylance, Matthias Ruebner, Emmanouil Saloustros, Elinor J. Sawyer, Rita K. Schmutzler, Andreas Schneeweiss, Christopher Scott, Mitul Shah, Snezhana Smichkoska, Melissa C. Southey, Jennifer Stone, Harald Surowy, Anthony J. Swerdlow, Rulla M. Tamimi, William J. Tapper, Lauren R. Teras, Mary Beth Terry, Rob A. E. M. Tollenaar, Ian Tomlinson, Melissa A. Troester, Thérèse Truong, Celine M. Vachon, Qin Wang, Amber N. Hurson, Robert Winqvist, Alicja Wolk, Argyrios Ziogas, Hiltrud Brauch, Montserrat García-Closas, Paul D. P. Pharoah, Douglas F. Easton, Georgia Chenevix-Trench, and Marjanka K. Schmidt
Subjects: Common germline genetic variants, Breast cancer-specific survival, Patient subgroups, Tumor biology, Systemic treatment, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract: Abstract Background Given the high heterogeneity among breast tumors, associations between common germline genetic variants and survival that may exist within specific subgroups could go undetected in an unstratified set of breast cancer patients. Methods We performed genome-wide association analyses within 15 subgroups of breast cancer patients based on prognostic factors, including hormone receptors, tumor grade, age, and type of systemic treatment. Analyses were based on 91,686 female patients of European ancestry from the Breast Cancer Association Consortium, including 7531 breast cancer-specific deaths over a median follow-up of 8.1 years. Cox regression was used to assess associations of common germline variants with 15-year and 5-year breast cancer-specific survival. We assessed the probability of these associations being true positives via the Bayesian false discovery probability (BFDP
Published: 2021
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23. Epidemiology of 40 blood biomarkers of one-carbon metabolism, vitamin status, inflammation, and renal and endothelial function among cancer-free older adults

Author: Hana Zahed, Mattias Johansson, Per M. Ueland, Øivind Midttun, Roger L. Milne, Graham G. Giles, Jonas Manjer, Malte Sandsveden, Arnulf Langhammer, Elin Pettersen Sørgjerd, Kjell Grankvist, Mikael Johansson, Neal D. Freedman, Wen-Yi Huang, Chu Chen, Ross Prentice, Victoria L. Stevens, Ying Wang, Loic Le Marchand, Lynne R. Wilkens, Stephanie J. Weinstein, Demetrius Albanes, Qiuyin Cai, William J. Blot, Alan A. Arslan, Anne Zeleniuch-Jacquotte, Xiao-Ou Shu, Wei Zheng, Jian-Min Yuan, Woon-Puay Koh, Kala Visvanathan, Howard D. Sesso, Xuehong Zhang, J. Michael Gaziano, Anouar Fanidi, David Muller, Paul Brennan, Florence Guida, and Hilary A. Robbins
Subjects: Medicine, Science
Abstract: Abstract Imbalances of blood biomarkers are associated with disease, and biomarkers may also vary non-pathologically across population groups. We described variation in concentrations of biomarkers of one-carbon metabolism, vitamin status, inflammation including tryptophan metabolism, and endothelial and renal function among cancer-free older adults. We analyzed 5167 cancer-free controls aged 40–80 years from 20 cohorts in the Lung Cancer Cohort Consortium (LC3). Centralized biochemical analyses of 40 biomarkers in plasma or serum were performed. We fit multivariable linear mixed effects models to quantify variation in standardized biomarker log-concentrations across four factors: age, sex, smoking status, and body mass index (BMI). Differences in most biomarkers across most factors were small, with 93% (186/200) of analyses showing an estimated difference lower than 0.25 standard-deviations, although most were statistically significant due to large sample size. The largest difference was for creatinine by sex, which was − 0.91 standard-deviations lower in women than men (95%CI − 0.98; − 0.84). The largest difference by age was for total cysteine (0.40 standard-deviation increase per 10-year increase, 95%CI 0.36; 0.43), and by BMI was for C-reactive protein (0.38 standard-deviation increase per 5-kg/m2 increase, 95%CI 0.34; 0.41). For 31 of 40 markers, the mean difference between current and never smokers was larger than between former and never smokers. A statistically significant (p
Published: 2021
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24. A case-only study to identify genetic modifiers of breast cancer risk for BRCA1/BRCA2 mutation carriers

Author: Juliette Coignard, Michael Lush, Jonathan Beesley, Tracy A. O’Mara, Joe Dennis, Jonathan P. Tyrer, Daniel R. Barnes, Lesley McGuffog, Goska Leslie, Manjeet K. Bolla, Muriel A. Adank, Simona Agata, Thomas Ahearn, Kristiina Aittomäki, Irene L. Andrulis, Hoda Anton-Culver, Volker Arndt, Norbert Arnold, Kristan J. Aronson, Banu K. Arun, Annelie Augustinsson, Jacopo Azzollini, Daniel Barrowdale, Caroline Baynes, Heko Becher, Marina Bermisheva, Leslie Bernstein, Katarzyna Białkowska, Carl Blomqvist, Stig E. Bojesen, Bernardo Bonanni, Ake Borg, Hiltrud Brauch, Hermann Brenner, Barbara Burwinkel, Saundra S. Buys, Trinidad Caldés, Maria A. Caligo, Daniele Campa, Brian D. Carter, Jose E. Castelao, Jenny Chang-Claude, Stephen J. Chanock, Wendy K. Chung, Kathleen B. M. Claes, Christine L. Clarke, GEMO Study Collaborators, EMBRACE Collaborators, J. Margriet Collée, Don M. Conroy, Kamila Czene, Mary B. Daly, Peter Devilee, Orland Diez, Yuan Chun Ding, Susan M. Domchek, Thilo Dörk, Isabel dos-Santos-Silva, Alison M. Dunning, Miriam Dwek, Diana M. Eccles, A. Heather Eliassen, Christoph Engel, Mikael Eriksson, D. Gareth Evans, Peter A. Fasching, Henrik Flyger, Florentia Fostira, Eitan Friedman, Lin Fritschi, Debra Frost, Manuela Gago-Dominguez, Susan M. Gapstur, Judy Garber, Vanesa Garcia-Barberan, Montserrat García-Closas, José A. García-Sáenz, Mia M. Gaudet, Simon A. Gayther, Andrea Gehrig, Vassilios Georgoulias, Graham G. Giles, Andrew K. Godwin, Mark S. Goldberg, David E. Goldgar, Anna González-Neira, Mark H. Greene, Pascal Guénel, Lothar Haeberle, Eric Hahnen, Christopher A. Haiman, Niclas Håkansson, Per Hall, Ute Hamann, Patricia A. Harrington, Steven N. Hart, Wei He, Frans B. L. Hogervorst, Antoinette Hollestelle, John L. Hopper, Darling J. Horcasitas, Peter J. Hulick, David J. Hunter, Evgeny N. Imyanitov, KConFab Investigators, HEBON Investigators, ABCTB Investigators, Agnes Jager, Anna Jakubowska, Paul A. James, Uffe Birk Jensen, Esther M. John, Michael E. Jones, Rudolf Kaaks, Pooja Middha Kapoor, Beth Y. Karlan, Renske Keeman, Elza Khusnutdinova, Johanna I. Kiiski, Yon-Dschun Ko, Veli-Matti Kosma, Peter Kraft, Allison W. Kurian, Yael Laitman, Diether Lambrechts, Loic Le Marchand, Jenny Lester, Fabienne Lesueur, Tricia Lindstrom, Adria Lopez-Fernández, Jennifer T. Loud, Craig Luccarini, Arto Mannermaa, Siranoush Manoukian, Sara Margolin, John W. M. Martens, Noura Mebirouk, Alfons Meindl, Austin Miller, Roger L. Milne, Marco Montagna, Katherine L. Nathanson, Susan L. Neuhausen, Heli Nevanlinna, Finn C. Nielsen, Katie M. O’Brien, Olufunmilayo I. Olopade, Janet E. Olson, Håkan Olsson, Ana Osorio, Laura Ottini, Tjoung-Won Park-Simon, Michael T. Parsons, Inge Sokilde Pedersen, Beth Peshkin, Paolo Peterlongo, Julian Peto, Paul D. P. Pharoah, Kelly-Anne Phillips, Eric C. Polley, Bruce Poppe, Nadege Presneau, Miquel Angel Pujana, Kevin Punie, Paolo Radice, Johanna Rantala, Muhammad U. Rashid, Gad Rennert, Hedy S. Rennert, Mark Robson, Atocha Romero, Maria Rossing, Emmanouil Saloustros, Dale P. Sandler, Regina Santella, Maren T. Scheuner, Marjanka K. Schmidt, Gunnar Schmidt, Christopher Scott, Priyanka Sharma, Penny Soucy, Melissa C. Southey, John J. Spinelli, Zoe Steinsnyder, Jennifer Stone, Dominique Stoppa-Lyonnet, Anthony Swerdlow, Rulla M. Tamimi, William J. Tapper, Jack A. Taylor, Mary Beth Terry, Alex Teulé, Darcy L. Thull, Marc Tischkowitz, Amanda E. Toland, Diana Torres, Alison H. Trainer, Thérèse Truong, Nadine Tung, Celine M. Vachon, Ana Vega, Joseph Vijai, Qin Wang, Barbara Wappenschmidt, Clarice R. Weinberg, Jeffrey N. Weitzel, Camilla Wendt, Alicja Wolk, Siddhartha Yadav, Xiaohong R. Yang, Drakoulis Yannoukakos, Wei Zheng, Argyrios Ziogas, Kristin K. Zorn, Sue K. Park, Mads Thomassen, Kenneth Offit, Rita K. Schmutzler, Fergus J. Couch, Jacques Simard, Georgia Chenevix-Trench, Douglas F. Easton, Nadine Andrieu, and Antonis C. Antoniou
Subjects: Science
Abstract: Breast cancer risk for BRCA1/BRCA2 mutation carriers varies depending on other genetic factors. Here, the authors perform a case-only genome-wide association study and highlight novel loci associated with breast cancer risk for BRCA1/BRCA2 mutation carriers.
Published: 2021
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25. Adiposity, metabolites, and colorectal cancer risk: Mendelian randomization study

Author: Caroline J. Bull, Joshua A. Bell, Neil Murphy, Eleanor Sanderson, George Davey Smith, Nicholas J. Timpson, Barbara L. Banbury, Demetrius Albanes, Sonja I. Berndt, Stéphane Bézieau, D. Timothy Bishop, Hermann Brenner, Daniel D. Buchanan, Andrea Burnett-Hartman, Graham Casey, Sergi Castellví-Bel, Andrew T. Chan, Jenny Chang-Claude, Amanda J. Cross, Albert de la Chapelle, Jane C. Figueiredo, Steven J. Gallinger, Susan M. Gapstur, Graham G. Giles, Stephen B. Gruber, Andrea Gsur, Jochen Hampe, Heather Hampel, Tabitha A. Harrison, Michael Hoffmeister, Li Hsu, Wen-Yi Huang, Jeroen R. Huyghe, Mark A. Jenkins, Corinne E. Joshu, Temitope O. Keku, Tilman Kühn, Sun-Seog Kweon, Loic Le Marchand, Christopher I. Li, Li Li, Annika Lindblom, Vicente Martín, Anne M. May, Roger L. Milne, Victor Moreno, Polly A. Newcomb, Kenneth Offit, Shuji Ogino, Amanda I. Phipps, Elizabeth A. Platz, John D. Potter, Conghui Qu, J. Ramón Quirós, Gad Rennert, Elio Riboli, Lori C. Sakoda, Clemens Schafmayer, Robert E. Schoen, Martha L. Slattery, Catherine M. Tangen, Kostas K. Tsilidis, Cornelia M. Ulrich, Fränzel J. B. van Duijnhoven, Bethany van Guelpen, Kala Visvanathan, Pavel Vodicka, Ludmila Vodickova, Hansong Wang, Emily White, Alicja Wolk, Michael O. Woods, Anna H. Wu, Peter T. Campbell, Wei Zheng, Ulrike Peters, Emma E. Vincent, and Marc J. Gunter
Subjects: Body mass index, Waist-to-hip ratio, Colorectal cancer, Mendelian randomization, Metabolism, NMR, Medicine
Abstract: Abstract Background Higher adiposity increases the risk of colorectal cancer (CRC), but whether this relationship varies by anatomical sub-site or by sex is unclear. Further, the metabolic alterations mediating the effects of adiposity on CRC are not fully understood. Methods We examined sex- and site-specific associations of adiposity with CRC risk and whether adiposity-associated metabolites explain the associations of adiposity with CRC. Genetic variants from genome-wide association studies of body mass index (BMI) and waist-to-hip ratio (WHR, unadjusted for BMI; N = 806,810), and 123 metabolites from targeted nuclear magnetic resonance metabolomics (N = 24,925), were used as instruments. Sex-combined and sex-specific Mendelian randomization (MR) was conducted for BMI and WHR with CRC risk (58,221 cases and 67,694 controls in the Genetics and Epidemiology of Colorectal Cancer Consortium, Colorectal Cancer Transdisciplinary Study, and Colon Cancer Family Registry). Sex-combined MR was conducted for BMI and WHR with metabolites, for metabolites with CRC, and for BMI and WHR with CRC adjusted for metabolite classes in multivariable models. Results In sex-specific MR analyses, higher BMI (per 4.2 kg/m2) was associated with 1.23 (95% confidence interval (CI) = 1.08, 1.38) times higher CRC odds among men (inverse-variance-weighted (IVW) model); among women, higher BMI (per 5.2 kg/m2) was associated with 1.09 (95% CI = 0.97, 1.22) times higher CRC odds. WHR (per 0.07 higher) was more strongly associated with CRC risk among women (IVW OR = 1.25, 95% CI = 1.08, 1.43) than men (IVW OR = 1.05, 95% CI = 0.81, 1.36). BMI or WHR was associated with 104/123 metabolites at false discovery rate-corrected P ≤ 0.05; several metabolites were associated with CRC, but not in directions that were consistent with the mediation of positive adiposity-CRC relations. In multivariable MR analyses, associations of BMI and WHR with CRC were not attenuated following adjustment for representative metabolite classes, e.g., the univariable IVW OR for BMI with CRC was 1.12 (95% CI = 1.00, 1.26), and this became 1.11 (95% CI = 0.99, 1.26) when adjusting for cholesterol in low-density lipoprotein particles. Conclusions Our results suggest that higher BMI more greatly raises CRC risk among men, whereas higher WHR more greatly raises CRC risk among women. Adiposity was associated with numerous metabolic alterations, but none of these explained associations between adiposity and CRC. More detailed metabolomic measures are likely needed to clarify the mechanistic pathways.
Published: 2020
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26. Circulating bilirubin levels and risk of colorectal cancer: serological and Mendelian randomization analyses

Author: Nazlisadat Seyed Khoei, Mazda Jenab, Neil Murphy, Barbara L. Banbury, Robert Carreras-Torres, Vivian Viallon, Tilman Kühn, Bas Bueno-de-Mesquita, Krasimira Aleksandrova, Amanda J. Cross, Elisabete Weiderpass, Magdalena Stepien, Andrew Bulmer, Anne Tjønneland, Marie-Christine Boutron-Ruault, Gianluca Severi, Franck Carbonnel, Verena Katzke, Heiner Boeing, Manuela M. Bergmann, Antonia Trichopoulou, Anna Karakatsani, Georgia Martimianaki, Domenico Palli, Giovanna Tagliabue, Salvatore Panico, Rosario Tumino, Carlotta Sacerdote, Guri Skeie, Susana Merino, Catalina Bonet, Miguel Rodríguez-Barranco, Leire Gil, Maria-Dolores Chirlaque, Eva Ardanaz, Robin Myte, Johan Hultdin, Aurora Perez-Cornago, Dagfinn Aune, Konstantinos K. Tsilidis, Demetrius Albanes, John A. Baron, Sonja I. Berndt, Stéphane Bézieau, Hermann Brenner, Peter T. Campbell, Graham Casey, Andrew T. Chan, Jenny Chang-Claude, Stephen J. Chanock, Michelle Cotterchio, Steven Gallinger, Stephen B. Gruber, Robert W. Haile, Jochen Hampe, Michael Hoffmeister, John L. Hopper, Li Hsu, Jeroen R. Huyghe, Mark A. Jenkins, Amit D. Joshi, Ellen Kampman, Susanna C. Larsson, Loic Le Marchand, Christopher I. Li, Li Li, Annika Lindblom, Noralane M. Lindor, Vicente Martín, Victor Moreno, Polly A. Newcomb, Kenneth Offit, Shuji Ogino, Patrick S. Parfrey, Paul D. P. Pharoah, Gad Rennert, Lori C. Sakoda, Clemens Schafmayer, Stephanie L. Schmit, Robert E. Schoen, Martha L. Slattery, Stephen N. Thibodeau, Cornelia M. Ulrich, Franzel J. B. van Duijnhoven, Korbinian Weigl, Stephanie J. Weinstein, Emily White, Alicja Wolk, Michael O. Woods, Anna H. Wu, Xuehong Zhang, Pietro Ferrari, Gabriele Anton, Annette Peters, Ulrike Peters, Marc J. Gunter, Karl-Heinz Wagner, and Heinz Freisling
Subjects: Bilirubin, Cancer, Colorectal cancer, Anti-oxidants, Mendelian randomization analysis, Medicine
Abstract: Abstract Background Bilirubin, a byproduct of hemoglobin breakdown and purported anti-oxidant, is thought to be cancer preventive. We conducted complementary serological and Mendelian randomization (MR) analyses to investigate whether alterations in circulating levels of bilirubin are associated with risk of colorectal cancer (CRC). We decided a priori to perform analyses separately in men and women based on suggestive evidence that associations may differ by sex. Methods In a case-control study nested in the European Prospective Investigation into Cancer and Nutrition (EPIC), pre-diagnostic unconjugated bilirubin (UCB, the main component of total bilirubin) concentrations were measured by high-performance liquid chromatography in plasma samples of 1386 CRC cases and their individually matched controls. Additionally, 115 single-nucleotide polymorphisms (SNPs) robustly associated (P
Published: 2020
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27. Genome-wide association meta-analysis identifies GP2 gene risk variants for pancreatic cancer

Author: Yingsong Lin, Masahiro Nakatochi, Yasuyuki Hosono, Hidemi Ito, Yoichiro Kamatani, Akihito Inoko, Hiromi Sakamoto, Fumie Kinoshita, Yumiko Kobayashi, Hiroshi Ishii, Masato Ozaka, Takashi Sasaki, Masato Matsuyama, Naoki Sasahira, Manabu Morimoto, Satoshi Kobayashi, Taito Fukushima, Makoto Ueno, Shinichi Ohkawa, Naoto Egawa, Sawako Kuruma, Mitsuru Mori, Haruhisa Nakao, Yasushi Adachi, Masumi Okuda, Takako Osaki, Shigeru Kamiya, Chaochen Wang, Kazuo Hara, Yasuhiro Shimizu, Tatsuo Miyamoto, Yuko Hayashi, Hiromichi Ebi, Tomohiro Kohmoto, Issei Imoto, Yumiko Kasugai, Yoshinori Murakami, Masato Akiyama, Kazuyoshi Ishigaki, Koichi Matsuda, Makoto Hirata, Kazuaki Shimada, Takuji Okusaka, Takahisa Kawaguchi, Meiko Takahashi, Yoshiyuki Watanabe, Kiyonori Kuriki, Aya Kadota, Rieko Okada, Haruo Mikami, Toshiro Takezaki, Sadao Suzuki, Taiki Yamaji, Motoki Iwasaki, Norie Sawada, Atsushi Goto, Kengo Kinoshita, Nobuo Fuse, Fumiki Katsuoka, Atsushi Shimizu, Satoshi S. Nishizuka, Kozo Tanno, Ken Suzuki, Yukinori Okada, Momoko Horikoshi, Toshimasa Yamauchi, Takashi Kadowaki, Herbert Yu, Jun Zhong, Laufey T. Amundadottir, Yuichiro Doki, Hideshi Ishii, Hidetoshi Eguchi, David Bogumil, Christopher A. Haiman, Loic Le Marchand, Masaki Mori, Harvey Risch, Veronica W. Setiawan, Shoichiro Tsugane, Kenji Wakai, Teruhiko Yoshida, Fumihiko Matsuda, Michiaki Kubo, Shogo Kikuchi, and Keitaro Matsuo
Subjects: Science
Abstract: Previous genome-wide association studies have identified risk loci for pancreatic cancer but were centered on individuals of European ancestry. Here the authors identify GP2 gene variants associated with pancreatic cancer susceptibility in populations of East Asian ancestry.
Published: 2020
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28. Protein-altering germline mutations implicate novel genes related to lung cancer development

Author: Xuemei Ji, Semanti Mukherjee, Maria Teresa Landi, Yohan Bosse, Philippe Joubert, Dakai Zhu, Ivan Gorlov, Xiangjun Xiao, Younghun Han, Olga Gorlova, Rayjean J. Hung, Yonathan Brhane, Robert Carreras-Torres, David C. Christiani, Neil Caporaso, Mattias Johansson, Geoffrey Liu, Stig E. Bojesen, Loic Le Marchand, Demetrios Albanes, Heike Bickeböller, Melinda C. Aldrich, William S. Bush, Adonina Tardon, Gad Rennert, Chu Chen, Jinyoung Byun, Konstantin H. Dragnev, John K. Field, Lambertus FA. Kiemeney, Philip Lazarus, Shan Zienolddiny, Stephen Lam, Matthew B. Schabath, Angeline S. Andrew, Pier A. Bertazzi, Angela C. Pesatori, Nancy Diao, Li Su, Lei Song, Ruyang Zhang, Natasha Leighl, Jakob S. Johansen, Anders Mellemgaard, Walid Saliba, Christopher Haiman, Lynne Wilkens, Ana Fernandez-Somoano, Guillermo Fernandez-Tardon, Erik H. F. M. van der Heijden, Jin Hee Kim, Michael P. A. Davies, Michael W. Marcus, Hans Brunnström, Jonas Manjer, Olle Melander, David C. Muller, Kim Overvad, Antonia Trichopoulou, Rosario Tumino, Gary E. Goodman, Angela Cox, Fiona Taylor, Penella Woll, Erich Wichmann, Thomas Muley, Angela Risch, Albert Rosenberger, Kjell Grankvist, Mikael Johansson, Frances Shepherd, Ming-Sound Tsao, Susanne M. Arnold, Eric B. Haura, Ciprian Bolca, Ivana Holcatova, Vladimir Janout, Milica Kontic, Jolanta Lissowska, Anush Mukeria, Simona Ognjanovic, Tadeusz M. Orlowski, Ghislaine Scelo, Beata Swiatkowska, David Zaridze, Per Bakke, Vidar Skaug, Lesley M. Butler, Kenneth Offit, Preethi Srinivasan, Chaitanya Bandlamudi, Matthew D. Hellmann, David B. Solit, Mark E. Robson, Charles M. Rudin, Zsofia K. Stadler, Barry S. Taylor, Michael F. Berger, Richard Houlston, John McLaughlin, Victoria Stevens, David C. Nickle, Ma’en Obeidat, Wim Timens, María Soler Artigas, Sanjay Shete, Hermann Brenner, Stephen Chanock, Paul Brennan, James D. McKay, and Christopher I. Amos
Subjects: Science
Abstract: In lung cancer, relatively few germline mutations are known to impact risk. Here the authors looked at rare variants in 39,146 individuals and find novel germline mutations associated with risk, as well as implicating ATM and a new candidate gene for lung cancer risk.
Published: 2020
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29. Functional informed genome‐wide interaction analysis of body mass index, diabetes and colorectal cancer risk

Author: Zhiyu Xia, Yu‐Ru Su, Paneen Petersen, Lihong Qi, Andre E. Kim, Jane C. Figueiredo, Yi Lin, Hongmei Nan, Lori C. Sakoda, Demetrius Albanes, Sonja I. Berndt, Stéphane Bézieau, Stephanie Bien, Daniel D. Buchanan, Graham Casey, Andrew T. Chan, David V. Conti, David A. Drew, Steven J. Gallinger, W. James Gauderman, Graham G. Giles, Stephen B. Gruber, Marc J. Gunter, Michael Hoffmeister, Mark A. Jenkins, Amit D. Joshi, Loic Le Marchand, Juan P. Lewinger, Li Li, Noralane M. Lindor, Victor Moreno, Neil Murphy, Rami Nassir, Polly A. Newcomb, Shuji Ogino, Gad Rennert, Mingyang Song, Xiaoliang Wang, Alicja Wolk, Michael O. Woods, Hermann Brenner, Emily White, Martha L. Slattery, Edward L. Giovannucci, Jenny Chang‐Claude, Paul D. P. Pharoah, Li Hsu, Peter T. Campbell, and Ulrike Peters
Subjects: BMI, colorectal cancer, diabetes, gene expression, gene‐environmental interaction, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract: Abstract Background Body mass index (BMI) and diabetes are established risk factors for colorectal cancer (CRC), likely through perturbations in metabolic traits (e.g. insulin resistance and glucose homeostasis). Identification of interactions between variation in genes and these metabolic risk factors may identify novel biologic insights into CRC etiology. Methods To improve statistical power and interpretation for gene‐environment interaction (G × E) testing, we tested genetic variants that regulate expression of a gene together for interaction with BMI (kg/m2) and diabetes on CRC risk among 26 017 cases and 20 692 controls. Each variant was weighted based on PrediXcan analysis of gene expression data from colon tissue generated in the Genotype‐Tissue Expression Project for all genes with heritability ≥1%. We used a mixed‐effects model to jointly measure the G × E interaction in a gene by partitioning the interactions into the predicted gene expression levels (fixed effects), and residual G × E effects (random effects). G × BMI analyses were stratified by sex as BMI‐CRC associations differ by sex. We used false discovery rates to account for multiple comparisons and reported all results with FDR
Published: 2020
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30. A meta-analysis of genome-wide association studies of multiple myeloma among men and women of African ancestry

Author: Zhaohui Du, Niels Weinhold, Gregory Chi Song, Kristin A. Rand, David J. Van Den Berg, Amie E. Hwang, Xin Sheng, Victor Hom, Sikander Ailawadhi, Ajay K. Nooka, Seema Singhal, Karen Pawlish, Edward S. Peters, Cathryn Bock, Ann Mohrbacher, Alexander Stram, Sonja I. Berndt, William J. Blot, Graham Casey, Victoria L. Stevens, Rick Kittles, Phyllis J. Goodman, W. Ryan Diver, Anselm Hennis, Barbara Nemesure, Eric A. Klein, Benjamin A. Rybicki, Janet L. Stanford, John S. Witte, Lisa Signorello, Esther M. John, Leslie Bernstein, Antoinette M. Stroup, Owen W. Stephens, Maurizio Zangari, Frits Van Rhee, Andrew Olshan, Wei Zheng, Jennifer J. Hu, Regina Ziegler, Sarah J. Nyante, Sue Ann Ingles, Michael F. Press, John David Carpten, Stephen J. Chanock, Jayesh Mehta, Graham A. Colditz, Jeffrey Wolf, Thomas G. Martin, Michael Tomasson, Mark A. Fiala, Howard Terebelo, Nalini Janakiraman, Laurence Kolonel, Kenneth C. Anderson, Loic Le Marchand, Daniel Auclair, Brian C.-H. Chiu, Elad Ziv, Daniel Stram, Ravi Vij, Leon Bernal-Mizrachi, Gareth J. Morgan, Jeffrey A. Zonder, Carol Ann Huff, Sagar Lonial, Robert Z. Orlowski, David V. Conti, Christopher A. Haiman, and Wendy Cozen
Subjects: Specialties of internal medicine, RC581-951
Abstract: Abstract: Persons of African ancestry (AA) have a twofold higher risk for multiple myeloma (MM) compared with persons of European ancestry (EA). Genome-wide association studies (GWASs) support a genetic contribution to MM etiology in individuals of EA. Little is known about genetic risk factors for MM in individuals of AA. We performed a meta-analysis of 2 GWASs of MM in 1813 cases and 8871 controls and conducted an admixture mapping scan to identify risk alleles. We fine-mapped the 23 known susceptibility loci to find markers that could better capture MM risk in individuals of AA and constructed a polygenic risk score (PRS) to assess the aggregated effect of known MM risk alleles. In GWAS meta-analysis, we identified 2 suggestive novel loci located at 9p24.3 and 9p13.1 at P < 1 × 10−6; however, no genome-wide significant association was noted. In admixture mapping, we observed a genome-wide significant inverse association between local AA at 2p24.1-23.1 and MM risk in AA individuals. Of the 23 known EA risk variants, 20 showed directional consistency, and 9 replicated at P < .05 in AA individuals. In 8 regions, we identified markers that better capture MM risk in persons with AA. AA individuals with a PRS in the top 10% had a 1.82-fold (95% confidence interval, 1.56-2.11) increased MM risk compared with those with average risk (25%-75%). The strongest functional association was between the risk allele for variant rs56219066 at 5q15 and lower ELL2 expression (P = 5.1 × 10−12). Our study shows that common genetic variation contributes to MM risk in individuals with AA.
Published: 2020
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31. A network analysis to identify mediators of germline-driven differences in breast cancer prognosis

Author: Maria Escala-Garcia, Jean Abraham, Irene L. Andrulis, Hoda Anton-Culver, Volker Arndt, Alan Ashworth, Paul L. Auer, Päivi Auvinen, Matthias W. Beckmann, Jonathan Beesley, Sabine Behrens, Javier Benitez, Marina Bermisheva, Carl Blomqvist, William Blot, Natalia V. Bogdanova, Stig E. Bojesen, Manjeet K. Bolla, Anne-Lise Børresen-Dale, Hiltrud Brauch, Hermann Brenner, Sara Y. Brucker, Barbara Burwinkel, Carlos Caldas, Federico Canzian, Jenny Chang-Claude, Stephen J. Chanock, Suet-Feung Chin, Christine L. Clarke, Fergus J. Couch, Angela Cox, Simon S. Cross, Kamila Czene, Mary B. Daly, Joe Dennis, Peter Devilee, Janet A. Dunn, Alison M. Dunning, Miriam Dwek, Helena M. Earl, Diana M. Eccles, A. Heather Eliassen, Carolina Ellberg, D. Gareth Evans, Peter A. Fasching, Jonine Figueroa, Henrik Flyger, Manuela Gago-Dominguez, Susan M. Gapstur, Montserrat García-Closas, José A. García-Sáenz, Mia M. Gaudet, Angela George, Graham G. Giles, David E. Goldgar, Anna González-Neira, Mervi Grip, Pascal Guénel, Qi Guo, Christopher A. Haiman, Niclas Håkansson, Ute Hamann, Patricia A. Harrington, Louise Hiller, Maartje J. Hooning, John L. Hopper, Anthony Howell, Chiun-Sheng Huang, Guanmengqian Huang, David J. Hunter, Anna Jakubowska, Esther M. John, Rudolf Kaaks, Pooja Middha Kapoor, Renske Keeman, Cari M. Kitahara, Linetta B. Koppert, Peter Kraft, Vessela N. Kristensen, Diether Lambrechts, Loic Le Marchand, Flavio Lejbkowicz, Annika Lindblom, Jan Lubiński, Arto Mannermaa, Mehdi Manoochehri, Siranoush Manoukian, Sara Margolin, Maria Elena Martinez, Tabea Maurer, Dimitrios Mavroudis, Alfons Meindl, Roger L. Milne, Anna Marie Mulligan, Susan L. Neuhausen, Heli Nevanlinna, William G. Newman, Andrew F. Olshan, Janet E. Olson, Håkan Olsson, Nick Orr, Paolo Peterlongo, Christos Petridis, Ross L. Prentice, Nadege Presneau, Kevin Punie, Dhanya Ramachandran, Gad Rennert, Atocha Romero, Mythily Sachchithananthan, Emmanouil Saloustros, Elinor J. Sawyer, Rita K. Schmutzler, Lukas Schwentner, Christopher Scott, Jacques Simard, Christof Sohn, Melissa C. Southey, Anthony J. Swerdlow, Rulla M. Tamimi, William J. Tapper, Manuel R. Teixeira, Mary Beth Terry, Heather Thorne, Rob A. E. M. Tollenaar, Ian Tomlinson, Melissa A. Troester, Thérèse Truong, Clare Turnbull, Celine M. Vachon, Lizet E. van der Kolk, Qin Wang, Robert Winqvist, Alicja Wolk, Xiaohong R. Yang, Argyrios Ziogas, Paul D. P. Pharoah, Per Hall, Lodewyk F. A. Wessels, Georgia Chenevix-Trench, Gary D. Bader, Thilo Dörk, Douglas F. Easton, Sander Canisius, and Marjanka K. Schmidt
Subjects: Science
Abstract: In breast cancer the contribution of different genetic variants to disease heritability is complex and not fully understood. Here, the authors present a network-based analysis in 84,567 patients studying ~7.3 million variants, identifying gene modules associated with breast cancer survival.
Published: 2020
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32. Physical activity and risks of breast and colorectal cancer: a Mendelian randomisation analysis

Author: Nikos Papadimitriou, Niki Dimou, Konstantinos K. Tsilidis, Barbara Banbury, Richard M. Martin, Sarah J. Lewis, Nabila Kazmi, Timothy M. Robinson, Demetrius Albanes, Krasimira Aleksandrova, Sonja I. Berndt, D. Timothy Bishop, Hermann Brenner, Daniel D. Buchanan, Bas Bueno-de-Mesquita, Peter T. Campbell, Sergi Castellví-Bel, Andrew T. Chan, Jenny Chang-Claude, Merete Ellingjord-Dale, Jane C. Figueiredo, Steven J. Gallinger, Graham G. Giles, Edward Giovannucci, Stephen B. Gruber, Andrea Gsur, Jochen Hampe, Heather Hampel, Sophia Harlid, Tabitha A. Harrison, Michael Hoffmeister, John L. Hopper, Li Hsu, José María Huerta, Jeroen R. Huyghe, Mark A. Jenkins, Temitope O. Keku, Tilman Kühn, Carlo La Vecchia, Loic Le Marchand, Christopher I. Li, Li Li, Annika Lindblom, Noralane M. Lindor, Brigid Lynch, Sanford D. Markowitz, Giovanna Masala, Anne M. May, Roger Milne, Evelyn Monninkhof, Lorena Moreno, Victor Moreno, Polly A. Newcomb, Kenneth Offit, Vittorio Perduca, Paul D. P. Pharoah, Elizabeth A. Platz, John D. Potter, Gad Rennert, Elio Riboli, Maria-Jose Sánchez, Stephanie L. Schmit, Robert E. Schoen, Gianluca Severi, Sabina Sieri, Martha L. Slattery, Mingyang Song, Catherine M. Tangen, Stephen N. Thibodeau, Ruth C. Travis, Antonia Trichopoulou, Cornelia M. Ulrich, Franzel J. B. van Duijnhoven, Bethany Van Guelpen, Pavel Vodicka, Emily White, Alicja Wolk, Michael O. Woods, Anna H. Wu, Ulrike Peters, Marc J. Gunter, and Neil Murphy
Subjects: Science
Abstract: Physical activity has been linked to lower risks of colorectal and breast cancer. Here, the authors present a Mendelian randomisation analysis supporting a potentially causal relationship between higher physical activity levels and lower risks of breast cancer and colorectal cancer.
Published: 2020
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33. Prediction and clinical utility of a contralateral breast cancer risk model

Author: Daniele Giardiello, Ewout W. Steyerberg, Michael Hauptmann, Muriel A. Adank, Delal Akdeniz, Carl Blomqvist, Stig E. Bojesen, Manjeet K. Bolla, Mariël Brinkhuis, Jenny Chang-Claude, Kamila Czene, Peter Devilee, Alison M. Dunning, Douglas F. Easton, Diana M. Eccles, Peter A. Fasching, Jonine Figueroa, Henrik Flyger, Montserrat García-Closas, Lothar Haeberle, Christopher A. Haiman, Per Hall, Ute Hamann, John L. Hopper, Agnes Jager, Anna Jakubowska, Audrey Jung, Renske Keeman, Iris Kramer, Diether Lambrechts, Loic Le Marchand, Annika Lindblom, Jan Lubiński, Mehdi Manoochehri, Luigi Mariani, Heli Nevanlinna, Hester S. A. Oldenburg, Saskia Pelders, Paul D. P. Pharoah, Mitul Shah, Sabine Siesling, Vincent T. H. B. M. Smit, Melissa C. Southey, William J. Tapper, Rob A. E. M. Tollenaar, Alexandra J. van den Broek, Carolien H. M. van Deurzen, Flora E. van Leeuwen, Chantal van Ongeval, Laura J. Van’t Veer, Qin Wang, Camilla Wendt, Pieter J. Westenend, Maartje J. Hooning, and Marjanka K. Schmidt
Subjects: Contralateral breast cancer, Risk prediction model, Clinical decision-making, BRCA mutation carriers, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract: Abstract Background Breast cancer survivors are at risk for contralateral breast cancer (CBC), with the consequent burden of further treatment and potentially less favorable prognosis. We aimed to develop and validate a CBC risk prediction model and evaluate its applicability for clinical decision-making. Methods We included data of 132,756 invasive non-metastatic breast cancer patients from 20 studies with 4682 CBC events and a median follow-up of 8.8 years. We developed a multivariable Fine and Gray prediction model (PredictCBC-1A) including patient, primary tumor, and treatment characteristics and BRCA1/2 germline mutation status, accounting for the competing risks of death and distant metastasis. We also developed a model without BRCA1/2 mutation status (PredictCBC-1B) since this information was available for only 6% of patients and is routinely unavailable in the general breast cancer population. Prediction performance was evaluated using calibration and discrimination, calculated by a time-dependent area under the curve (AUC) at 5 and 10 years after diagnosis of primary breast cancer, and an internal-external cross-validation procedure. Decision curve analysis was performed to evaluate the net benefit of the model to quantify clinical utility. Results In the multivariable model, BRCA1/2 germline mutation status, family history, and systemic adjuvant treatment showed the strongest associations with CBC risk. The AUC of PredictCBC-1A was 0.63 (95% prediction interval (PI) at 5 years, 0.52–0.74; at 10 years, 0.53–0.72). Calibration-in-the-large was -0.13 (95% PI: -1.62–1.37), and the calibration slope was 0.90 (95% PI: 0.73–1.08). The AUC of Predict-1B at 10 years was 0.59 (95% PI: 0.52–0.66); calibration was slightly lower. Decision curve analysis for preventive contralateral mastectomy showed potential clinical utility of PredictCBC-1A between thresholds of 4–10% 10-year CBC risk for BRCA1/2 mutation carriers and non-carriers. Conclusions We developed a reasonably calibrated model to predict the risk of CBC in women of European-descent; however, prediction accuracy was moderate. Our model shows potential for improved risk counseling, but decision-making regarding contralateral preventive mastectomy, especially in the general breast cancer population where limited information of the mutation status in BRCA1/2 is available, remains challenging.
Published: 2019
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34. Smoking related lung cancer mortality by education and sex in Norway

Author: Merethe S. Hansen, Idlir Licaj, Tonje Braaten, Arnulf Langhammer, Loic Le Marchand, and Inger Torhild Gram
Subjects: Cohort study, Lung cancer mortality, Smoking, Education, Sex differences, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Published: 2019
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35. Publisher Correction: Shared heritability and functional enrichment across six solid cancers

Author: Xia Jiang, Hilary K. Finucane, Fredrick R. Schumacher, Stephanie L. Schmit, Jonathan P. Tyrer, Younghun Han, Kyriaki Michailidou, Corina Lesseur, Karoline B. Kuchenbaecker, Joe Dennis, David V. Conti, Graham Casey, Mia M. Gaudet, Jeroen R. Huyghe, Demetrius Albanes, Melinda C. Aldrich, Angeline S. Andrew, Irene L. Andrulis, Hoda Anton-Culver, Antonis C. Antoniou, Natalia N. Antonenkova, Susanne M. Arnold, Kristan J. Aronson, Banu K. Arun, Elisa V. Bandera, Rosa B. Barkardottir, Daniel R. Barnes, Jyotsna Batra, Matthias W. Beckmann, Javier Benitez, Sara Benlloch, Andrew Berchuck, Sonja I. Berndt, Heike Bickeböller, Stephanie A. Bien, Carl Blomqvist, Stefania Boccia, Natalia V. Bogdanova, Stig E. Bojesen, Manjeet K. Bolla, Hiltrud Brauch, Hermann Brenner, James D. Brenton, Mark N. Brook, Joan Brunet, Hans Brunnström, Daniel D. Buchanan, Barbara Burwinkel, Ralf Butzow, Gabriella Cadoni, Trinidad Caldés, Maria A. Caligo, Ian Campbell, Peter T. Campbell, Géraldine Cancel-Tassin, Lisa Cannon-Albright, Daniele Campa, Neil Caporaso, André L. Carvalho, Andrew T. Chan, Jenny Chang-Claude, Stephen J. Chanock, Chu Chen, David C. Christiani, Kathleen B. M. Claes, Frank Claessens, Judith Clements, J. Margriet Collée, Marcia Cruz Correa, Fergus J. Couch, Angela Cox, Julie M. Cunningham, Cezary Cybulski, Kamila Czene, Mary B. Daly, Anna deFazio, Peter Devilee, Orland Diez, Manuela Gago-Dominguez, Jenny L. Donovan, Thilo Dörk, Eric J. Duell, Alison M. Dunning, Miriam Dwek, Diana M. Eccles, Christopher K. Edlund, Digna R. Velez Edwards, Carolina Ellberg, D. Gareth Evans, Peter A. Fasching, Robert L. Ferris, Triantafillos Liloglou, Jane C. Figueiredo, Olivia Fletcher, Renée T. Fortner, Florentia Fostira, Silvia Franceschi, Eitan Friedman, Steven J. Gallinger, Patricia A. Ganz, Judy Garber, José A. García-Sáenz, Simon A. Gayther, Graham G. Giles, Andrew K. Godwin, Mark S. Goldberg, David E. Goldgar, Ellen L. Goode, Marc T. Goodman, Gary Goodman, Kjell Grankvist, Mark H. Greene, Henrik Gronberg, Jacek Gronwald, Pascal Guénel, Niclas Håkansson, Per Hall, Ute Hamann, Freddie C. Hamdy, Robert J. Hamilton, Jochen Hampe, Aage Haugen, Florian Heitz, Rolando Herrero, Peter Hillemanns, Michael Hoffmeister, Estrid Høgdall, Yun-Chul Hong, John L. Hopper, Richard Houlston, Peter J. Hulick, David J. Hunter, David G. Huntsman, Gregory Idos, Evgeny N. Imyanitov, Sue Ann Ingles, Claudine Isaacs, Anna Jakubowska, Paul James, Mark A. Jenkins, Mattias Johansson, Mikael Johansson, Esther M. John, Amit D. Joshi, Radka Kaneva, Beth Y. Karlan, Linda E. Kelemen, Tabea Kühl, Kay-Tee Khaw, Elza Khusnutdinova, Adam S. Kibel, Lambertus A. Kiemeney, Jeri Kim, Susanne K. Kjaer, Julia A. Knight, Manolis Kogevinas, Zsofia Kote-Jarai, Stella Koutros, Vessela N. Kristensen, Jolanta Kupryjanczyk, Martin Lacko, Stephan Lam, Diether Lambrechts, Maria Teresa Landi, Philip Lazarus, Nhu D. Le, Eunjung Lee, Flavio Lejbkowicz, Heinz-Josef Lenz, Goska Leslie, Davor Lessel, Jenny Lester, Douglas A. Levine, Li Li, Christopher I. Li, Annika Lindblom, Noralane M. Lindor, Geoffrey Liu, Fotios Loupakis, Jan Lubiński, Lovise Maehle, Christiane Maier, Arto Mannermaa, Loic Le Marchand, Sara Margolin, Taymaa May, Lesley McGuffog, Alfons Meindl, Pooja Middha, Austin Miller, Roger L. Milne, Robert J. MacInnis, Francesmary Modugno, Marco Montagna, Victor Moreno, Kirsten B. Moysich, Lorelei Mucci, Kenneth Muir, Anna Marie Mulligan, Katherine L. Nathanson, David E. Neal, Andrew R. Ness, Susan L. Neuhausen, Heli Nevanlinna, Polly A. Newcomb, Lisa F. Newcomb, Finn Cilius Nielsen, Liene Nikitina-Zake, Børge G. Nordestgaard, Robert L. Nussbaum, Kenneth Offit, Edith Olah, Ali Amin Al Olama, Olufunmilayo I. Olopade, Andrew F. Olshan, Håkan Olsson, Ana Osorio, Hardev Pandha, Jong Y. Park, Nora Pashayan, Michael T. Parsons, Tanja Pejovic, Kathryn L. Penney, Wilbert H. M. Peters, Catherine M. Phelan, Amanda I. Phipps, Dijana Plaseska-Karanfilska, Miranda Pring, Darya Prokofyeva, Paolo Radice, Kari Stefansson, Susan J. Ramus, Leon Raskin, Gad Rennert, Hedy S. Rennert, Elizabeth J. van Rensburg, Marjorie J. Riggan, Harvey A. Risch, Angela Risch, Monique J. Roobol, Barry S. Rosenstein, Mary Anne Rossing, Kim De Ruyck, Emmanouil Saloustros, Dale P. Sandler, Elinor J. Sawyer, Matthew B. Schabath, Johanna Schleutker, Marjanka K. Schmidt, V. Wendy Setiawan, Hongbing Shen, Erin M. Siegel, Weiva Sieh, Christian F. Singer, Martha L. Slattery, Karina Dalsgaard Sorensen, Melissa C. Southey, Amanda B. Spurdle, Janet L. Stanford, Victoria L. Stevens, Sebastian Stintzing, Jennifer Stone, Karin Sundfeldt, Rebecca Sutphen, Anthony J. Swerdlow, Eloiza H. Tajara, Catherine M. Tangen, Adonina Tardon, Jack A. Taylor, M. Dawn Teare, Manuel R. Teixeira, Mary Beth Terry, Kathryn L. Terry, Stephen N. Thibodeau, Mads Thomassen, Line Bjørge, Marc Tischkowitz, Amanda E. Toland, Diana Torres, Paul A. Townsend, Ruth C. Travis, Nadine Tung, Shelley S. Tworoger, Cornelia M. Ulrich, Nawaid Usmani, Celine M. Vachon, Els Van Nieuwenhuysen, Ana Vega, Miguel Elías Aguado-Barrera, Qin Wang, Penelope M. Webb, Clarice R. Weinberg, Stephanie Weinstein, Mark C. Weissler, Jeffrey N. Weitzel, Catharine M. L. West, Emily White, Alice S. Whittemore, H-Erich Wichmann, Fredrik Wiklund, Robert Winqvist, Alicja Wolk, Penella Woll, Michael Woods, Anna H. Wu, Xifeng Wu, Drakoulis Yannoukakos, Wei Zheng, Shanbeh Zienolddiny, Argyrios Ziogas, Kristin K. Zorn, Jacqueline M. Lane, Richa Saxena, Duncan Thomas, Rayjean J. Hung, Brenda Diergaarde, James McKay, Ulrike Peters, Li Hsu, Montserrat García-Closas, Rosalind A. Eeles, Georgia Chenevix-Trench, Paul J. Brennan, Christopher A. Haiman, Jacques Simard, Douglas F. Easton, Stephen B. Gruber, Paul D. P. Pharoah, Alkes L. Price, Bogdan Pasaniuc, Christopher I. Amos, Peter Kraft, and Sara Lindström
Subjects: Science
Abstract: An amendment to this paper has been published and can be accessed via a link at the top of the paper.
Published: 2019
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36. Interethnic differences in pancreatic cancer incidence and risk factors: The Multiethnic Cohort

Author: Brian Z. Huang, Daniel O. Stram, Loic Le Marchand, Christopher A. Haiman, Lynne R. Wilkens, Stephen J. Pandol, Zuo‐Feng Zhang, Kristine R. Monroe, and Veronica Wendy Setiawan
Subjects: cohort, epidemiology, ethnicity, incidence, minority, pancreatic cancer, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract: Abstract While disparity in pancreatic cancer incidence between blacks and whites has been observed, few studies have examined disparity in other ethnic minorities. We evaluated variations in pancreatic cancer incidence and assessed the extent to which known risk factors account for differences in pancreatic cancer risk among African Americans, Native Hawaiians, Japanese Americans, Latino Americans, and European Americans in the Multiethnic Cohort Study. Risk factor data were obtained from the baseline questionnaire. Cox regression was used to estimate the relative risks (RRs) and 95% confidence intervals (CIs) for pancreatic cancer associated with risk factors and ethnicity. During an average 16.9‐year follow‐up, 1,532 incident pancreatic cancer cases were identified among 184,559 at‐risk participants. Family history of pancreatic cancer (RR 1.97, 95% CI 1.50‐2.58), diabetes (RR 1.32, 95% CI 1.14‐1.54), body mass index ≥30 kg/m2 (RR 1.25, 95% CI 1.08‐1.46), current smoking (
Published: 2019
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37. Joint association of mammographic density adjusted for age and body mass index and polygenic risk score with breast cancer risk

Author: Celine M. Vachon, Christopher G. Scott, Rulla M. Tamimi, Deborah J. Thompson, Peter A. Fasching, Jennifer Stone, Melissa C. Southey, Stacey Winham, Sara Lindström, Jenna Lilyquist, Graham G. Giles, Roger L. Milne, Robert J. MacInnis, Laura Baglietto, Jingmei Li, Kamila Czene, Manjeet K. Bolla, Qin Wang, Joe Dennis, Lothar Haeberle, Mikael Eriksson, Peter Kraft, Robert Luben, Nick Wareham, Janet E. Olson, Aaron Norman, Eric C. Polley, Gertraud Maskarinec, Loic Le Marchand, Christopher A. Haiman, John L. Hopper, Fergus J. Couch, Douglas F. Easton, Per Hall, Nilanjan Chatterjee, and Montse Garcia-Closas
Subjects: Breast density, Breast cancer risk, Polygenic risk score, Genetic variation, Risk models, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract: Abstract Background Mammographic breast density, adjusted for age and body mass index, and a polygenic risk score (PRS), comprised of common genetic variation, are both strong risk factors for breast cancer and increase discrimination of risk models. Understanding their joint contribution will be important to more accurately predict risk. Methods Using 3628 breast cancer cases and 5126 controls of European ancestry from eight case-control studies, we evaluated joint associations of a 77-single nucleotide polymorphism (SNP) PRS and quantitative mammographic density measures with breast cancer. Mammographic percent density and absolute dense area were evaluated using thresholding software and examined as residuals after adjusting for age, 1/BMI, and study. PRS and adjusted density phenotypes were modeled both continuously (per 1 standard deviation, SD) and categorically. We fit logistic regression models and tested the null hypothesis of multiplicative joint associations for PRS and adjusted density measures using likelihood ratio and global and tail-based goodness of fit tests within the subset of six cohort or population-based studies. Results Adjusted percent density (odds ratio (OR) = 1.45 per SD, 95% CI 1.38–1.52), adjusted absolute dense area (OR = 1.34 per SD, 95% CI 1.28–1.41), and the 77-SNP PRS (OR = 1.52 per SD, 95% CI 1.45–1.59) were associated with breast cancer risk. There was no evidence of interaction of the PRS with adjusted percent density or dense area on risk of breast cancer by either the likelihood ratio (P > 0.21) or goodness of fit tests (P > 0.09), whether assessed continuously or categorically. The joint association (OR) was 2.60 in the highest categories of adjusted PD and PRS and 0.34 in the lowest categories, relative to women in the second density quartile and middle PRS quintile. Conclusions The combined associations of the 77-SNP PRS and adjusted density measures are generally well described by multiplicative models, and both risk factors provide independent information on breast cancer risk.
Published: 2019
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38. Shared heritability and functional enrichment across six solid cancers

Author: Xia Jiang, Hilary K. Finucane, Fredrick R. Schumacher, Stephanie L. Schmit, Jonathan P. Tyrer, Younghun Han, Kyriaki Michailidou, Corina Lesseur, Karoline B. Kuchenbaecker, Joe Dennis, David V. Conti, Graham Casey, Mia M. Gaudet, Jeroen R. Huyghe, Demetrius Albanes, Melinda C. Aldrich, Angeline S. Andrew, Irene L. Andrulis, Hoda Anton-Culver, Antonis C. Antoniou, Natalia N. Antonenkova, Susanne M. Arnold, Kristan J. Aronson, Banu K. Arun, Elisa V. Bandera, Rosa B. Barkardottir, Daniel R. Barnes, Jyotsna Batra, Matthias W. Beckmann, Javier Benitez, Sara Benlloch, Andrew Berchuck, Sonja I. Berndt, Heike Bickeböller, Stephanie A. Bien, Carl Blomqvist, Stefania Boccia, Natalia V. Bogdanova, Stig E. Bojesen, Manjeet K. Bolla, Hiltrud Brauch, Hermann Brenner, James D. Brenton, Mark N. Brook, Joan Brunet, Hans Brunnström, Daniel D. Buchanan, Barbara Burwinkel, Ralf Butzow, Gabriella Cadoni, Trinidad Caldés, Maria A. Caligo, Ian Campbell, Peter T. Campbell, Géraldine Cancel-Tassin, Lisa Cannon-Albright, Daniele Campa, Neil Caporaso, André L. Carvalho, Andrew T. Chan, Jenny Chang-Claude, Stephen J. Chanock, Chu Chen, David C. Christiani, Kathleen B. M. Claes, Frank Claessens, Judith Clements, J. Margriet Collée, Marcia Cruz Correa, Fergus J. Couch, Angela Cox, Julie M. Cunningham, Cezary Cybulski, Kamila Czene, Mary B. Daly, Anna deFazio, Peter Devilee, Orland Diez, Manuela Gago-Dominguez, Jenny L. Donovan, Thilo Dörk, Eric J. Duell, Alison M. Dunning, Miriam Dwek, Diana M. Eccles, Christopher K. Edlund, Digna R Velez Edwards, Carolina Ellberg, D. Gareth Evans, Peter A. Fasching, Robert L. Ferris, Triantafillos Liloglou, Jane C. Figueiredo, Olivia Fletcher, Renée T. Fortner, Florentia Fostira, Silvia Franceschi, Eitan Friedman, Steven J. Gallinger, Patricia A. Ganz, Judy Garber, José A. García-Sáenz, Simon A. Gayther, Graham G. Giles, Andrew K. Godwin, Mark S. Goldberg, David E. Goldgar, Ellen L. Goode, Marc T. Goodman, Gary Goodman, Kjell Grankvist, Mark H. Greene, Henrik Gronberg, Jacek Gronwald, Pascal Guénel, Niclas Håkansson, Per Hall, Ute Hamann, Freddie C. Hamdy, Robert J. Hamilton, Jochen Hampe, Aage Haugen, Florian Heitz, Rolando Herrero, Peter Hillemanns, Michael Hoffmeister, Estrid Høgdall, Yun-Chul Hong, John L. Hopper, Richard Houlston, Peter J. Hulick, David J. Hunter, David G. Huntsman, Gregory Idos, Evgeny N. Imyanitov, Sue Ann Ingles, Claudine Isaacs, Anna Jakubowska, Paul James, Mark A. Jenkins, Mattias Johansson, Mikael Johansson, Esther M. John, Amit D. Joshi, Radka Kaneva, Beth Y. Karlan, Linda E. Kelemen, Tabea Kühl, Kay-Tee Khaw, Elza Khusnutdinova, Adam S. Kibel, Lambertus A. Kiemeney, Jeri Kim, Susanne K. Kjaer, Julia A. Knight, Manolis Kogevinas, Zsofia Kote-Jarai, Stella Koutros, Vessela N. Kristensen, Jolanta Kupryjanczyk, Martin Lacko, Stephan Lam, Diether Lambrechts, Maria Teresa Landi, Philip Lazarus, Nhu D. Le, Eunjung Lee, Flavio Lejbkowicz, Heinz-Josef Lenz, Goska Leslie, Davor Lessel, Jenny Lester, Douglas A. Levine, Li Li, Christopher I. Li, Annika Lindblom, Noralane M. Lindor, Geoffrey Liu, Fotios Loupakis, Jan Lubiński, Lovise Maehle, Christiane Maier, Arto Mannermaa, Loic Le Marchand, Sara Margolin, Taymaa May, Lesley McGuffog, Alfons Meindl, Pooja Middha, Austin Miller, Roger L. Milne, Robert J. MacInnis, Francesmary Modugno, Marco Montagna, Victor Moreno, Kirsten B. Moysich, Lorelei Mucci, Kenneth Muir, Anna Marie Mulligan, Katherine L. Nathanson, David E. Neal, Andrew R. Ness, Susan L. Neuhausen, Heli Nevanlinna, Polly A. Newcomb, Lisa F. Newcomb, Finn Cilius Nielsen, Liene Nikitina-Zake, Børge G. Nordestgaard, Robert L. Nussbaum, Kenneth Offit, Edith Olah, Ali Amin Al Olama, Olufunmilayo I. Olopade, Andrew F. Olshan, Håkan Olsson, Ana Osorio, Hardev Pandha, Jong Y. Park, Nora Pashayan, Michael T. Parsons, Tanja Pejovic, Kathryn L. Penney, Wilbert H M. Peters, Catherine M. Phelan, Amanda I. Phipps, Dijana Plaseska-Karanfilska, Miranda Pring, Darya Prokofyeva, Paolo Radice, Kari Stefansson, Susan J. Ramus, Leon Raskin, Gad Rennert, Hedy S. Rennert, Elizabeth J. van Rensburg, Marjorie J. Riggan, Harvey A. Risch, Angela Risch, Monique J. Roobol, Barry S. Rosenstein, Mary Anne Rossing, Kim De Ruyck, Emmanouil Saloustros, Dale P. Sandler, Elinor J. Sawyer, Matthew B. Schabath, Johanna Schleutker, Marjanka K. Schmidt, V. Wendy Setiawan, Hongbing Shen, Erin M. Siegel, Weiva Sieh, Christian F. Singer, Martha L. Slattery, Karina Dalsgaard Sorensen, Melissa C. Southey, Amanda B. Spurdle, Janet L. Stanford, Victoria L. Stevens, Sebastian Stintzing, Jennifer Stone, Karin Sundfeldt, Rebecca Sutphen, Anthony J. Swerdlow, Eloiza H. Tajara, Catherine M. Tangen, Adonina Tardon, Jack A. Taylor, M. Dawn Teare, Manuel R. Teixeira, Mary Beth Terry, Kathryn L. Terry, Stephen N. Thibodeau, Mads Thomassen, Line Bjørge, Marc Tischkowitz, Amanda E. Toland, Diana Torres, Paul A. Townsend, Ruth C. Travis, Nadine Tung, Shelley S. Tworoger, Cornelia M. Ulrich, Nawaid Usmani, Celine M. Vachon, Els Van Nieuwenhuysen, Ana Vega, Miguel Elías Aguado-Barrera, Qin Wang, Penelope M. Webb, Clarice R. Weinberg, Stephanie Weinstein, Mark C. Weissler, Jeffrey N. Weitzel, Catharine M. L. West, Emily White, Alice S. Whittemore, H-Erich Wichmann, Fredrik Wiklund, Robert Winqvist, Alicja Wolk, Penella Woll, Michael Woods, Anna H. Wu, Xifeng Wu, Drakoulis Yannoukakos, Wei Zheng, Shanbeh Zienolddiny, Argyrios Ziogas, Kristin K. Zorn, Jacqueline M. Lane, Richa Saxena, Duncan Thomas, Rayjean J. Hung, Brenda Diergaarde, James McKay, Ulrike Peters, Li Hsu, Montserrat García-Closas, Rosalind A. Eeles, Georgia Chenevix-Trench, Paul J. Brennan, Christopher A. Haiman, Jacques Simard, Douglas F. Easton, Stephen B. Gruber, Paul D. P. Pharoah, Alkes L. Price, Bogdan Pasaniuc, Christopher I. Amos, Peter Kraft, and Sara Lindström
Subjects: Science
Abstract: Similarities in cancers can be studied to interrogate their etiology. Here, the authors use genome-wide association study summary statistics from six cancer types based on 296,215 cases and 301,319 controls of European ancestry, showing that solid tumours arising from different tissues share a degree of common germline genetic basis.
Published: 2019
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39. Genetic discovery and risk characterization in type 2 diabetes across diverse populations

Author: Linda M. Polfus, Burcu F. Darst, Heather Highland, Xin Sheng, Maggie C.Y. Ng, Jennifer E. Below, Lauren Petty, Stephanie Bien, Xueling Sim, Wei Wang, Pierre Fontanillas, Yesha Patel, Michael Preuss, Claudia Schurmann, Zhaohui Du, Yingchang Lu, Suhn K. Rhie, Joseph M. Mercader, Teresa Tusie-Luna, Clicerio González-Villalpando, Lorena Orozco, Cassandra N. Spracklen, Brian E. Cade, Richard A. Jensen, Meng Sun, Yoonjung Yoonie Joo, Ping An, Lisa R. Yanek, Lawrence F. Bielak, Salman Tajuddin, Aude Nicolas, Guanjie Chen, Laura Raffield, Xiuqing Guo, Wei-Min Chen, Girish N. Nadkarni, Mariaelisa Graff, Ran Tao, James S. Pankow, Martha Daviglus, Qibin Qi, Eric A. Boerwinkle, Simin Liu, Lawrence S. Phillips, Ulrike Peters, Chris Carlson, Lynne R. Wikens, Loic Le Marchand, Kari E. North, Steven Buyske, Charles Kooperberg, Ruth J.F. Loos, Daniel O. Stram, and Christopher A. Haiman
Subjects: Type 2 Diabetes, Genetic Risk Score, Genetics, QH426-470
Abstract: Summary: Genomic discovery and characterization of risk loci for type 2 diabetes (T2D) have been conducted primarily in individuals of European ancestry. We conducted a multiethnic genome-wide association study of T2D among 53,102 cases and 193,679 control subjects from African, Hispanic, Asian, Native Hawaiian, and European population groups in the Population Architecture Genomics and Epidemiology (PAGE) and Diabetes Genetics Replication and Meta-analysis (DIAGRAM) Consortia. In individuals of African ancestry, we discovered a risk variant in the TGFB1 gene (rs11466334, risk allele frequency (RAF) = 6.8%, odds ratio [OR] = 1.27, p = 2.06 × 10−8), which replicated in independent studies of African ancestry (p = 6.26 × 10−23). We identified a multiethnic risk variant in the BACE2 gene (rs13052926, RAF = 14.1%, OR = 1.08, p = 5.75 × 10−9), which also replicated in independent studies (p = 3.45 × 10−4). We also observed a significant difference in the performance of a multiethnic genetic risk score (GRS) across population groups (pheterogeneity = 3.85 × 10−20). Comparing individuals in the top GRS risk category (40%–60%), the OR was highest in Asians (OR = 3.08) and European (OR = 2.94) ancestry populations, followed by Hispanic (OR = 2.39), Native Hawaiian (OR = 2.02), and African ancestry (OR = 1.57) populations. These findings underscore the importance of genetic discovery and risk characterization in diverse populations and the urgent need to further increase representation of non-European ancestry individuals in genetics research to improve genetic-based risk prediction across populations.
Published: 2021
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40. Genome-wide association meta-analysis identifies pleiotropic risk loci for aerodigestive squamous cell cancers.

Author: Corina Lesseur, Aida Ferreiro-Iglesias, James D McKay, Yohan Bossé, Mattias Johansson, Valerie Gaborieau, Maria Teresa Landi, David C Christiani, Neil C Caporaso, Stig E Bojesen, Christopher I Amos, Sanjay Shete, Geoffrey Liu, Gadi Rennert, Demetrius Albanes, Melinda C Aldrich, Adonina Tardon, Chu Chen, Liloglou Triantafillos, John K Field, Marion Dawn Teare, Lambertus A Kiemeney, Brenda Diergaarde, Robert L Ferris, Shanbeh Zienolddiny, Stephen Lam, Andrew F Olshan, Mark C Weissler, Martin Lacko, Angela Risch, Heike Bickeböller, Andy R Ness, Steve Thomas, Loic Le Marchand, Matthew B Schabath, Victor Wünsch-Filho, Eloiza H Tajara, Angeline S Andrew, Gary M Clifford, Philip Lazarus, Kjell Grankvist, Mikael Johansson, Susanne Arnold, Olle Melander, Hans Brunnström, Stefania Boccia, Gabriella Cadoni, Wim Timens, Ma'en Obeidat, Xiangjun Xiao, Richard S Houlston, Rayjean J Hung, and Paul Brennan
Subjects: Genetics, QH426-470
Abstract: Squamous cell carcinomas (SqCC) of the aerodigestive tract have similar etiological risk factors. Although genetic risk variants for individual cancers have been identified, an agnostic, genome-wide search for shared genetic susceptibility has not been performed. To identify novel and pleotropic SqCC risk variants, we performed a meta-analysis of GWAS data on lung SqCC (LuSqCC), oro/pharyngeal SqCC (OSqCC), laryngeal SqCC (LaSqCC) and esophageal SqCC (ESqCC) cancers, totaling 13,887 cases and 61,961 controls of European ancestry. We identified one novel genome-wide significant (Pmeta
Published: 2021
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41. Associations of the gut microbiome with hepatic adiposity in the Multiethnic Cohort Adiposity Phenotype Study

Author: Meredith A. J. Hullar, Isaac C. Jenkins, Timothy W. Randolph, Keith R. Curtis, Kristine R. Monroe, Thomas Ernst, John A. Shepherd, Daniel O. Stram, Iona Cheng, Bruce S. Kristal, Lynne R. Wilkens, Adrian Franke, Loic Le Marchand, Unhee Lim, and Johanna W. Lampe
Subjects: nonalcoholic fatty liver disease (nafld), inflammation, hepatocellular carcinoma, chronic liver disease, ethnic groups, genetics, diabetes, metabolic syndrome, Diseases of the digestive system. Gastroenterology, RC799-869
Abstract: Nonalcoholic fatty liver disease (NAFLD) is a risk factor for liver cancer and prevalence varies by ethnicity. Along with genetic and lifestyle factors, the gut microbiome (GM) may contribute to NAFLD and its progression to advanced liver disease. Our cross-sectional analysis assessed the association of the GM with hepatic adiposity among African American, Japanese American, White, Latino, and Native Hawaiian participants in the Multiethnic Cohort. We used MRI to measure liver fat and determine nonalcoholic fatty liver disease (NAFLD) status (n = 511 cases) in 1,544 participants, aged 60–77 years, with 12–53% overall adiposity (BMI of 17.8–46.2 kg/m2). The GM was measured by 16S rRNA gene sequencing and, on a subset, by metagenomic sequencing. Alpha diversity was lower overall with NAFLD and in certain ethnicities (African Americans, Whites, and Latinos). In models regressing genus on NAFLD status, 62 of 149 genera (40%) exhibited a significant interaction between NAFLD and ethnicity stratified analysis found 69 genera significantly associated with NAFLD in at least one ethnic group. No single genus was significantly associated with NAFLD across all ethnicities. In contrast, the same bacterial metabolic pathways were over-represented in participants with NAFLD regardless of ethnicity. Imputed secondary bile acid and carbohydrate pathways were associated with NAFLD, the latter of which was corroborated by metagenomics, although different genera in different ethnicities were associated with these pathways. Overall, we found that NAFLD was associated with altered bacterial composition and metabolism, and that bacterial endotoxin, assessed by plasma lipopolysaccharide binding protein (LBP), may mediate liver fat-associated systemic inflammation in a manner that seems to vary by ethnicity.
Published: 2021
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42. Hemochromatosis risk genotype is not associated with colorectal cancer or age at its diagnosis

Author: Gail P. Jarvik, Xiaoliang Wang, Pierre Fontanillas, Esther Kim, Sirisak Chanprasert, Adam S. Gordon, Lisa Bastarache, Kris V. Kowdley, Tabitha Harrison, Elisabeth A. Rosenthal, Ian B. Stanaway, Stéphane Bézieau, Stephanie J. Weinstein, Polly A. Newcomb, Graham Casey, Elizabeth A. Platz, Kala Visvanathan, Loic Le Marchand, Cornelia M. Ulrich, Sheetal Hardikar, Christopher I. Li, Franzel J.B. van Duijnhoven, Andrea Gsur, Peter T. Campbell, Victor Moreno, Pavel Vodička, Hermann Brenner, Jenny Chang-Claude, Michael Hoffmeister, Martha L. Slattery, Marc J. Gunter, Elom K. Aglago, Sergi Castellví-Bel, Sun-Seog Kweon, Andrew T. Chan, Li Li, Wei Zheng, D. Timothy Bishop, Graham G. Giles, Gad Rennert, Kenneth Offit, Temitope O. Keku, Michael O. Woods, Jochen Hampe, Bethan Van Guelpen, Steven J. Gallinger, Albert de la Chapelle, Heather Hampel, Sonja I. Berndt, Catherine M. Tangen, Annika Lindblom, Alicja Wolk, Andrea Burnett-Hartman, Anna H. Wu, Emily White, Stephen B. Gruber, Mark A. Jenkins, Joanna Mountain, Ulrike Peters, and David R. Crosslin
Subjects: iron, ferritin, population screening, age of onset, colon cancer, genetic, Genetics, QH426-470
Abstract: Summary: Homozygotes for the higher penetrance hemochromatosis risk allele, HFE c.845G>A (p.Cys282Tyr, or C282Y), have been reported to be at a 2- to 3-fold increased risk for colorectal cancer (CRC). These results have been reported for small sample size studies with no information about age at diagnosis for CRC. An association with age at diagnosis might alter CRC screening recommendations. We analyzed two large European ancestry datasets to assess the association of HFE genotype with CRC risk and age at CRC diagnosis. The first dataset included 59,733 CRC or advanced adenoma cases and 72,351 controls from a CRC epidemiological study consortium. The second dataset included 13,564 self-reported CRC cases and 2,880,218 controls from the personal genetics company, 23andMe. No association of the common hereditary hemochromatosis (HH) risk genotype and CRC was found in either dataset. The odds ratios (ORs) for the association of CRC and HFE C282Y homozygosity were 1.08 (95% confidence interval [CI], 0.91–1.29; p = 0.4) and 1.01 (95% CI, 0.78–1.31, p = 0.9) in the two cohorts, respectively. Age at CRC diagnosis also did not differ by HFE C282Y/C282Y genotype in either dataset. These results indicate no increased CRC risk in individuals with HH genotypes and suggest that persons with HH risk genotypes can follow population screening recommendations for CRC.
Published: 2020
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43. Minority-centric meta-analyses of blood lipid levels identify novel loci in the Population Architecture using Genomics and Epidemiology (PAGE) study.

Author: Yao Hu, Mariaelisa Graff, Jeffrey Haessler, Steven Buyske, Stephanie A Bien, Ran Tao, Heather M Highland, Katherine K Nishimura, Niha Zubair, Yingchang Lu, Marie Verbanck, Austin T Hilliard, Derek Klarin, Scott M Damrauer, Yuk-Lam Ho, VA Million Veteran Program, Peter W F Wilson, Kyong-Mi Chang, Philip S Tsao, Kelly Cho, Christopher J O'Donnell, Themistocles L Assimes, Lauren E Petty, Jennifer E Below, Ozan Dikilitas, Daniel J Schaid, Matthew L Kosel, Iftikhar J Kullo, Laura J Rasmussen-Torvik, Gail P Jarvik, Qiping Feng, Wei-Qi Wei, Eric B Larson, Frank D Mentch, Berta Almoguera, Patrick M Sleiman, Laura M Raffield, Adolfo Correa, Lisa W Martin, Martha Daviglus, Tara C Matise, Jose Luis Ambite, Christopher S Carlson, Ron Do, Ruth J F Loos, Lynne R Wilkens, Loic Le Marchand, Chris Haiman, Daniel O Stram, Lucia A Hindorff, Kari E North, Charles Kooperberg, Iona Cheng, and Ulrike Peters
Subjects: Genetics, QH426-470
Abstract: Lipid levels are important markers for the development of cardio-metabolic diseases. Although hundreds of associated loci have been identified through genetic association studies, the contribution of genetic factors to variation in lipids is not fully understood, particularly in U.S. minority groups. We performed genome-wide association analyses for four lipid traits in over 45,000 ancestrally diverse participants from the Population Architecture using Genomics and Epidemiology (PAGE) Study, followed by a meta-analysis with several European ancestry studies. We identified nine novel lipid loci, five of which showed evidence of replication in independent studies. Furthermore, we discovered one novel gene in a PrediXcan analysis, minority-specific independent signals at eight previously reported loci, and potential functional variants at two known loci through fine-mapping. Systematic examination of known lipid loci revealed smaller effect estimates in African American and Hispanic ancestry populations than those in Europeans, and better performance of polygenic risk scores based on minority-specific effect estimates. Our findings provide new insight into the genetic architecture of lipid traits and highlight the importance of conducting genetic studies in diverse populations in the era of precision medicine.
Published: 2020
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44. Next steps in studying the human microbiome and health in prospective studies, Bethesda, MD, May 16–17, 2017

Author: Rashmi Sinha, Habibul Ahsan, Martin Blaser, J. Gregory Caporaso, Joseph Russell Carmical, Andrew T. Chan, Anthony Fodor, Mitchell H. Gail, Curtis C. Harris, Kathy Helzlsouer, Curtis Huttenhower, Rob Knight, Heidi H. Kong, Gabriel Y. Lai, Diane Leigh Smith Hutchinson, Loic Le Marchand, Hongzhe Li, Michael J. Orlich, Jianxin Shi, Ann Truelove, Mukesh Verma, Emily Vogtmann, Owen White, Walter Willett, Wei Zheng, Somdat Mahabir, and Christian Abnet
Subjects: Microbiome, Prospective, Cohort, Biospecimen, Cancer, Epidemiology, Microbial ecology, QR100-130
Abstract: Abstract The National Cancer Institute (NCI) sponsored a 2-day workshop, “Next Steps in Studying the Human Microbiome and Health in Prospective Studies,” in Bethesda, Maryland, May 16–17, 2017. The workshop brought together researchers in the field to discuss the challenges of conducting microbiome studies, including study design, collection and processing of samples, bioinformatics and statistical methods, publishing results, and ensuring reproducibility of published results. The presenters emphasized the great potential of microbiome research in understanding the etiology of cancer. This report summarizes the workshop and presents practical suggestions for conducting microbiome studies, from workshop presenters, moderators, and participants.
Published: 2018
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45. Fine mapping of MHC region in lung cancer highlights independent susceptibility loci by ethnicity

Author: Aida Ferreiro-Iglesias, Corina Lesseur, James McKay, Rayjean J. Hung, Younghun Han, Xuchen Zong, David Christiani, Mattias Johansson, Xiangjun Xiao, Yafang Li, David C. Qian, Xuemei Ji, Geoffrey Liu, Neil Caporaso, Ghislaine Scelo, David Zaridze, Anush Mukeriya, Milica Kontic, Simona Ognjanovic, Jolanta Lissowska, Małgorzata Szołkowska, Beata Swiatkowska, Vladimir Janout, Ivana Holcatova, Ciprian Bolca, Milan Savic, Miodrag Ognjanovic, Stig Egil Bojesen, Xifeng Wu, Demetrios Albanes, Melinda C. Aldrich, Adonina Tardon, Ana Fernandez-Somoano, Guillermo Fernandez-Tardon, Loic Le Marchand, Gadi Rennert, Chu Chen, Jennifer Doherty, Gary Goodman, Heike Bickeböller, H-Erich Wichmann, Angela Risch, Albert Rosenberger, Hongbing Shen, Juncheng Dai, John K. Field, Michael Davies, Penella Woll, M. Dawn Teare, Lambertus A. Kiemeney, Erik H. F. M. van der Heijden, Jian-Min Yuan, Yun-Chul Hong, Aage Haugen, Shanbeh Zienolddiny, Stephen Lam, Ming-Sound Tsao, Mikael Johansson, Kjell Grankvist, Matthew B. Schabath, Angeline Andrew, Eric Duell, Olle Melander, Hans Brunnström, Philip Lazarus, Susanne Arnold, Stacey Slone, Jinyoung Byun, Ahsan Kamal, Dakai Zhu, Maria Teresa Landi, Christopher I. Amos, and Paul Brennan
Subjects: Science
Abstract: Abstract Lung cancer has several genetic associations identified within the major histocompatibility complex (MHC); although the basis for these associations remains elusive. Here, we analyze MHC genetic variation among 26,044 lung cancer patients and 20,836 controls densely genotyped across the MHC, using the Illumina Illumina OncoArray or Illumina 660W SNP microarray. We impute sequence variation in classical HLA genes, fine-map MHC associations for lung cancer risk with major histologies and compare results between ethnicities. Independent and novel associations within HLA genes are identified in Europeans including amino acids in the HLA-B*0801 peptide binding groove and an independent HLA-DQB1*06 loci group. In Asians, associations are driven by two independent HLA allele sets that both increase risk in HLA-DQB1*0401 and HLA-DRB1*0701; the latter better represented by the amino acid Ala-104. These results implicate several HLA–tumor peptide interactions as the major MHC factor modulating lung cancer susceptibility.
Published: 2018
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46. Identification of susceptibility pathways for the role of chromosome 15q25.1 in modifying lung cancer risk

Author: Xuemei Ji, Yohan Bossé, Maria Teresa Landi, Jiang Gui, Xiangjun Xiao, David Qian, Philippe Joubert, Maxime Lamontagne, Yafang Li, Ivan Gorlov, Mariella de Biasi, Younghun Han, Olga Gorlova, Rayjean J. Hung, Xifeng Wu, James McKay, Xuchen Zong, Robert Carreras-Torres, David C. Christiani, Neil Caporaso, Mattias Johansson, Geoffrey Liu, Stig E. Bojesen, Loic Le Marchand, Demetrios Albanes, Heike Bickeböller, Melinda C. Aldrich, William S. Bush, Adonina Tardon, Gad Rennert, Chu Chen, M. Dawn Teare, John K. Field, Lambertus A. Kiemeney, Philip Lazarus, Aage Haugen, Stephen Lam, Matthew B. Schabath, Angeline S. Andrew, Hongbing Shen, Yun-Chul Hong, Jian-Min Yuan, Pier A. Bertazzi, Angela C. Pesatori, Yuanqing Ye, Nancy Diao, Li Su, Ruyang Zhang, Yonathan Brhane, Natasha Leighl, Jakob S. Johansen, Anders Mellemgaard, Walid Saliba, Christopher Haiman, Lynne Wilkens, Ana Fernandez-Somoano, Guillermo Fernandez-Tardon, Erik H. F. M. van der Heijden, Jin Hee Kim, Juncheng Dai, Zhibin Hu, Michael P. A. Davies, Michael W. Marcus, Hans Brunnström, Jonas Manjer, Olle Melander, David C. Muller, Kim Overvad, Antonia Trichopoulou, Rosario Tumino, Jennifer Doherty, Gary E. Goodman, Angela Cox, Fiona Taylor, Penella Woll, Irene Brüske, Judith Manz, Thomas Muley, Angela Risch, Albert Rosenberger, Kjell Grankvist, Mikael Johansson, Frances Shepherd, Ming-Sound Tsao, Susanne M. Arnold, Eric B. Haura, Ciprian Bolca, Ivana Holcatova, Vladimir Janout, Milica Kontic, Jolanta Lissowska, Anush Mukeria, Simona Ognjanovic, Tadeusz M. Orlowski, Ghislaine Scelo, Beata Swiatkowska, David Zaridze, Per Bakke, Vidar Skaug, Shanbeh Zienolddiny, Eric J. Duell, Lesley M. Butler, Woon-Puay Koh, Yu-Tang Gao, Richard Houlston, John McLaughlin, Victoria Stevens, David C. Nickle, Ma’en Obeidat, Wim Timens, Bin Zhu, Lei Song, María Soler Artigas, Martin D. Tobin, Louise V. Wain, Fangyi Gu, Jinyoung Byun, Ahsan Kamal, Dakai Zhu, Rachel F. Tyndale, Wei-Qi Wei, Stephen Chanock, Paul Brennan, and Christopher I. Amos
Subjects: Science
Abstract: The chromosome 15q25.1 locus is a leading susceptibility region for lung cancer. Here, the authors interrogate three GWAS cohorts with 42,901 individuals to investigate potential pathological pathways such as gated channel activity and neuroactive ligand receptor interaction in lung cancer etiology.
Published: 2018
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47. Identification of nine new susceptibility loci for endometrial cancer

Author: Tracy A. O’Mara, Dylan M. Glubb, Frederic Amant, Daniela Annibali, Katie Ashton, John Attia, Paul L. Auer, Matthias W. Beckmann, Amanda Black, Manjeet K. Bolla, Hiltrud Brauch, Hermann Brenner, Louise Brinton, Daniel D. Buchanan, Barbara Burwinkel, Jenny Chang-Claude, Stephen J. Chanock, Chu Chen, Maxine M. Chen, Timothy H. T. Cheng, Christine L. Clarke, Mark Clendenning, Linda S. Cook, Fergus J. Couch, Angela Cox, Marta Crous-Bous, Kamila Czene, Felix Day, Joe Dennis, Jeroen Depreeuw, Jennifer Anne Doherty, Thilo Dörk, Sean C. Dowdy, Matthias Dürst, Arif B. Ekici, Peter A. Fasching, Brooke L. Fridley, Christine M. Friedenreich, Lin Fritschi, Jenny Fung, Montserrat García-Closas, Mia M. Gaudet, Graham G. Giles, Ellen L. Goode, Maggie Gorman, Christopher A. Haiman, Per Hall, Susan E. Hankison, Catherine S. Healey, Alexander Hein, Peter Hillemanns, Shirley Hodgson, Erling A. Hoivik, Elizabeth G. Holliday, John L. Hopper, David J. Hunter, Angela Jones, Camilla Krakstad, Vessela N. Kristensen, Diether Lambrechts, Loic Le Marchand, Xiaolin Liang, Annika Lindblom, Jolanta Lissowska, Jirong Long, Lingeng Lu, Anthony M. Magliocco, Lynn Martin, Mark McEvoy, Alfons Meindl, Kyriaki Michailidou, Roger L. Milne, Miriam Mints, Grant W. Montgomery, Rami Nassir, Håkan Olsson, Irene Orlow, Geoffrey Otton, Claire Palles, John R. B. Perry, Julian Peto, Loreall Pooler, Jennifer Prescott, Tony Proietto, Timothy R. Rebbeck, Harvey A. Risch, Peter A. W. Rogers, Matthias Rübner, Ingo Runnebaum, Carlotta Sacerdote, Gloria E. Sarto, Fredrick Schumacher, Rodney J. Scott, V. Wendy Setiawan, Mitul Shah, Xin Sheng, Xiao-Ou Shu, Melissa C. Southey, Anthony J. Swerdlow, Emma Tham, Jone Trovik, Constance Turman, Jonathan P. Tyrer, Celine Vachon, David VanDen Berg, Adriaan Vanderstichele, Zhaoming Wang, Penelope M. Webb, Nicolas Wentzensen, Henrica M. J. Werner, Stacey J. Winham, Alicja Wolk, Lucy Xia, Yong-Bing Xiang, Hannah P. Yang, Herbert Yu, Wei Zheng, Paul D. P. Pharoah, Alison M. Dunning, Peter Kraft, Immaculata De Vivo, Ian Tomlinson, Douglas F. Easton, Amanda B. Spurdle, and Deborah J. Thompson
Subjects: Science
Abstract: Endometrial cancer is the most common invasive gynaecological cancer in developed countries. Here a meta-analysis identifies an additional nine novel endometrial cancer risk loci and eQTL analysis reveals risk variants associate with reduced expression of negative regulators of oncogenic signal transduction proteins.
Published: 2018
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48. Fine-mapping of prostate cancer susceptibility loci in a large meta-analysis identifies candidate causal variants

Author: Tokhir Dadaev, Edward J. Saunders, Paul J. Newcombe, Ezequiel Anokian, Daniel A. Leongamornlert, Mark N. Brook, Clara Cieza-Borrella, Martina Mijuskovic, Sarah Wakerell, Ali Amin Al Olama, Fredrick R. Schumacher, Sonja I. Berndt, Sara Benlloch, Mahbubl Ahmed, Chee Goh, Xin Sheng, Zhuo Zhang, Kenneth Muir, Koveela Govindasami, Artitaya Lophatananon, Victoria L. Stevens, Susan M. Gapstur, Brian D. Carter, Catherine M. Tangen, Phyllis Goodman, Ian M. Thompson, Jyotsna Batra, Suzanne Chambers, Leire Moya, Judith Clements, Lisa Horvath, Wayne Tilley, Gail Risbridger, Henrik Gronberg, Markus Aly, Tobias Nordström, Paul Pharoah, Nora Pashayan, Johanna Schleutker, Teuvo L. J. Tammela, Csilla Sipeky, Anssi Auvinen, Demetrius Albanes, Stephanie Weinstein, Alicja Wolk, Niclas Hakansson, Catharine West, Alison M. Dunning, Neil Burnet, Lorelei Mucci, Edward Giovannucci, Gerald Andriole, Olivier Cussenot, Géraldine Cancel-Tassin, Stella Koutros, Laura E. Beane Freeman, Karina Dalsgaard Sorensen, Torben Falck Orntoft, Michael Borre, Lovise Maehle, Eli Marie Grindedal, David E. Neal, Jenny L. Donovan, Freddie C. Hamdy, Richard M. Martin, Ruth C. Travis, Tim J. Key, Robert J. Hamilton, Neil E. Fleshner, Antonio Finelli, Sue Ann Ingles, Mariana C. Stern, Barry Rosenstein, Sarah Kerns, Harry Ostrer, Yong-Jie Lu, Hong-Wei Zhang, Ninghan Feng, Xueying Mao, Xin Guo, Guomin Wang, Zan Sun, Graham G. Giles, Melissa C. Southey, Robert J. MacInnis, Liesel M. FitzGerald, Adam S. Kibel, Bettina F. Drake, Ana Vega, Antonio Gómez-Caamaño, Laura Fachal, Robert Szulkin, Martin Eklund, Manolis Kogevinas, Javier Llorca, Gemma Castaño-Vinyals, Kathryn L. Penney, Meir Stampfer, Jong Y. Park, Thomas A. Sellers, Hui-Yi Lin, Janet L. Stanford, Cezary Cybulski, Dominika Wokolorczyk, Jan Lubinski, Elaine A. Ostrander, Milan S. Geybels, Børge G. Nordestgaard, Sune F. Nielsen, Maren Weisher, Rasmus Bisbjerg, Martin Andreas Røder, Peter Iversen, Hermann Brenner, Katarina Cuk, Bernd Holleczek, Christiane Maier, Manuel Luedeke, Thomas Schnoeller, Jeri Kim, Christopher J. Logothetis, Esther M. John, Manuel R. Teixeira, Paula Paulo, Marta Cardoso, Susan L. Neuhausen, Linda Steele, Yuan Chun Ding, Kim De Ruyck, Gert De Meerleer, Piet Ost, Azad Razack, Jasmine Lim, Soo-Hwang Teo, Daniel W. Lin, Lisa F. Newcomb, Davor Lessel, Marija Gamulin, Tomislav Kulis, Radka Kaneva, Nawaid Usmani, Chavdar Slavov, Vanio Mitev, Matthew Parliament, Sandeep Singhal, Frank Claessens, Steven Joniau, Thomas Van den Broeck, Samantha Larkin, Paul A. Townsend, Claire Aukim-Hastie, Manuela Gago-Dominguez, Jose Esteban Castelao, Maria Elena Martinez, Monique J. Roobol, Guido Jenster, Ron H. N. van Schaik, Florence Menegaux, Thérèse Truong, Yves Akoli Koudou, Jianfeng Xu, Kay-Tee Khaw, Lisa Cannon-Albright, Hardev Pandha, Agnieszka Michael, Andrzej Kierzek, Stephen N. Thibodeau, Shannon K. McDonnell, Daniel J. Schaid, Sara Lindstrom, Constance Turman, Jing Ma, David J. Hunter, Elio Riboli, Afshan Siddiq, Federico Canzian, Laurence N. Kolonel, Loic Le Marchand, Robert N. Hoover, Mitchell J. Machiela, Peter Kraft, The PRACTICAL (Prostate Cancer Association Group to Investigate Cancer-Associated Alterations in the Genome) Consortium, Matthew Freedman, Fredrik Wiklund, Stephen Chanock, Brian E. Henderson, Douglas F. Easton, Christopher A. Haiman, Rosalind A. Eeles, David V. Conti, and Zsofia Kote-Jarai
Subjects: Science
Abstract: Prostate cancer (PrCa) involves a large heritable genetic component. Here, the authors perform multivariate fine-mapping of known PrCa GWAS loci, identifying variants enriched for biological function, explaining more familial relative risk, and with potential application in clinical risk profiling.
Published: 2018
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49. Sex and ethnic/racial-specific risk factors for gallbladder disease

Author: Jane C. Figueiredo, Christopher Haiman, Jacqueline Porcel, James Buxbaum, Daniel Stram, Neal Tambe, Wendy Cozen, Lynne Wilkens, Loic Le Marchand, and Veronica Wendy Setiawan
Subjects: Gallbladder, Stones, Cholecystectomy, Ethnicity/race, Diseases of the digestive system. Gastroenterology, RC799-869
Abstract: Abstract Background Gallbladder disease (GBD) is a highly prevalent condition; however, little is known about potential differences in risk factors by sex and ethnicity/race. Our aim was to evaluate dietary, reproductive and obesity-related factors and GBD in multiethnic populations. Methods We performed a prospective analysis from the Multiethnic Cohort study who self-identified as non-Hispanic White (n = 32,103), African American (n = 30,209), Japanese (n = 35,987), Native Hawaiian (n = 6942) and Latino (n = 39,168). GBD cases were identified using Medicare and California hospital discharge files (1993–2012) and self-completed questionnaires. We used exposure information on the baseline questionnaire to identify exposures of interest. Associations were estimated by hazard ratios and 95% confidence intervals using Cox models adjusted for confounders. Result After a median 10.7 years of follow-up, there were 13,437 GBD cases. BMI over 25 kg/m2, diabetes, past and current smoking, red meat consumption, saturated fat and cholesterol were significant risk factors across ethnic/racial populations (p-trends
Published: 2017
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50. Author Correction: A case-only study to identify genetic modifiers of breast cancer risk for BRCA1/BRCA2 mutation carriers

Author: Juliette Coignard, Michael Lush, Jonathan Beesley, Tracy A. O’Mara, Joe Dennis, Jonathan P. Tyrer, Daniel R. Barnes, Lesley McGuffog, Goska Leslie, Manjeet K. Bolla, Muriel A. Adank, Simona Agata, Thomas Ahearn, Kristiina Aittomäki, Irene L. Andrulis, Hoda Anton-Culver, Volker Arndt, Norbert Arnold, Kristan J. Aronson, Banu K. Arun, Annelie Augustinsson, Jacopo Azzollini, Daniel Barrowdale, Caroline Baynes, Heko Becher, Marina Bermisheva, Leslie Bernstein, Katarzyna Białkowska, Carl Blomqvist, Stig E. Bojesen, Bernardo Bonanni, Ake Borg, Hiltrud Brauch, Hermann Brenner, Barbara Burwinkel, Saundra S. Buys, Trinidad Caldés, Maria A. Caligo, Daniele Campa, Brian D. Carter, Jose E. Castelao, Jenny Chang-Claude, Stephen J. Chanock, Wendy K. Chung, Kathleen B. M. Claes, Christine L. Clarke, GEMO Study Collaborators, EMBRACE Collaborators, J. Margriet Collée, Don M. Conroy, Kamila Czene, Mary B. Daly, Peter Devilee, Orland Diez, Yuan Chun Ding, Susan M. Domchek, Thilo Dörk, Isabel dos-Santos-Silva, Alison M. Dunning, Miriam Dwek, Diana M. Eccles, A. Heather Eliassen, Christoph Engel, Mikael Eriksson, D. Gareth Evans, Peter A. Fasching, Henrik Flyger, Florentia Fostira, Eitan Friedman, Lin Fritschi, Debra Frost, Manuela Gago-Dominguez, Susan M. Gapstur, Judy Garber, Vanesa Garcia-Barberan, Montserrat García-Closas, José A. García-Sáenz, Mia M. Gaudet, Simon A. Gayther, Andrea Gehrig, Vassilios Georgoulias, Graham G. Giles, Andrew K. Godwin, Mark S. Goldberg, David E. Goldgar, Anna González-Neira, Mark H. Greene, Pascal Guénel, Lothar Haeberle, Eric Hahnen, Christopher A. Haiman, Niclas Håkansson, Per Hall, Ute Hamann, Patricia A. Harrington, Steven N. Hart, Wei He, Frans B. L. Hogervorst, Antoinette Hollestelle, John L. Hopper, Darling J. Horcasitas, Peter J. Hulick, David J. Hunter, Evgeny N. Imyanitov, KConFab Investigators, HEBON Investigators, ABCTB Investigators, Agnes Jager, Anna Jakubowska, Paul A. James, Uffe Birk Jensen, Esther M. John, Michael E. Jones, Rudolf Kaaks, Pooja Middha Kapoor, Beth Y. Karlan, Renske Keeman, Elza Khusnutdinova, Johanna I. Kiiski, Yon-Dschun Ko, Veli-Matti Kosma, Peter Kraft, Allison W. Kurian, Yael Laitman, Diether Lambrechts, Loic Le Marchand, Jenny Lester, Fabienne Lesueur, Tricia Lindstrom, Adria Lopez-Fernández, Jennifer T. Loud, Craig Luccarini, Arto Mannermaa, Siranoush Manoukian, Sara Margolin, John W. M. Martens, Noura Mebirouk, Alfons Meindl, Austin Miller, Roger L. Milne, Marco Montagna, Katherine L. Nathanson, Susan L. Neuhausen, Heli Nevanlinna, Finn C. Nielsen, Katie M. O’Brien, Olufunmilayo I. Olopade, Janet E. Olson, Håkan Olsson, Ana Osorio, Laura Ottini, Tjoung-Won Park-Simon, Michael T. Parsons, Inge Sokilde Pedersen, Beth Peshkin, Paolo Peterlongo, Julian Peto, Paul D. P. Pharoah, Kelly-Anne Phillips, Eric C. Polley, Bruce Poppe, Nadege Presneau, Miquel Angel Pujana, Kevin Punie, Paolo Radice, Johanna Rantala, Muhammad U. Rashid, Gad Rennert, Hedy S. Rennert, Mark Robson, Atocha Romero, Maria Rossing, Emmanouil Saloustros, Dale P. Sandler, Regina Santella, Maren T. Scheuner, Marjanka K. Schmidt, Gunnar Schmidt, Christopher Scott, Priyanka Sharma, Penny Soucy, Melissa C. Southey, John J. Spinelli, Zoe Steinsnyder, Jennifer Stone, Dominique Stoppa-Lyonnet, Anthony Swerdlow, Rulla M. Tamimi, William J. Tapper, Jack A. Taylor, Mary Beth Terry, Alex Teulé, Darcy L. Thull, Marc Tischkowitz, Amanda E. Toland, Diana Torres, Alison H. Trainer, Thérèse Truong, Nadine Tung, Celine M. Vachon, Ana Vega, Joseph Vijai, Qin Wang, Barbara Wappenschmidt, Clarice R. Weinberg, Jeffrey N. Weitzel, Camilla Wendt, Alicja Wolk, Siddhartha Yadav, Xiaohong R. Yang, Drakoulis Yannoukakos, Wei Zheng, Argyrios Ziogas, Kristin K. Zorn, Sue K. Park, Mads Thomassen, Kenneth Offit, Rita K. Schmutzler, Fergus J. Couch, Jacques Simard, Georgia Chenevix-Trench, Douglas F. Easton, Nadine Andrieu, and Antonis C. Antoniou
Subjects: Science
Abstract: A Correction to this paper has been published: https://doi.org/10.1038/s41467-021-23162-4
Published: 2021
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