Polygenic scores for risk of pancreatic ductal adenocarcinoma: evaluation of novel and published models

作者：Samuel O. Antwi, Brandon J. Coombes, Erin E. Carlson, Nicholas B. Larson, Kari G. Rabe, Hunter J. Atkinson, Shounak Majumder, William R. Bamlet, D SCHAID, Jun Zhong, David McKean, Alan A. Arslan, Laura E. Beane Freeman, Paige M. Bracci, Federico Canzian, Thérèse Truong, Josh Atkins, Mengmeng Du, Steven Gallinger, Phyllis J. Goodman, Verena Katzke, Daniele Campa, Charles Kooperberg, Loic Le Marchand, Rachel Ε. Neale, Alpa V. Patel, Jean Wactawski‐Wende, Sandra Perdomo, Xie Shu, Kala Visvanathan, Stephen K. Van Den Eeden, Emily White, Wei Zheng, Demetrius Albanes, Gabriella Andreotti, Paul Brennan, Stephen J. Chanock, Yu Chen, Burcu Darst, Pietro Ferrari, Edward Giovannucci, Michael Goggins, Christopher Haiman, Manal Hassan, Rayjean J. Hung, Jones, Peter Kraft, Núria Malats, Steven Moore, Kimmie Ng, Ulrike Peters, Miquel Porta, Nathaniel Rothman, Maria-José Sánchez, Howard D. Sesso, Debra T. Silverman, Melissa C. Southey, Roger L. Milne, Caroline Y. Um, Herbert Yu, Chen Yuan, Mayo-RGC Project Generation, James R. Cerhan, Fergus J. Couch, Nicholas B. Larson, Eric W. Klee, Zachary S. Fredericksen, Mine Cicek, Janet E. Olson, Lisa K. Colborn, Andrew J. Danielsen, Jonathan J. Harrington, Aris Baras, Gonçalo Abecasis, Adolfo Ferrando, Giovanni Coppola, Andrew Deubler, Luca Lotta, John D. Overton, Jeffrey G. Reid, Alan Shuldiner, Katherine Siminovitch, Jason Portnoy, Marcus B. Jones, Lyndon Mitnaul, Alison Fenney, Jonathan Marchini, Manuel Allen Revez Ferreira, Maya Ghoussaini, Mona Nafde, William Salerno, C Willer, Lourdes Crane, Christina Beechert, Erin Fuller, Laura M. Cremona, Eugene Kalyuskin, Hang Du, Caitlin Forsythe, Zhenhua Gu, Kristy Guevara, Michael Lattari, Alexander Lopez, Kia Manoochehri, Prathyusha Challa, Manasi Pradhan, Raymond Reynoso, Ricardo Schiavo, Maria Sotiropoulos Padilla, Chenggu Wang, Sarah E. Wolf, Manan Goyal, George Mitra, Sanjay Sreeram, Rouel Lanche, Vrushali Mahajan, Sai Lakshmi Vasireddy, Gisu Eom, Krishna Pawan Punuru, Sujit Gokhale, Benjamin Sultan, Pooja Mule, Mudasar Sarwar, Muhammad Aqeel, Xiaodong Bai, Lance Zhang, Sean O’Keeffe, Razvan Panea, Evan Edelstein, Ayesha Rasool, Evan K. Maxwell, Boris Boutkov, Alexander Gorovits, Ju Guan, Lukas Habegger, Alicia Hawes, Olga Krasheninina, Samantha Zarate, Adam J. Mansfield, Joshua Backman, Kathy Burch, Adrián Campos, Liron Ganel, Sheila Gaynor, Benjamin Geraghty, Arkopravo Ghosh, Salvador Romero Martinez, Christopher Gillies, Lauren Gurski, E. Jorgenson, Tyler Joseph, Michael Kessler, Jack Kosmicki, Adam Locke, Priyanka Nakka, Karl Landheer, Olivier Delaneau, Anthony Marcketta, Joelle Mbatchou, Arden Moscati, Anita Pandit, Jonathan Ross, Carlo Sidore, Eli Stahl, Timothy Thornton, Sailaja Vedantam, Rujin Wang, Kuan-Han Wu, Bin Ye, Blair Zhang, Andrey Ziyatdinov, Yuxin Zou, Jingning Zhang, Kyoko Watanabe, Mira Tang, Frank Wendt, Suganthi Balasubramanian, Suying Bao, Kathie Sun, Chuanyi Zhang, Sean Yu, Aaron Zhang, David Corrigan, Dhruv Shidhaye, Chen Wang, Keyrun Adhikari, Alexander Lachmann, Brian Hobbs, Jon Silver, William Palmer, Rita Guerreiro, Amit Joshi, Antoine Baldassari, Sarah Graham, Ernst Mayerhofer, Erola Pairó Castiñeira, Mary Haas, Niek Verweij, George Hindy, Jonas Bovijn, Tanima De, Luanluan Sun, Olukayode Sosina, Arthur Gilly, Peter Dornbos, Juan Rodriguez-Flores, Moeen Riaz, Manav Kapoor, Gannie Tzoneva, Momodou Jallow, Anna Alkelai, Ariane Ayer, Veera Rajagopal, Sahar Gelfman, Vijay Kumar, Jacqueline Otto, Jose Bras, Silvia Álvarez, Jessie Brown, Hossein Khiabanian, Joana Revez, Kimberly Skead, Valentina Zavala, Jae Soon Sul, Lei Chen, Sam Choi, Amy Damask, Nan Lin, Charles Paulding, Sameer Malhotra, Joseph Herman, Michelle G. LeBlanc, Nadia Rana, Jennifer Rico‐Varela, Jaimee Hernandez, Larizbeth Romero, Ashley Paynter, Randi Schwartz, Jody Hankins, Anna Han, Samuel Hart, Ryan Smith, Ann Perez-Beals, Gina Solari, Johannie Rivera-Picart, Michelle Pagan, Sunilbe Siceron, Harvey A. Risch, Brian M. Wolpin, Rachael Z. Stolzenberg‐Solomon, Alison P. Klein, Laufey T. Ámundadóttir, Ann L. Oberg · 发表于：npj Precision Oncology · 年份：2026 · DOI：10.1038/s41698-026-01479-x · 研究领域：Genetic Associations and Epidemiology、Pancreatic and Hepatic Oncology Research、Cholangiocarcinoma and Gallbladder Cancer Studies

Polygenic risk scores (PRSs) may enhance risk stratification for pancreatic ductal adenocarcinoma (PDAC), but existing models vary widely in design, predictive performance, and cross-ancestry transferability. We developed genome-wide PRSs using Bayesian methods (LDpred2 and PRS-CS) and p value thresholding (PRSice-2) and systematically evaluated these alongside 13 published PRSs to identify models with robust predictive performance across ancestries. Using GWAS summary statistics from 7531 cases and 10,631 controls, we derived the PRSs and tested associations in an independent sample of 4508 PDAC cases and 46,189 controls, with adjustment for well-established PDAC risk factors. Among all models, the genome-wide LDpred2-based PRS showed the strongest association with PDAC (OR = 1.57 per standard deviation increase; 95% CI: 1.51-1.62) and significantly improved discrimination beyond established risk factors alone (AUC = 0.74-0.76; p < 0.0001). Importantly, the genome-wide LDpred2 PRS demonstrated consistent associations across African, Admixed American, and European ancestry groups, whereas the best-performing published PRS was associated with PDAC risk only in individuals of European ancestry. These findings support genome-wide PRSs as a promising framework for multi-ancestry risk stratification for PDAC and to inform targeted early detection strategies.