Cancer type-specific variation in patterns of driver alterations across 50,000 tumors

作者：Chaitanya Bandlamudi, Daniel M. Muldoon, Ino de Bruijn, Mingxuan Zhang, Michael V. Gormally, Emily C. Harrold, Subhiksha Nandakumar, Shaleigh Smith, Mark Jeng, Sydney Woods, Kanika Arora, Walid K. Chatila, Bastien Nguyen, Henry Walch, Jun Hee Woo, Craig M. Bielski, Christopher Fong, Thinh N. Tran, Gaofei Zhao, Miika Mehine, Maria A. Perry, Sam E. Tischfield, Allison L. Richards, Suraj Rajendran, Hongxin Zhang, Christoph Kreitzer, Ronak Shah, Risha Huq, Jesse Galle, Tina Alano, Ramyasree Madupuri, Ritika Kundra, Justin Jee, Karl Pichotta, Michele Waters, Richard A. Hickman, Josephine K. Dermawan, Jie-Fu Chen, Anton Safonov, Konrad H. Stopsack, Ritesh R. Kotecha, Hira Rizvi, Claire F. Friedman, Pedram Razavi, Ezra Y. Rosen, Yonina R. Murciano-Goroff, Luc G.T. Morris, James A. Fagin, Ingo K. Mellinghoff, Ping Chi, Neerav Shukla, Adam J. Schoenfeld, Gregory J. Riely, Charles M. Rudin, Alexander D. Drilon, Jake June-Koo Lee, Hikmat Al-Ahmadie, Gopa Iyer, Anna M. Varghese, Eileen M. O'Reilly, Zsofia K. Stadler, Mark E. Robson, Ed Reznik, JianJiong Gao, Diana Mandelker, Irina Ostrovnaya, Satshil Rana, Gowtham Jayakumaran, Anita S. Bowman, Abhinita Mohanty, Anoop Rema Balakrishnan, Aijazuddin Syed, Ryan Ptashkin, Jacklyn Casanova, Debyani Chakravarty, Ryma Benayed, Maria E. Arcila, Sarat Chandarlapaty, Helena A. Yu, Neal Rosen, Mark T.A. Donoghue, Christopher A. Klebanoff, Rona Yaeger, A. Rose Brannon, Ahmet Zehir, Marc Ladanyi, Nikolaus Schultz, David B. Solit, Michael F. Berger · 发表于：Cancer Cell · 年份：2026 · DOI：10.1016/j.ccell.2026.03.003 · 被引用次数：4 · 研究领域：Cancer Genomics and Diagnostics、Mathematical Biology Tumor Growth、Multiple and Secondary Primary Cancers

The oncogenic impact of somatic driver alterations is shaped by tissue context. Classifying alterations by cancer type and evaluating their context-specific properties requires large cohorts of genomically profiled and clinically annotated tumors. Here, we define cancer type-specific patterns of driver alterations, including 164 newly identified hotspots, in 54,331 tumors from 48,179 patients spanning 448 histological cancer subtypes. One-third of all drivers arose in non-canonical contexts and exhibited distinct features, including increased subclonality, later emergence, and divergent biological properties. Within cancer types, gene fusions and other distinct patterns of co-occurring drivers are indicative of earlier age of disease onset. We also identify ancestry-specific differences in human leukocyte antigen (HLA)-restricted driver neoantigens affecting T cell receptor therapy eligibility, and demonstrate cancer-type-specific patterns of intrinsic resistance via somatic HLA loss. Our findings highlight that functional roles of driver alterations depend on the cancer types and clinical contexts in which they arise.