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

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.

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Journal
Cancer Cell
Published
2026-03-01
DOI
https://doi.org/10.1016/j.ccell.2026.03.003
Primary Topic
Cancer Genomics and Diagnostics
Type
article
Field-Weighted Citation Impact
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article

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

Aijazuddin Syed, Debyani Chakravarty, Ritika Kundra, Jun Hee Woo et al.
Cancer Cell
Cancer Genomics and Diagnostics
article

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

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

Abstract

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.

Cancer Cell
Memorial Sloan Kettering Cancer Center (US), University of Management and Technology (US), Technology Management Company (United States) (US), Cancer Research And Biostatistics (US), Center for Orthopaedics (US), Molecular Oncology (United States) (US), Organogenesis (United States) (US)
Good health and well-being
Openalex Percentile: Top 7%
Cancer Genomics and Diagnostics
DOIOpen Access PDFOpenAlex
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