Abstract 56: COSMIC: Advancing the cancer genomics knowledgebase of somatic mutations.

Abstract COSMIC (Catalogue Of Somatic Mutations in Cancer) has evolved from an initial catalogue to the world's most comprehensive knowledgebase of somatic variants in cancer, built upon a foundation of continuous, expert curation. COSMIC currently aggregates over 29 million unique somatic variants carefully curated from 1.5 million samples, establishing an essential resource for studying the cancer genome. This rich dataset is the result of extensive, dedicated work, drawing on insights from more than 30,000 scientific publications and major studies. COSMIC is structured into a suite of specialized modules that collectively transform raw genomic variants into biologically and clinically meaningful insight. These include the Cancer Gene Census (CGC), which systematically classifies causal cancer genes; the Cancer Mutation Census (CMC), which distinguishes driver from passenger mutations through computational and evidence-based annotation; Mutational Signatures, which captures genome-wide mutagenic processes; COSMIC 3D, which contextualizes variants within protein structures; and the Actionability and Resistance resources, which map genomic alterations to therapeutic response and resistance mechanisms. Together, these modules provide a framework essential for interpreting somatic variant landscapes in precision oncology. We highlight ongoing research on the next iteration of the Cancer Mutation Census (CMC v2), designed to enhance COSMIC’s ability to extract biologically meaningful signals from large-scale somatic datasets. CMC v2 applies refined background models to identify mutation hotspots at the amino acid level across cancer genes in a pan-cancer context, focusing on positions exhibiting statistically significant enrichment of somatic variants. This approach isolates non-random, spatially coherent clusters of mutations that represent strong candidates for driver activity. Although currently under development, these analyses demonstrate the potential of CMC v2 to provide higher-resolution insights into cancer gene dysregulation and support more nuanced interpretation of tumor evolution. The development of CMC v2 marks a key step in COSMIC’s evolution toward more data-driven, biologically grounded interpretation of cancer variants. By integrating statistical modeling with expert insight, CMC v2 refines our capacity to distinguish meaningful mutational patterns from background noise across diverse tumor contexts. These advances exemplify COSMIC’s ongoing commitment to translating large-scale genomics into actionable biological knowledge. As the knowledgebase continues to expand and engage with the global cancer research community, COSMIC remains an indispensable foundation for understanding cancer gene function, refining biomarker discovery, and supporting precision oncology. Citation Format: Madhumita Madhumita, Madiha Ahmed, Joanna Argasinska, David Armstrong, Nidhi Bindal Dhir, Denise Carvalho-Silva, Lucie Chadelle, Patrick Dao, Stephen Duke, Giovanna Fasanella, Muhammad Fouzan, Abishekraj Gnanasambandam, Avirup Neogi, Susan Haller, Bhavana Harsha, Balazs Hetenyi, Leonie Hodges, Steven Jupe, Rachel Lyne, Thomas Maurel, Karen McLaren, Thomas Mutimer, Sumodh Nair, Hanna Najgebauer, Helder Pedro, Sophie Poole, Amaia Sangrador-Vegas, Zoe Sheard, Manpreet Singh Chawla, Michael Starkey, Rebecca Steele, Sari Ward, Ellen Wiedemann, Jennifer Wilding, Siew Yit Yong, Jon Teague. COSMIC: Advancing the cancer genomics knowledgebase of somatic mutations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 56.