Abstract LB401: The genomic landscape of likely human precancers

Abstract Precancers represent a diverse collection of lesions that occupy an intermediate state between normal tissues and malignant tumors, yet their biological and clinical definition remains unsettled. To provide a genomic foundation for refining this continuum, we analyzed 1,495 precancers across 17 tissue types using uniformly processed whole-genome and whole-exome sequencing data. This pan-tissue resource reveals striking heterogeneity in the mutational and structural features of precancers, ranging from genomically quiet lesions with minimal alterations to highly aberrant genomes resembling those of invasive cancers. Mutational signature analysis identifies 27 single-base substitution signatures, all previously observed in cancer, indicating that the mutational processes active in malignant cancer are often active at the earliest stages of tumorigenesis. Driver-gene analyses revealed 100 unique genes under positive selection, with TP53 and CDKN2A emerging as the most frequently inactivated, often via biallelic “double-hit” events preceding invasion. Comparative analyses with corresponding cancers showed a progressive enrichment of copy-number alterations, driver mutations, and mutational signatures associated with defective DNA repair and exogenous carcinogens. Random-forest models highlight that cancers converge on a state of extensive genomic disruption, irrespective of the particular mutational processes involved, indicating that canonical tissue-specific driver phenotypes emerge from a backdrop of generic accumulation of genomic alterations that distinguish malignant transformation across tissues. Collectively, this unified atlas of human precancers clarifies the genomic transitions from benign to malignant states, and suggests that many canonical “cancer drivers” may act primarily as general fitness-enhancing alterations detectable well before invasion. These findings provide a genomic framework to support emerging efforts toward molecularly informed early detection and precision prevention strategies in oncology. Citation Format: Christopher D. Steele, Yudou He, Scott M. Lippman, Ludmil B. Alexandrov. The genomic landscape of likely human precancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(8_Suppl):Abstract nr LB401.