Whole genome sequencing of endometrial cancer identifies novel subgroups, drivers, and actionable alterations

作者：Sebastian Meyer, Ben Kinnersley, Katarzyna Kedzierska, Ignacio Soriano, Eszter Lakatos, Claudia Arnedo-Pac, Richard Culliford, Avraam Tapinos, Laura Knight, Yannick Comoglio, Anna Frangou, Alex Cornish, Aliah Hawari, Daniel Chubb, Amit Sud, Boris Noyvert, S. Thorn, Helen White, Alona Sosinsky, Ahmed A. Ahmed, James D. Brenton, Núria López-Bigas, Andrea Sottoriva, Tjalling Bosse, Emma J. Davidson, Richard Edmondson, Trevor Graham, Ian Tomlinson, Richard S. Houlston, Andreas Gruber, David C. Wedge, David N. Church · 发表于：bioRxiv (Cold Spring Harbor Laboratory) · 年份：2026 · DOI：10.64898/2026.06.15.730391 · 研究领域：Endometrial and Cervical Cancer Treatments、Genetic factors in colorectal cancer、Cancer Genomics and Diagnostics

ABSTRACT Endometrial cancer (EC) is the most common gynaecological malignancy in high income countries, and is increasing in incidence. While molecular stratification has improved its management, precision care is hampered by incomplete characterization of the EC genome. We address this by analysis of whole genome sequencing (WGS) of 665 ECs generated by the UK Genomics England 100,000 Genome Project (100kGP). 5% of cases were associated with germline pathogenic variants in cancer genes, including BRCA1 which we confirmed predisposes to EC. We identified 107 putative coding driver genes, 35% of which had no prior established role in EC. Novel structural variants included gains of MYCN and loss of its negative regulator NEDD4.1 which were significantly mutually exclusive in copy number (CN) high tumours. Immunogenomic analysis confirmed selection for driver alterations of low immunogenicity based on patient HLA haplotype, and pervasive immune escape through multiple mechanisms. Unsupervised clustering of mutational signatures and genomic alterations identified known and novel molecular subgroups, including a CN-high subset with mutational signatures of homologous recombination deficiency (HRD) and favourable outcome. Independent prognostic value of single nucleotide variant (SNV) burden, CN burden and multiple coding drivers, along with the identification of targetable molecular alterations in over one-third of cases, underscores the promise of WGS for precision medicine in EC...