Clonal origin and early lineage divergence in adenosquamous carcinoma

<h2>Summary</h2> Cancers of distinct histological subtypes are traditionally thought to arise from different cells of origin. However, alternative models propose that multipotent epithelial progenitors or late-stage transdifferentiation events may give rise to diverse tumor lineages, leaving the pathogenesis of adenosquamous carcinomas unresolved. Given the universal involvement of high-risk human papillomavirus in cervical carcinogenesis, cervical adenosquamous carcinoma offers a unique model to investigate tumor lineage relationships within a shared etiologic context. Here, we integrated histopathological, virological, and genomic analyses of microdissected glandular and squamous components from mixed tumors. Strikingly, both malignant elements displayed identical virological features and shared somatic alterations. Following early lineage separation, the two distinct (pre)cancerous entities evolved independently, exhibiting no component-specific mutational signatures. Taken together, these findings demonstrate that glandular and squamous populations from adenosquamous carcinomas follow independent evolutionary trajectories from a single progenitor cell, providing robust validation in human cancers of the concept of early clonal divergence.