mutations and deletions define a distinct subtype of cervical adenocarcinoma.

Between 10 and 20% of cervical cancers are adenocarcinomas with poorer five-year survival and higher recurrence. To identify somatic alterations driving cervical cancer, we performed whole-exome sequencing of 308 subjects with invasive disease from Guatemala and Venezuela. Consistent with other studies, there is a higher rate of mutations in adenocarcinomas versus squamous cell carcinomas (SCC), especially in HPV-negative tumors. We identified a higher rate of mutations and deletions (23%) in the tumor suppressor gene in adenocarcinomas versus SCC. This result was confirmed in the AACR Project Genie and Caris cohorts. Whole-genome sequencing and SNP-array data identified significant numbers of focal deletions on chr19p that disrupt , undetected by exome sequencing. In one tumor, HPV integration disrupts . Chr19p is commonly deleted in cervical cancer, and we document a high rate of independent inversions, chromosomal translocations, and breakage-fusion-bridge events that provide the second hit to . Significantly, alterations are associated with a younger age of onset and poorer overall survival and survival on immunotherapy. Apart from , mutations and amplification are prevalent cervical cancer drivers. mutations and deletions co-occur significantly with YAP1 amplifications, suggesting an interaction between these pathways. In contrast, STK alterations are mutually exclusive to mutation, suggesting redundancy. Cervical adenocarcinomas exhibit significantly lower (PD-L1) expression and a poorer response to immune checkpoint inhibitors (ICIs). mutations are associated with poor responses to ICI in other cancers, and elucidating the role of STK11 in cervical cancer may improve targeted and immunotherapies.