<i>STK11</i> 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 <i>TP53</i> 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 <i>STK11</i> 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 <i>STK11</i>, undetected by exome sequencing. In one tumor, HPV integration disrupts <i>STK11</i>. 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 <i>STK11</i>. Significantly, <i>STK11</i> alterations are associated with a younger age of onset and poorer overall survival and survival on immunotherapy. Apart from <i>STK11</i>, <i>PIK3CA</i> mutations and <i>YAP1</i> amplification are prevalent cervical cancer drivers. <i>STK11</i> mutations and deletions co-occur significantly with YAP1 amplifications, suggesting an interaction between these pathways. In contrast, STK<i>11</i> alterations are mutually exclusive to <i>PIK3CA</i> mutation, suggesting redundancy. Cervical adenocarcinomas exhibit significantly lower <i>CD274</i> (PD-L1) expression and a poorer response to immune checkpoint inhibitors (ICIs). <i>STK11</i> 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.