Integrative genomic and transcriptomic profiles from a prospective cervical cancer study

Abstract Cervical cancer (CC) is a global public health concern, with frequent relapses and limited therapeutic options for metastatic disease. The RAIDs project, launched by the Curie Institute, aims to improve molecular characterization and risk stratification in CC. High-quality primary frozen tumor samples from 291 (WES), 302 (sWGS), and 270 (RNA-seq) patients enrolled in the Bio-RAIDs European study (NCT02428842) were analyzed alongside clinical data. Frequent alterations included PIK3CA (30%), KMT2D (11%), and KMT2C (11%). Only TERT mutations (13%) were significantly associated with poor progression-free survival (PFS). Targetable mutations in PIK3CA (30%), KRAS (4%), ERBB2 (4%), and FGFR3 fusions (5%), were found in 57% of patients. Transcriptomic analysis identified TERT and the Senescence pathway as significantly linked to PFS and to necrosis. Gene expression deconvolution showed no significant variation across immune populations. Integrative likelihood-based boosting analysis of 234 patients identified GNAQ and THUMPD1 as protective factors for PFS, while necrosis, age >50 years, advanced FIGO stage (III/IV), and HPV-negative status were associated with significantly poorer outcomes. These integrative multi-omics analyses revealed novel prognostic biomarkers in CC and identified over 50 clinically actionable mutations. Transcriptomic profiles were associated with both genetic alterations and histopathological features, suggesting new paths for precision medicine in CC.