This study presents the comprehensive genomic and molecular characterization of 228 primary cervical cancers, the largest such study to date. Key findings include notable APOBEC mutagenesis patterns and the identification of novel significantly mutated genes such as SHKBP1, ERBB3, CASP8, HLA-A, and TGFBR2. Amplifications of immune targets CD274 (PD-L1) and PDCD1LG2 (PD-L2) were observed, as well as the BCAR4 long non-coding RNA, which is associated with response to lapatinib. Integration of human papilloma virus (HPV) was observed in all HPV18-related samples and 76% of HPV16-related samples, associated with structural aberrations and increased target-gene expression. A unique set of endometrial-like cervical cancers, predominantly HPV-negative with high frequencies of KRAS, ARID1A, and PTEN mutations, was identified. Integrative clustering of 178 samples identified keratin-low squamous, keratin-high squamous, and adenocarcinoma-rich subgroups. These molecular analyses reveal new potential therapeutic targets for cervical cancers. Cervical cancer accounts for 528,000 new cases and 266,000 deaths worldwide each year. Ninety-five percent of cases are caused by persistent infections with carcinogenic HPVs. Effective prophylactic vaccines against the most important carcinogenic HPV types are available, but the number of people receiving the vaccine remains low. Although early cervical cancer can be treated with surgery or radiation, metastatic cervical cancer is incurable and new therapeutic approaches are needed. Most HPV infections are cleared within months, but some persist and express viral oncogenes that inactivate p53 and RB, leading to increased genomic instability, accumulation of somatic mutations, and in some cases, integration of HPV into the host genome. The association with cancer risk and histological subtypes varies among carcinogenic HPV types, but the reasons for these differences are poorly understood. The study presents a comprehensive analysis of invasive cervical cancer as part of The Cancer Genome Atlas (TCGA) project, focusing on identifying novel clinical and molecular associations as well as functionally altered signalling pathways that may drive tumorigenesis and serve as prognostic or therapeutic markers. The study identified 14 genes significantly mutated (SMGs) with false-discovery rates (FDR) < 0.1. SHKBP1, ERBB3, CASP8, HLA-A, and TGFBR2 were identified as novel SMGs in cervical cancer. PIK3CA had mostly activating helical-domain E542K and E545K mutations. The underlying nucleotide substitution pattern in the E542K and E545K mutations is associated with mutagenesis by a subclass of APOBEC cyThis study presents the comprehensive genomic and molecular characterization of 228 primary cervical cancers, the largest such study to date. Key findings include notable APOBEC mutagenesis patterns and the identification of novel significantly mutated genes such as SHKBP1, ERBB3, CASP8, HLA-A, and TGFBR2. Amplifications of immune targets CD274 (PD-L1) and PDCD1LG2 (PD-L2) were observed, as well as the BCAR4 long non-coding RNA, which is associated with response to lapatinib. Integration of human papilloma virus (HPV) was observed in all HPV18-related samples and 76% of HPV16-related samples, associated with structural aberrations and increased target-gene expression. A unique set of endometrial-like cervical cancers, predominantly HPV-negative with high frequencies of KRAS, ARID1A, and PTEN mutations, was identified. Integrative clustering of 178 samples identified keratin-low squamous, keratin-high squamous, and adenocarcinoma-rich subgroups. These molecular analyses reveal new potential therapeutic targets for cervical cancers. Cervical cancer accounts for 528,000 new cases and 266,000 deaths worldwide each year. Ninety-five percent of cases are caused by persistent infections with carcinogenic HPVs. Effective prophylactic vaccines against the most important carcinogenic HPV types are available, but the number of people receiving the vaccine remains low. Although early cervical cancer can be treated with surgery or radiation, metastatic cervical cancer is incurable and new therapeutic approaches are needed. Most HPV infections are cleared within months, but some persist and express viral oncogenes that inactivate p53 and RB, leading to increased genomic instability, accumulation of somatic mutations, and in some cases, integration of HPV into the host genome. The association with cancer risk and histological subtypes varies among carcinogenic HPV types, but the reasons for these differences are poorly understood. The study presents a comprehensive analysis of invasive cervical cancer as part of The Cancer Genome Atlas (TCGA) project, focusing on identifying novel clinical and molecular associations as well as functionally altered signalling pathways that may drive tumorigenesis and serve as prognostic or therapeutic markers. The study identified 14 genes significantly mutated (SMGs) with false-discovery rates (FDR) < 0.1. SHKBP1, ERBB3, CASP8, HLA-A, and TGFBR2 were identified as novel SMGs in cervical cancer. PIK3CA had mostly activating helical-domain E542K and E545K mutations. The underlying nucleotide substitution pattern in the E542K and E545K mutations is associated with mutagenesis by a subclass of APOBEC cy