title: Integrated genomic and molecular characterization of cervical cancer.
abstract: Cervical cancer remains one of the leading causes of cancer-related deaths worldwide. Here we report the extensive molecular characterization of 228 primary cervical cancers, one of the largest comprehensive genomic studies of cervical cancer to date. We observed notable APOBEC mutagenesis patterns and identified SHKBP1, ERBB3, CASP8, HLA-A and TGFBR2 as novel significantly mutated genes in cervical cancer. We also discovered amplifications in immune targets CD274 (also known as PD-L1) and PDCD1LG2 (also known as PD-L2), and the BCAR4 long non-coding RNA, which has been associated with response to lapatinib. Integration of human papilloma virus (HPV) was observed in all HPV18-related samples and 76% of HPV16-related samples, and was associated with structural aberrations and increased target-gene expression. We identified a unique set of endometrial-like cervical cancers, comprised predominantly of HPV-negative tumours with relatively high frequencies of KRAS, ARID1A and PTEN mutations. 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.
mesh_terms: D000071479:APOBEC-1 Deaminase / Q000235:genetics; D000230:Adenocarcinoma / Q000235:genetics; D060890:B7-H1 Antigen / Q000235:genetics; D002294:Carcinoma, Squamous Cell / Q000235:genetics; D053181:Caspase 8 / Q000235:genetics; D004268:DNA-Binding Proteins; D005260:Female; D023281:Genomics; D015234:HLA-A Antigens / Q000235:genetics; D052162:Human papillomavirus 16 / Q000235:genetics / Q000302:isolation & purification; D006801:Humans; D007633:Keratins / Q000235:genetics; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D058990:Molecular Targeted Therapy; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics; D051059:PTEN Phosphohydrolase / Q000235:genetics; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D061027:Programmed Cell Death 1 Ligand 2 Protein / Q000235:genetics; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D040901:Proteomics; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics; D062085:RNA, Long Noncoding / Q000235:genetics; D020893:Receptor, ErbB-3 / Q000235:genetics; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D014157:Transcription Factors / Q000235:genetics; D002583:Uterine Cervical Neoplasms / Q000145:classification / Q000188:drug therapy / Q000235:genetics*; D016662:Virus Integration
chemical_list: D000071479:APOBEC-1 Deaminase; D060890:B7-H1 Antigen; D053181:Caspase 8; D004268:DNA-Binding Proteins; D015234:HLA-A Antigens; D007633:Keratins; D020929:Mitogen-Activated Protein Kinase Kinases; D009687:Nuclear Proteins; D051059:PTEN Phosphohydrolase; D019869:Phosphatidylinositol 3-Kinases; D061027:Programmed Cell Death 1 Ligand 2 Protein; D017346:Protein Serine-Threonine Kinases; D016283:Proto-Oncogene Proteins p21(ras); D062085:RNA, Long Noncoding; D020893:Receptor, ErbB-3; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta; D014157:Transcription Factors; C112476:ARID1A protein, human; C553206:BCAR4 non-coding RNA, human; C423236:CD274 protein, human; C117307:KRAS protein, human; C556977:PDCD1LG2 protein, human; C581292:ERBB3 protein, human; C494929:PTEN protein, human; C505530:CASP8 protein, human