The cellular origins of cervical cancer and the histological differentiation of human papillomavirus (HPV)-infected cells remain unexplained. To gain new insights into the carcinogenesis and histological differentiation of HPV-associated cervical cancer, we focused on cervical cancer with mixed histological types. We conducted genomic and transcriptomic analyses of cervical cancers with mixed histological types. The commonality of the cellular origins of these cancers was inferred using phylogenetic analysis and by assessing the HPV integration sites. Carcinogenesis was estimated by analyzing human gene expression profiles in different histological types. Among 42 cervical cancers with known HPV types, mixed histological types were detected in four cases, and three of them were HPV18-positive. Phylogenetic analysis of these three cases revealed that the different histological types had a common cell of origin. Moreover, the HPV-derived transcriptome and HPV integration sites were common among different histological types, suggesting that HPV integration could occur

Background Small cell carcinoma of the uterine cervix (SCCC) is a rare and highly malignant human papillomavirus (HPV)‐associated cancer in which human genes related to the integration site can serve as a target for precision medicine. The aim of our study was to establish a workflow for precision medicine of HPV‐associated cancer using patient‐derived organoid. Methods Organoid was established from the biopsy of a patient diagnosed with HPV18‐positive SCCC. Therapeutic targets were identified by whole exome sequencing (WES) and RNA‐seq analysis. Drug sensitivity testing was performed using organoids and organoid‐derived mouse xenograft model. Results WES revealed that both the original tumor and organoid had 19 somatic variants in common, including the KRAS p.G12D pathogenic variant. Meanwhile, RNA‐seq revealed that HPV18 was integrated into chromosome 8 at 8q24.21 with increased expression of the proto‐oncogene MYC. Drug sensitivity testing revealed that a KRAS pathway inhibitor exerted strong anti‐cancer effects on the SCCC organoid compared to a MYC inhibitor, which were also confirmed in the xenograft model. Conclusion In this study, we confirmed two strategies for identifying therapeutic targets of HPV‐derived SCCC, WES for identifying pathogenic variants and RNA sequencing for identifying HPV integration sites. Organoid culture is an effective tool for unveiling the oncogenic process of rare tumors and can be a breakthrough for the development of precision medicine for patients with HPV‐positive SCCC.

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Approximately 95% of cervical cancer are caused by human papillomavirus (HPV) infection. Although it is estimated that HPV-associated cervical cancer will decrease with the widespread use of HPV vaccine, it may take time for HPV-associated cervical cancer to be eliminated. For the appropriate management of HPV-associated cervical cancer, it is important to understand the detailed mechanisms of cervical cancer development. First, the cellular origin of most cervical cancers is thought to be cells in the squamocolumnar junction (SCJ) of the uterine cervix. Therefore, it is important to understand the characteristics of SCJ for cervical cancer screening and treatment. Second, cervical cancer is caused by high risk HPV (HR-HPV) infection, however, the manner of progression to cervical cancer differs depending on the type of HR-HPV: HPV16 is characterized by a stepwise carcinogenesis, HPV18 is difficult to detect in precancerous lesions, and HPV52, 58 tends to remain in the state of cervical intraepithelial neoplasia (CIN). Third, in addition to the type of HPV, the involvement of the human immune response is also important in the progression and regression of cervical cancer. In this review, we demonstrate the carcinogenesis mechanism of HPV-associated cervical cancer, management of CIN, and the current treatment of CIN and cervical cancer.

e13510 Background: Although tumor molecular profiling has now become prevalent, next-generation sequencing (NGS)-based molecular profiling with adequate annotation is limited in recurrent endometrial cancers. We investigated the frequency of alterations in cancer-related genes in a Japanese cohort of incurable endometrial cancer patients. Methods: We enrolled 102 endometrial cancer patients, who had discontinued standard therapy, and extracted tumor DNA from their formalin-fixed paraffin-embedded specimens. Oncomine Comprehensive Assay v3 (ThermoFisher), which covers 161 cancer genes, was used as a comprehensive NGS assay. We only defined variants with the annotations “pathogenic” or “likely pathogenic.” Oncogenicity and actionability were defined with the Oncomine Knowledgebase and “Chrovis database” ( https://chrov.is/ ). The protocol was approved by the institutional ethics committee at each institute, and written informed consent was obtained from all patients before enrollment. Results: The ratios of pathogenic mutations in the PI3K-AKT pathway were 34.3%, 15.7%, and 3.9% for PIK3CA, PTEN, and AKT1, while those in the receptor tyrosine kinase-RAS-MAPK pathway were 3.9%, 2.0%, 3.9%, and 1.0% for FGFR2, KRAS, NF1, and BRAF, respectively. The pathogenic mutation ratios of TP53, ATM, CTNNB1, and FBXW7 were 21.6%, 3.9%, 10.8%, and 9.8%, respectively. In addition to 5.9% of MSH2 variants (five patients with 5-20% and one patient with 56% variant allele frequency (VAF)), pathogenic variants of BRCA1 and/or BRCA2 were identified in 7.8% (seven patients with 5-20% and one with 40% VAFs). Three fusion genes were identified in three patients ( TPR- NTRK1, ESR1- CCDC170, and TBL1XR1- PIK3CA). “Actionable” gene variants (applicable for clinical trials or approved drug available in Japan) were identified in 49.0% of patients. Candidate drugs for patients with actionable variants included ROS1/TRK, AKT, immune checkpoint, and PARP inhibitors. Conclusions: Molecular profiling in poor-prognostic endometrial cancer highlighted the significance of DNA-repair related genes ( TP53, ATM, BRCA1, and BRCA2) and Wnt-beta catenin signaling pathway, and the infrequent alterations in PTEN and KRAS genes, although PIK3CA was frequently mutated. Our data suggest that targeting DNA repair pathway (including PARP inhibitors), may be a treatment option in certain endometrial cancer patients. Clinical trial information: UMIN000027294.