Abstract A085: Long-read whole genome sequencing identifies STK11 and YAP1 genes as novel biomarkers for treating invasive cervical cancer

Abstract Purpose of the study: Invasive cervical cancer (ICC) is the leading cause of cancer-related deaths among women in low-income regions, with approximately 70% of cases caused by high-risk human papillomavirus (HPV) strains—primarily HPV 16 and HPV 18. HPV infection triggers the production of viral oncoproteins E6 and E7, which interfere with the tumor suppressor proteins p53 and pRb, respectively, leading to disrupted cell cycle control and uncontrolled cellular proliferation. Moreover, only a few targeted therapies are approved for treatment. Methods: To address this gap, we conducted exome sequencing on 400 ICC fresh frozen samples from Guatemala, the country with one of the highest incidences of cervical cancer globally. We also performed long-read whole genome sequencing (WGS) on 29 cervical cancer cell lines with a coverage depth ranging from 50 to 100x. Additionally, ICC data from public database like TCGA was included in the analysis. Results: Our lab previously identified that YAP1 oncogene amplification (11%) is associated with earlier diagnosis (12 years earlier on average), poorer survival, and a novel aggressive cervical cancer subtype, more prevalent in minority populations. Treatment with the PIK3CA inhibitor Alpelisib reduced proliferation in YAP1 amplified cervical cancer cell lines, like CaSki, SNU1000, SNU1299, QG-U, C4I and CERV-215 but had no effect on PIK3CA wildtype cells. We also observed that STK11, a tumor suppressor gene, is frequently altered in ICC. Exome sequencing data from Guatemala revealed that 32% of tumors (25% in adenocarcinoma (ASC) and 7% in squamous cell carcinoma (SCC)) have STK11 alterations, consistent with our WGS data showing alterations in 35% of cervical cancer cell lines. These mutations are associated with a 10-year earlier age of diagnosis in minority populations. Furthermore, we noticed that STK11 and YAP1 are both functionally involved in the same Hippo signaling pathway. Interestingly, we found in TCGA that 24% of STK11 wild-type cases have YAP1 amplifications while only 8% of STK11 altered cases have YAP1 amplification (p=0.009), exhibiting a co-occurrence of STK11 alterations with YAP1 amplification. Conclusion & Prospects: We propose a model that HPV E7 oncoprotein and STK11 alterations activate YAP1, promoting oncogenesis. Therefore, co-occurrence of STK11 alterations and HPV infection may synergize to promote more aggressive cancers through hyper-activation of YAP1. Presently, we are validating our observations in highly expressed STK11 cervical cancer cell lines (direct RNA sequencing data) through siRNA transfection and protein expression. This suggests that evaluating YAP1 expression in STK11-deleted cell lines could uncover additional opportunities for targeted therapies and screening invasive cervical cancer cases for STK11 and YAP1 gene alterations may help identify women who are more likely to respond favorably to targeted therapies. Citation Format: Sonam Tulsyan, Emma Robinson, Hong Lou, Wen Luo, Yi Xie, Qian Yang, Isabele Rodriguez, Eduardo Gharzouzi, Enrique Alvirez, Michael Dean. Long-read whole genome sequencing identifies STK11 and YAP1 genes as novel biomarkers for treating invasive cervical cancer [abstract]. In: Proceedings of the 18th AACR Conference on the Science of Cancer Health Disparities; 2025 Sep 18-21; Baltimore, MD. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2025;34(9 Suppl):Abstract nr A085.