In 2022, about 19,880 women will be newly diagnosed with ovarian cancer (OC), out of which around 12,180 will die. Epithelial Ovarian Cancer (EOC) represents approximately 95% of all OC and is the fifth leading cause of cancer-related deaths in women (deadliest among all gynecological malignancies). Standard treatment for EOC includes surgery, platinum-based chemotherapy, and radiation therapy. Despite these advancements (more than 90% of patients relapse), not all racial and ethnic groups have benefited equally. For instance, the five-year survival rate for OC grew from 33% to 48% among non-Hispanic White women but declined from 44% to 41% among African American (AA) women. The higher tendency to develop chemoresistance in AA women further contributes to their worst survival. No precise mechanisms that contribute to OC racial health disparity have been explained. We aim to delineate the genetic and molecular mechanisms responsible for driving aggressive tumor growth in AA women that disproportionately affect outcomes. This would aid in developing precision therapeutics and eliminate racial disparity in OC outcomes. Analysis of the TCGA data for OC revealed that the Lymphoblastic Leukemia-Derived Sequence 1 (LYL1) gene is one of the frequently amplified genes in OC. About 12% of all the OC shows LYL1 gene amplification. Interestingly, analysis based on ethnicity revealed a remarkable 36% of LYL1 amplification in AA EOC patients, which is one of the top genes after MYC. Importantly, EOC patients with high levels of LYL1 expression (n=202) had a lower survival rate (p=0.003) than those with low levels of LYL1 expression (n=1640). To further confirm the oncogenic functions of LYL1, we analyzed LYL1 expression in EOC cell lines compared to normal fallopian tube epithelial cells (FTECs) and its contribution to OC cell growth and metastatic potential. As expected, LYL1 is upregulated in most of the EOC cell lines compared to normal FTECs, and siRNA-mediated downregulation of LYL1 in EOC cell lines decreased their clonogenic, migration and invasion potential. Conversely, ectopic expression of LYL1 in an EOC cell line expressing low or undetectable levels of LYL1 exhibited increased potential for migration, invasion, and ability to form tumor spheroids. To validate these in vitro studies, we implanted the OVCAR8 cell xenografts transuded with lentivirus-mediated non-targeting shRNAs or shLYL1 into immunocompromised mice. Consistent with the in vitro data, LYL1 expressing OVCAR8 cell xenograft tumors grew aggressively with widespread metastasis in the peritoneum and distant organs. In contrast, LYL1 knockdown tumor xenografts grew slow and showed decreased metastasis. Together, our results show that upregulated or amplified LYL1 in EOC promotes aggressive tumor growth and may contribute to racial disparity in EOC, as this gene is amplified in over 36% of AA OC patients compared to 12% of White patients. Additionally, our studies suggest that LYL1 could be a poor prognostic marker for OC and racial disparities in OC outcomes.
Citation Format: Naresh Sah, Swetha Peddibhotla, Bayley Richardson, Pamela Luna, Neel A. Bansal, Chinnadurai Mani, Mark Reedy, Komaraiah Palle. Oncogenic role for upregulated lymphoblastic leukemia derived sequence-1 in the progression of ovarian cancer and its metastasis [abstract]. In: Proceedings of the 15th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2022 Sep 16-19; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2022;31(1 Suppl):Abstract nr A084.