Abstract 5247: Overexpression of methylenetetrahydrofolate dehydrogenase 1 like (MTHFD1L) in bladder cancer: A potential therapeutic target
Authors: Marie-Lisa Eich, Maria D. Rodriguez Pena, Darshan S. Chandrashekar, Jennifer B. Gordetsky, George J. Netto, Sooryanarayana Varambally
Journal: Cancer Research (2019)

Abstract Introduction: Methylenetetrahydrofolate dehydrogenase 1 (MTHFD1L) is a mitochondrial enzyme involved in the folate cycle by catalyzing the reaction of formyl-tetrahydrofolate to format and tetrahydrofolate (THF). THF is crucial for de novo purine and thymidylate synthesis and is also involved in the regeneration of methionine. Cancer cells rely on purines derived from the de novo pathway for the nucleotides whereas normal cells favor the salvage pathway. Thus, MTHFD1L could be a valuable therapeutic target for anticancer drug design. This study aimed to examine MTHFD1L expression in bladder cancer (BLCA). Material and Methods: Applying the publicly available cancer transcriptome database UALCAN, we searched for overexpressed genes in bladder cancer associated with survival probability. These in silico analyses indicated a high expression of MTHFD1L in bladder cancer. Furthermore, MTHFD1L expression was analyzed in different molecular subtypes, stage and race groups. Survival probability in MTHFD1L low-and high-expressing tumors was also assessed using UALCAN. Additionally, by searching the publicly available data base Human Protein Atlas we analyzed MTHFD1L immunostaining patterns in bladder cancer. Results: We analyzed data for 19 normal bladder tissues and 408 primary bladder cancers from the TCGA dataset. MTHFD1L was significantly (p&amp;lt;0.0001) overexpressed in tumorous tissue compared to normal. This overexpression was observed independent of stage, race and age. Furthermore, we found a higher number of MTHFD1L mRNA transcripts in tumors belonging to the basal/squamous and in the neuronal TCGA subtype. Kaplan-Meier survival analysis indicated a poorer survival in patients with high MTHFD1L expression (p=0.05). Evaluation of immunohistochemistry staining pattern in bladder cancer using the Human Protein Atlas database showed a differential expression among human bladder cancer tissues. We are performing in vitro studies to evaluate the role of MTHFD1L in bladder cancer initiation and progression. Conclusions: Our preliminary findings on MTHFD1L suggest that its overexpression is associated with poor patient survival in bladder cancer. These results suggest that MTHFD1L could be important in the biology of BLCA and a potential target for therapy. Future studies will investigate the functional significance of MTHFD1L and its regulation in bladder cancer. Citation Format: Marie-Lisa Eich, Maria D. Rodriguez Pena, Darshan S. Chandrashekar, Jennifer B. Gordetsky, George J. Netto, Sooryanarayana Varambally. Overexpression of methylenetetrahydrofolate dehydrogenase 1 like (MTHFD1L) in bladder cancer: A potential therapeutic target [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 5247.