In-silico analysis and functional evaluation of regulatory FH gene polymorphism (rs1414493) in breast cancer patients

Metabolic reprogramming is a hallmark of cancer, driven in part by the metabolic plasticity of tumor cells. Understanding the mechanisms underlying this plasticity is critical to elucidating its role in breast cancer development. In this study, we investigated the genetic variation in the fumarate hydratase (FH) enzyme, focusing on the single nucleotide polymorphism (SNP) rs1414493, and its association with breast cancer. FH is a key metabolic enzyme that also functions as a tumor suppressor. The SNP is located in the transcription factor binding sites of the regulatory region of FH. Previously, this variant was reported to promote overall survival in Lung cancer. Our analysis revealed a high frequency of the rs1414493 variant in breast cancer patients from the Malwa region of Punjab. However, no significant association was observed between this SNP and breast cancer risk, based on genotype and allele distributions (P = 0.78 and P = 0.32, respectively). Despite this, in-silico analyses suggested that rs1414493, located in the distal promoter region of FH, may influence breast cancer metabolism. Specifically, our findings indicate the presence of a novel binding site for the transcription factor GATA1 at this SNP location. We hypothesize that FH and GATA1 may act as interdependent factors contributing to breast cancer susceptibility. Further investigation into the role of GATA1 in breast cancer is warranted, particularly in the context of its potential impact on cancer cell metabolism.