HIRA loss is frequent but not universal in human fumarate hydratase-deficient renal cell carcinoma and defines divergent oncogenic programs.

Fumarate hydratase-deficient renal cell carcinoma (FH-dRCC) is a rare and highly aggressive malignancy driven by fumarate accumulation and widespread epigenetic reprogramming. Although Valcarcel-Jimenez et al. have demonstrated that loss of the histone chaperone Hira is a critical and necessary event for the malignant transformation of Fh1-deficient cells through activation of MYC-dependent transcriptional programs based on murine models, by analyzing HIRA protein expression and transcriptomic profiles in a multicenter cohort of human FH-dRCC tumors harboring either germline or somatic FH mutations, we found that HIRA loss was frequent (73.9%, 17/23) but not universal. Although HIRA status was not associated with clinical outcomes, transcriptomic analyses revealed two divergent oncogenic programs: HIRA-negative tumors are characterized by activation of MYC and mTORC1 signaling, whereas HIRA-positive tumors preferentially engage Wnt and Notch pathways. These findings suggest that HIRA loss is not an obligate event in human FH-dRCC tumorigenesis, but instead may direct toward distinct molecular trajectories.