Association of SETD2 mutation with prognostic features and susceptibility to acute kidney injury in renal cell carcinoma.

554 Background: Renal cell carcinoma (RCC) ranks 8 most lethal cancers and is responsible for about 140,000 deaths worldwide each year. Acute kidney injury (AKI) is a frequent complication in this population, SETD2, a histone methyltransferase that mediates H3K36 trimethylation, plays a crucial role in maintaining chromatin stability and DNA repair. Loss-of-function mutations, seen in approximately 15% of clear-cell RCC, are associated with poorer outcomes, and impaired tubular recovery, increasing susceptibility to AKI. With next-generation sequencing now routinely used in RCC, SETD2 status is increasingly available and may help identify patients at greater risk for treatment-related kidney injury, supporting more personalized nephroprotective care. Methods: Five non-overlapping datasets totaling 781 RCC cases (TCGA, DFCI, UTokyo, and MSK cohorts) were analyzed alongside a systematic literature review (PubMed, EMBASE, genomic databases, cutoff August 2025) to assess renal, molecular, and therapeutic outcomes by SETD2 mutation status, including AKI definitions, treatment type, and survival endpoints. Results: Analysis of TCGA-KIRC data on cBioPortal showed that SETD2 alterations were present in about 13% of patients (101 of 780). The SETD2-altered group had a shorter median overall survival of 64.6 months compared with 116.8 months in the unaltered group (p=0.121). Disease-free survival was significantly worse in SETD2-mutated tumors (p=0.0073, q=0.029), while progression-free survival showed a similar trend (p=0.056). Disease-specific survival did not differ significantly (p=0.45). in preclinical models,Suppression of SETD2 enhances renal recovery following injury, supporting its role as a modulator of kidney protection (Wang Y et al., Cell Death Dis. 2023). AKI occurs in 30–55% of RCC patients after nephrectomy and 5–18% during systemic therapy (Kukreja 2020; Seethapathy 2019; Coca 2012). While no human dataset links SETD2 directly to AKI, experimental models show that SETD2 loss impairs tubular repair and mitochondrial stability, promotes oxidative stress, and that its suppression reduces ferroptosis and improves renal recovery (Wang Y et al., Cell Death Dis. 2023). These data suggest SETD2 deficiency may heighten renal vulnerability and worsen outcomes in RCC. Conclusions: SETD2 mutations occur in a significant subset of RCC and are associated with poorer disease-free survival and molecular features of chromatin instability. Although clinical data directly linking SETD2 loss to AKI are lacking, preclinical evidence demonstrates that SETD2 deficiency impairs tubular repair, promotes oxidative stress, and increases susceptibility to renal injury. These findings suggest that SETD2 status may serve as a dual biomarker of tumor aggressiveness and renal vulnerability, warranting prospective evaluation in precision onco-nephrology studies.