<i>FGD1</i> splice variants as predictors of brain and bone metastatic organotropism in clear cell renal cell carcinoma.

577 Background: Approximately 30% of patients with ccRCC present with metastatic disease (stage IV) and close to half of patients with stage III disease will recur during follow-up surveillance. Two of the most common and morbid sites of metastatic development are brain and bone metastasis. Existing treatment guidelines do not recommend routine brain or bone directed imaging during either initial staging or surveillance in the absence of clinical signs or symptoms. A group of recurrently altered aberrant splice variants in primary ccRCC tumors associated with metastatic progression have previously been identified. Our study aims to investigate metastatic organotropism of the FGD1 -splice variant ( FGD1 -SV) to refine risk stratification and therapeutic decision-making as cabozantinib is drug with activity at these disease sites. Methods: This study leveraged the ORIEN AVATAR network, a data-sharing alliance of 18 NCI-designated cancer centers, to evaluate the presence of FGD1 -SV in a cohort of 1,001 clear cell renal cell carcinoma (ccRCC) patients using bulk RNA-sequencing (RNA-seq). Samples with three or more FGD1 -SV reads were classified as positive. Clinical and survival data were collected, and Kaplan-Meier curves were generated. Odds ratios (ORs) evaluated the presence of FGD1 -SV on brain and bone metastases, while hazard ratios (HRs) assessed association with cabozantinib response. Of 1,037 RNA-seq samples, 84 were metastatic tumor specimens. The relationship between FGD1 -SV positivity and metastasis to common sites was assessed with Fisher's exact test. Results: Brain and bone metastases demonstrated the highest FGD1 -SV positivity (50% and 44%, respectively). A grouped comparison of brain and bone metastases versus all other common metastatic sites (adrenal, lymph node, pancreas, lung, and liver) revealed significant enrichment of FGD1 -SV in these metastases (OR 5.33, 95% CI [1.64 - 18.42], p=0.002). FGD1 -SV positivity in primary tumors was associated with greater risk of recurrence after surgical resection (p=0.0029). Furthermore, FGD1 -SV positive tumors were associated with poor survival when not treated with cabozantinib (HR 2.04, 95% CI [1.20 - 3.45], p=0.01). Conclusions: FGD1 -SV positivity is significantly associated with brain and bone metastatic organotropism in ccRCC. Our findings warrant prospective studies to validate these results and investigate the integration of FGD1 -SV into clinical decision-making, potentially guiding surveillance and therapeutic approaches in high-risk and metastatic patients.