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35FGD1 splice variant as a novel biomarker for inferior clinical outcomes and development of brain and bone metastasis in clear cell renal cell carcinoma
Abstract   Open access   Peer reviewed

35FGD1 splice variant as a novel biomarker for inferior clinical outcomes and development of brain and bone metastasis in clear cell renal cell carcinoma

Alex Soupir, Alyssa Obermayer, Kapil Avasthi, Youngchul Kim, Justin Miller, Mitchell Hayes, Nicholas Abreu, Roy Elias, Nirmish Singla, Michele Churchman, …
The oncologist (Dayton, Ohio), Vol.30(Supplement_2), oyaf276036
10/01/2025
DOI: 10.1093/oncolo/oyaf276.036
PMCID: PMC12509662
url
https://doi.org/10.1093/oncolo/oyaf276.036View
Published (Version of record) Open Access

Abstract

Abstract Background Currently, no reliable tissue or blood-based biomarkers exist for clear cell renal cell carcinoma (ccRCC), neither in the localized nor metastatic setting. Two of the most common and morbid sites of metastatic development are brain and bone metastases (B&BM). Existing treatment guidelines do not recommend routine brain or bone directed imaging during surveillance after curative treatment or upon initial staging for metastatic patient in the absence of clinical signs or symptoms. Previously identified recurrent somatic splice variants (SV) in ccRCC may hold promise for novel biomarker development. One such splice variant significantly associated with increased progression and decreased survival among ccRCC patients was FYVE, RhoGEF and PH domain-containing protein 1 (FGD1; Chang et al. Eur Urol, 2022 Oct). Our study aims to validate clinical outcomes for tumors with the FGD1-splice variant (FGD1-SV), investigate metastatic organotropism associated with FGD1-SV and explore the feasibility of plasma-based detection assay for FGD1-SV among ccRCC patients. Methods Patient tumor samples from Moffitt Cancer Center and the ORIEN cohort, a data-sharing alliance of 18 NCI-designated cancer centers, were identified. The detection of FGD1-SV was evaluated in a cohort of 105 primary ccRCC tumors from Moffitt patients and 1037 ccRCC patients from ORIEN, which includes 84 metastatic tumors, using bulk RNA-sequencing. For bulk RNA-sequencing analysis, samples with three or more FGD1-SV reads were classified as positive. Kaplan-Meier curves were used to examine associations with clinical variables. The relationship between FGD1-SV positivity and metastatic site was assessed with Fisher’s exact test. Additionally, pre-surgery plasma, post-surgery plasma, and tissue specimens prospectively collected from 64 ccRCC patients undergoing surgery were examined using a novel multiplexed PCR-sequencing assay. Read count from PCR data was log2 transformed and then normalized using housekeeping genes. Batch effect was corrected using COMBAT. Results Among 105 Moffitt patients, we detected the FGD1-SV in 15 patients and these patients were at significantly elevated risk for the development of brain metastasis during follow-up compared to those patients without the variant (HR 10.38; 95%CI 2.13-50.6; P = .004). We then evaluated the presence of FGD1-SV among the 84 metastatic samples from the ORIEN cohort. Here we found B&BM demonstrated the highest FGD1-SV detection rate (50% brain and 44% bone, respectively) and enrichment compared to other sites (Figure 1A). Among 1008 primary tumors from ORIEN, FGD1-SV positive tumors were validated for their association with inferior overall survival (P = .0029). Our PCR assay among the prospective cohort (n = 64) found a strong association of the FGD1-SV in tumor samples with aggressive histology, including WHO grade (ANOVA P  = < .0001; Figure 1B) and the presence of rhabdoid features (P = .0001; Figure 1C). Lastly, we found significantly higher FGD1-SV in plasma collected before surgery than plasma collected after surgery (P = .007.) Conclusions FGD1-SV is significantly associated with poorer clinical outcomes and increased risk of B&BM in ccRCC patients. Initial studies examining FGD1-SV detection in patient plasma and tumor through a practical PCR-based assay demonstrates feasibility and correlates with important pathological outcomes. Further studies are needed to investigate the integration of FGD1-SV into clinical decision-making, potentially guiding personalized surveillance and staging strategies.
 brain and bone metastasis liquid biopsy FGD1 splice variant

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