Machaalani M., Saliby R. M., Saad E., Steiner C., Zhong C., Yekedüz E., ...Daha Fazla
JOURNAL OF CLINICAL ONCOLOGY, cilt.43, sa.16_suppl, ss.1, 2025 (SCI-Expanded, Scopus)
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Yayın Türü:
Makale / Tam Makale
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Cilt numarası:
43
Sayı:
16_suppl
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Basım Tarihi:
2025
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Doi Numarası:
10.1200/jco.2025.43.16_suppl.4546
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Dergi Adı:
JOURNAL OF CLINICAL ONCOLOGY
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Derginin Tarandığı İndeksler:
Science Citation Index Expanded (SCI-EXPANDED), Scopus, PASCAL, CAB Abstracts, CINAHL, Gender Studies Database, International Pharmaceutical Abstracts, Veterinary Science Database, Nature Index
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Sayfa Sayıları:
ss.1
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Ankara Üniversitesi Adresli:
Evet
Özet
4546
Background:
Kidney injury molecule-1 (KIM-1) is a transmembrane protein that is overexpressed in renal cell carcinoma (RCC) and correlated with clinical outcomes in localized and metastatic disease. Nevertheless, association between circulating KIM-1 protein levels and the underlying tumor biology represented by genomic and transcriptomic correlates is not well understood.
Methods:
KIM-1 was measured in plasma at baseline (C1D1) and at C3D1 using an MSD electrochemiluminescence-based assay. Differential gene expression (DGE) and gene set enrichment analysis (GSEA) were performed using DESeq2, with KIM-1 treated as a continuous variable. Associations between circulating KIM-1 levels and clinical, genomic, and transcriptomic tissue data from the JAVELIN Renal 101 trial were evaluated using the Wilcoxon rank-sum test (for categorical groups) and Cox regression (for time-to-event outcomes).
Results:
Plasma for analysis was available from 612 patients (69% of the ITT population), including 323 treated with avelumab plus axitinib and 289 with sunitinib. Elevated baseline KIM-1 levels were correlated with higher tumor burden as assessed by the sum of tumor diameters (Spearman’s ρ = 0.55, p < 0.0001), decreased with tumor shrinkage (p < 0.0001), and were associated with poorer PFS (HR 1.32 per unit increase in log KIM-1, 95% confidence interval (CI) 1.16–1.49, p < 0.0001) and OS (HR 1.96 per unit increase in log KIM-1, 95% CI 1.61–2.37, p < 0.0001). Higher KIM-1 levels were found in IMDC poor–risk versus intermediate–risk (p < 0.0001) and in intermediate–risk versus favorable–risk groups (p < 0.001). Loss-of-function (LOF)
BAP1
mutations, associated with more aggressive disease, were associated with higher KIM-1 RNA expression (p < 0.0001) and protein expression (p = 0.038) and remained significant after adjustment for tumor burden as assessed by linear regression residuals. Transcriptomic analysis showed that RNA expression levels of
HAVCR1
, the gene coding KIM-1, were associated with circulating KIM-1 protein (Spearman’s ρ = 0.31, p < 0.0001), and that higher KIM-1 levels were associated with interferon gamma response whereas lower KIM-1 levels were associated with a hypoxia transcriptional program. Higher circulating KIM-1 was also associated with enrichment for proliferative versus angiogenic gene expression signatures (p = 0.013). The findings were independent of therapy arms.
Conclusions:
We present the first integrative clinical, transcriptomic, and genomic evaluation of circulating KIM-1. High KIM-1 is a biomarker of poor prognosis in RCC and correlates with specific LOF mutations and transcriptions programs. Prospective studies are needed for the clinical implementation of KIM-1 as a biomarker in RCC.