{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,4]],"date-time":"2026-08-04T08:47:16Z","timestamp":1785833236574,"version":"3.56.0"},"reference-count":54,"publisher":"PeerJ","license":[{"start":{"date-parts":[[2026,8,4]],"date-time":"2026-08-04T00:00:00Z","timestamp":1785801600000},"content-version":"unspecified","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Universiti Malaya Research Grant","award":["RG393-17AFR"],"award-info":[{"award-number":["RG393-17AFR"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Sarcomatoid transformation in clear cell renal cell carcinoma (ccRCC) is associated with highly aggressive clinical behaviour and poor prognosis. The molecular basis underlying this transformation remains poorly defined.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Formalin-fixed paraffin-embedded tumour samples from four patients with sarcomatoid ccRCC were analysed. Matched sarcomatoid, clear cell, and adjacent normal kidney tissues were subjected to gene expression profiling using the NanoString nCounter PanCancer Pathways Panel. Differential gene expression and pathway enrichment analyses were performed. External validation was conducted using The Cancer Genome Atlas Kidney Renal Clear Cell Carcinoma (TCGA-KIRC) dataset, and Gene Set Enrichment Analysis (GSEA) was used to assess pathway-level alterations.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Unsupervised clustering demonstrated clear segregation of sarcomatoid, clear cell, and normal kidney tissues. In the clear cell component,\n                      <jats:italic>GDF6<\/jats:italic>\n                      ,\n                      <jats:italic>VEGFA<\/jats:italic>\n                      , and\n                      <jats:italic>FGF11<\/jats:italic>\n                      were significantly upregulated, whereas\n                      <jats:italic>SFRP1<\/jats:italic>\n                      ,\n                      <jats:italic>PDGFRA<\/jats:italic>\n                      , and\n                      <jats:italic>FGF1<\/jats:italic>\n                      were downregulated, consistent with TCGA-KIRC validation. In the sarcomatoid component, 85 genes were differentially expressed relative to normal kidney tissue, including marked upregulation of\n                      <jats:italic>COL11A1<\/jats:italic>\n                      ,\n                      <jats:italic>MMP9<\/jats:italic>\n                      , and\n                      <jats:italic>IL20RB<\/jats:italic>\n                      , and downregulation of\n                      <jats:italic>PPARGC1A<\/jats:italic>\n                      ,\n                      <jats:italic>SFRP1<\/jats:italic>\n                      , and\n                      <jats:italic>LRP2<\/jats:italic>\n                      . Comparison between sarcomatoid and clear cell components identified 53 differentially expressed genes, with prominent upregulation of\n                      <jats:italic>MMP9<\/jats:italic>\n                      and\n                      <jats:italic>FN1<\/jats:italic>\n                      . Pathway analysis revealed activation of epithelial-mesenchymal transition, cell cycle progression, DNA repair, and extracellular matrix remodelling pathways in sarcomatoid tissue. GSEA confirmed enrichment of epithelial-mesenchymal transition and proliferative signalling pathways.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>\n                      Sarcomatoid transformation in ccRCC is characterised by coordinated activation of epithelial-mesenchymal transition and invasive signalling pathways.\n                      <jats:italic>MMP9<\/jats:italic>\n                      and\n                      <jats:italic>FN1<\/jats:italic>\n                      emerge as key candidate biomarkers of sarcomatoid transformation and may have potential diagnostic and therapeutic relevance.\n                    <\/jats:p>\n                  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