AXL and SRC in clear cell renal cell carcinoma: absence of mutations, rare alternative splicing events, but association of protein expression with poor prognosis
Abstract Novel treatment options for metastatic renal cell carcinomas (RCC) include specific MET inhibitors, GAS6/AXL inhibitors, and SRC inhibitors. The interplay between c‐MET, SRC, AXL expression, and their gene mutation patterns in different renal carcinoma subtypes is unclear. To improve the un...
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Wiley
2025-05-01
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| Series: | The Journal of Pathology: Clinical Research |
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| Online Access: | https://doi.org/10.1002/2056-4538.70028 |
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| author | Muriel D Brada Tülay Karakulak Peter Schraml Martina Haberecker Dorothea Rutishauser Jeffrey S Ross Daniel Eberli Holger Moch |
| author_facet | Muriel D Brada Tülay Karakulak Peter Schraml Martina Haberecker Dorothea Rutishauser Jeffrey S Ross Daniel Eberli Holger Moch |
| author_sort | Muriel D Brada |
| collection | DOAJ |
| description | Abstract Novel treatment options for metastatic renal cell carcinomas (RCC) include specific MET inhibitors, GAS6/AXL inhibitors, and SRC inhibitors. The interplay between c‐MET, SRC, AXL expression, and their gene mutation patterns in different renal carcinoma subtypes is unclear. To improve the understanding of these signaling pathways, we analyzed c‐MET, AXL, and SRC expression in 590 clear cell RCC (ccRCC) and 127 papillary RCC (pRCC) by immunohistochemistry and integrated sequencing data to investigate the frequency of MET, AXL, and SRC gene mutations, their expression levels, and the presence of splice variants. In TCGA and in Foundation Medicine, Inc. (FMI) datasets, AXL and SRC gene alterations were extremely rare (<2%) or absent in ccRCC (n = 531 and 2,781, respectively) and pRCC (n = 290 and 566, respectively). On the other hand, MET mutations or amplifications were found in 9.7% (TCGA) and 10.2% (FMI) of pRCC. We show that strong SRC staining intensity by immunohistochemistry is associated with high tumor stage, high grade, and shorter survival in ccRCC (p < 0.001 each). AXL expression correlates with high stage and grade in ccRCC (p < 0.001 each). Both SRC and AXL expression were independent prognostic parameters in multivariate analysis (p < 0.05). MET expression is associated with longer survival in pRCC (p < 0.05). Our TCGA data analysis aligns with SRC immunohistochemistry findings on tumor stage and shorter survival in ccRCC. TCGA expression data showed a moderate positive correlation between AXL and c‐MET in pRCC. In addition, we identified alternative splicing events reported for AXL in pRCC, and MET and SRC in ccRCC, across various alternative splicing databases. In conclusion, we identified high SRC expression as a biomarker for poor prognosis of ccRCC. Our data demonstrate c‐MET, AXL, and SRC signaling pathway interactions independent of c‐MET, AXL, and SRC mutations in ccRCC. |
| format | Article |
| id | doaj-art-7e92da4e6c534064a3f6a0a47aa4435c |
| institution | Kabale University |
| issn | 2056-4538 |
| language | English |
| publishDate | 2025-05-01 |
| publisher | Wiley |
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| series | The Journal of Pathology: Clinical Research |
| spelling | doaj-art-7e92da4e6c534064a3f6a0a47aa4435c2025-08-20T03:48:23ZengWileyThe Journal of Pathology: Clinical Research2056-45382025-05-01113n/an/a10.1002/2056-4538.70028AXL and SRC in clear cell renal cell carcinoma: absence of mutations, rare alternative splicing events, but association of protein expression with poor prognosisMuriel D Brada0Tülay Karakulak1Peter Schraml2Martina Haberecker3Dorothea Rutishauser4Jeffrey S Ross5Daniel Eberli6Holger Moch7Department of Pathology and Molecular Pathology University Hospital Zurich Zurich SwitzerlandDepartment of Pathology and Molecular Pathology University Hospital Zurich Zurich SwitzerlandDepartment of Pathology and Molecular Pathology University Hospital Zurich Zurich SwitzerlandDepartment of Pathology and Molecular Pathology University Hospital Zurich Zurich SwitzerlandDepartment of Pathology and Molecular Pathology University Hospital Zurich Zurich SwitzerlandFoundation Medicine, Inc. Cambridge MA USADepartment of Urology University Hospital Zurich Zurich SwitzerlandDepartment of Pathology and Molecular Pathology University Hospital Zurich Zurich SwitzerlandAbstract Novel treatment options for metastatic renal cell carcinomas (RCC) include specific MET inhibitors, GAS6/AXL inhibitors, and SRC inhibitors. The interplay between c‐MET, SRC, AXL expression, and their gene mutation patterns in different renal carcinoma subtypes is unclear. To improve the understanding of these signaling pathways, we analyzed c‐MET, AXL, and SRC expression in 590 clear cell RCC (ccRCC) and 127 papillary RCC (pRCC) by immunohistochemistry and integrated sequencing data to investigate the frequency of MET, AXL, and SRC gene mutations, their expression levels, and the presence of splice variants. In TCGA and in Foundation Medicine, Inc. (FMI) datasets, AXL and SRC gene alterations were extremely rare (<2%) or absent in ccRCC (n = 531 and 2,781, respectively) and pRCC (n = 290 and 566, respectively). On the other hand, MET mutations or amplifications were found in 9.7% (TCGA) and 10.2% (FMI) of pRCC. We show that strong SRC staining intensity by immunohistochemistry is associated with high tumor stage, high grade, and shorter survival in ccRCC (p < 0.001 each). AXL expression correlates with high stage and grade in ccRCC (p < 0.001 each). Both SRC and AXL expression were independent prognostic parameters in multivariate analysis (p < 0.05). MET expression is associated with longer survival in pRCC (p < 0.05). Our TCGA data analysis aligns with SRC immunohistochemistry findings on tumor stage and shorter survival in ccRCC. TCGA expression data showed a moderate positive correlation between AXL and c‐MET in pRCC. In addition, we identified alternative splicing events reported for AXL in pRCC, and MET and SRC in ccRCC, across various alternative splicing databases. In conclusion, we identified high SRC expression as a biomarker for poor prognosis of ccRCC. Our data demonstrate c‐MET, AXL, and SRC signaling pathway interactions independent of c‐MET, AXL, and SRC mutations in ccRCC.https://doi.org/10.1002/2056-4538.70028renal cell carcinomagene expressiontyrosine kinase inhibitor |
| spellingShingle | Muriel D Brada Tülay Karakulak Peter Schraml Martina Haberecker Dorothea Rutishauser Jeffrey S Ross Daniel Eberli Holger Moch AXL and SRC in clear cell renal cell carcinoma: absence of mutations, rare alternative splicing events, but association of protein expression with poor prognosis The Journal of Pathology: Clinical Research renal cell carcinoma gene expression tyrosine kinase inhibitor |
| title | AXL and SRC in clear cell renal cell carcinoma: absence of mutations, rare alternative splicing events, but association of protein expression with poor prognosis |
| title_full | AXL and SRC in clear cell renal cell carcinoma: absence of mutations, rare alternative splicing events, but association of protein expression with poor prognosis |
| title_fullStr | AXL and SRC in clear cell renal cell carcinoma: absence of mutations, rare alternative splicing events, but association of protein expression with poor prognosis |
| title_full_unstemmed | AXL and SRC in clear cell renal cell carcinoma: absence of mutations, rare alternative splicing events, but association of protein expression with poor prognosis |
| title_short | AXL and SRC in clear cell renal cell carcinoma: absence of mutations, rare alternative splicing events, but association of protein expression with poor prognosis |
| title_sort | axl and src in clear cell renal cell carcinoma absence of mutations rare alternative splicing events but association of protein expression with poor prognosis |
| topic | renal cell carcinoma gene expression tyrosine kinase inhibitor |
| url | https://doi.org/10.1002/2056-4538.70028 |
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