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Comprehensive analysis of 34 MiT family translocation renal cell carcinomas and review of the literature: investigating prognostic markers and therapy targets
- Publication Year :
- 2020
-
Abstract
- Summary Recently cabozantinib, a tyrosine kinase inhibitor with activity against VEGF, MET, AXL, and downregulating cathepsin K in vitro, has been proposed for the treatment of advanced clear and non-clear renal cell carcinomas. Since it is well known that cathepsin K is expressed in the majority of MiT family translocation renal cell carcinomas, we investigated cathepsin K, MET, AXL, and VEGF in a large series of those tumours, looking for possible predictive markers. We collected the clinicopathological features of 34 genetically confirmed MiT family translocation renal cell carcinomas [26 Xp11 and 8 t(6;11) renal cell carcinomas] and studied them using an immunohistochemical panel including PAX8, cathepsin K, HMB45, Melan-A, CD68 (PG-M1), CK7, CA9, MET, AXL and by FISH for VEGFA and MET. Cathepsin K was expressed in 14 of 26, HMB45 in 8 of 25, and Melan-A in 4 of 23 Xp11 renal cell carcinomas, whereas labelling for CK7 and CA9 was minimal. In t(6;11) renal cell carcinoma, cathepsin K and melanogenesis markers were constantly positive, whereas CK7 and CA9 were negative. None of the 34 carcinomas showed CD68 (PG-M1) and AXL expression. One aggressive Xp11 renal cell carcinoma showed increased VEGFA gene copy number (4–5 copies) with concurrent gains of TFE3 and TFEB. None of the 34 carcinomas showed MET gene amplification, whereas staining for MET was found in 7 of 8 t(6;11) and in 16 of 24 Xp11 renal cell carcinomas, and in the latter cases, when the expression was >50%, correlated with aggressiveness (p=0.0049). In Xp11 renal cell carcinomas, the aggressiveness was also correlated with larger tumour size (p=0.0008) and the presence of necrosis (p=0.027) but not nucleolar grading (p=1). Interestingly, in patients with tumours exhibiting two of three parameters (necrosis, larger tumour size and MET immunolabelling >50%) an aggressive clinical behaviour was observed in 88% of cases. In conclusion, cathepsin K, CD68 (PG-M1), CK7, CA9, and PAX8 is a useful panel for the diagnosis. Larger tumour size, the presence of necrosis and MET immunohistochemical expression correlate with aggressive behaviour in Xp11 renal cell carcinomas, especially in combination. VEGF, MET, cathepsin K but not AXL may be potential predictive markers for targeted therapy in MiT family translocation renal cell carcinomas.
- Subjects :
- 0301 basic medicine
Male
Cell
Cathepsin K
kidney carcinoma
TFE3
cabozantinib
cathepsin K
FISH
immunohistochemistry
predictive markers
prognosis
target therapy
Translocation renal cell carcinoma
Tyrosine-kinase inhibitor
Translocation, Genetic
chemistry.chemical_compound
0302 clinical medicine
Renal cell carcinoma
Medicine
Child
Middle Aged
Proto-Oncogene Proteins c-met
Prognosis
Kidney Neoplasms
medicine.anatomical_structure
030220 oncology & carcinogenesis
Immunohistochemistry
Female
predictive marker
prognosi
Adult
Cabozantinib
Adolescent
medicine.drug_class
Pathology and Forensic Medicine
03 medical and health sciences
Young Adult
Proto-Oncogene Proteins
Humans
Carcinoma, Renal Cell
Aged
Chromosomes, Human, X
Settore MED/08 - ANATOMIA PATOLOGICA
business.industry
Receptor Protein-Tyrosine Kinases
medicine.disease
Axl Receptor Tyrosine Kinase
030104 developmental biology
chemistry
Cancer research
INGLESE
PAX8
business
Biomarkers
Subjects
Details
- Language :
- English
- Database :
- OpenAIRE
- Accession number :
- edsair.doi.dedup.....7bc949f6673b336593f32ae7d708de5b