Analysis of potential receptor tyrosine kinase targets in intimal and mural sarcomas.
Primary sarcomas of the great vessels are very rare neoplasms and only a few cases have been reported. They are divided into the two broad categories of intimal or luminal and mural sarcomas. We analysed eight advanced high-grade sarcomas originating from major vessels (seven intimal and one mural sarcoma) by means of immunohistochemistry and FISH analysis for PDGFRA, PDGFRB, EGFR and KIT receptor tyrosine kinases (RTKs), together with immunoprecipitation/western blotting, sequencing of the corresponding genes, and the search for cognate ligands. The intimal sarcomas showed a wide spectrum of morphologies and immunophenotypes, whereas the mural sarcoma had common leiomyosarcomatous features. Regardless of their category, all of the cases had a PDGFRA-deregulated cytogenetic profile mainly consisting of an amplification cluster; five were also polysomic for PDGFRB, whereas three showed disomy. Six cases had a deregulated EGFR gene, and c-Kit gene status was similar to that of PDGFRA. In one case, biochemical analysis revealed the presence of activated and highly expressed PDGFRA, PDGFRB and EGFR, whereas KIT was expressed at reference level. Sequencing of the corresponding genes revealed no activating mutations in any of the analysed receptors. The cognate ligands were detected in all cases. In predictive terms, the evidence of gene amplification/high polysomy of several RTKs, together with PDGFRA, PDGFRB and EGFR expression and phosphorylation, suggests that these tumours may be sensitive to RTK-inhibiting treatments.
Tamborini
E
E
Experimental Molecular Pathology, Department of Pathology, Fondazione IRCCS Istituto Nazionale dei Tumori di Miano, Via G Venezian 1, 20133 Milan, Italy.
Casieri
P
P
Miselli
F
F
Orsenigo
M
M
Negri
T
T
Piacenza
C
C
Stacchiotti
S
S
Gronchi
A
A
Pastorino
U
U
Pierotti
M A
MA
Pilotti
S
S
D000328:Adult; D015153:Blotting, Western / Q000379:methods; D003331:Coronary Vessels / Q000201:enzymology*; D066246:ErbB Receptors / Q000032:analysis / Q000235:genetics; D005260:Female; D005784:Gene Amplification / Q000235:genetics; D006338:Heart Neoplasms / Q000201:enzymology* / Q000235:genetics; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D016130:Immunophenotyping; D047468:Immunoprecipitation; D017404:In Situ Hybridization, Fluorescence / Q000379:methods; D008024:Ligands; D008297:Male; D008875:Middle Aged; D019009:Proto-Oncogene Proteins c-kit / Q000032:analysis / Q000235:genetics; D020794:Receptor Protein-Tyrosine Kinases / Q000032:analysis* / Q000235:genetics; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000032:analysis / Q000235:genetics; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000032:analysis / Q000235:genetics; D012509:Sarcoma / Q000201:enzymology* / Q000235:genetics
D008024:Ligands; C512478:EGFR protein, human; D066246:ErbB Receptors; D019009:Proto-Oncogene Proteins c-kit; D020794:Receptor Protein-Tyrosine Kinases; D020796:Receptor, Platelet-Derived Growth Factor alpha; D020797:Receptor, Platelet-Derived Growth Factor beta