We examined secondary KIT mutations in exons 13 and 17 and secondary PDGFRA mutation in exon 18 in sixteen progressive tumors and/or metastasis (from overall 22 samples).
PDGFRα and KIT, targets of the multi-kinase inhibitor sunitinib which is one of the current choices of first-line drug in metastasized ccRCC patients, were expressed at relatively low levels in tumor tissues, whereas significantly increased in normal kidney.
The presented work has the potential to allow physicians to identify papillary thyroid cancer patients at risk of metastases by using the novel immuno-PET imaging assay based on PDGFRα-targeting antibody [<sup>64</sup>Cu]Cu-NOTA-D13C6.
When either PDGFRα or PDGF-AA was used to predict the presence of metastases, the sensitivity achieved was 86% and 88%, respectively, whereas specificities were lower at 71% and 61%, respectively.
In addition to VEGFR1/2, expression of PDGFR α/β in particular has been documented as characteristic of metastatic disease correlating with poor prognosis.
Therefore, PDGFRα expression distinguishes two functionally unique CAF populations in breast tumors and metastases and may have important implications for patient stratification and precision therapeutics.
PDGFRα has been reported to induce de novo synthesis of LAMB1 protein in a Sjogren syndrome antigen B (La/SSB)-dependent manner in a murine metastasis model.
Patients exhibiting PDGFRα at time of diagnosis are three times more likely to exhibit nodal metastases and are 18 times more likely to recur within 5years than those patients lacking PDGFRα expression.
The difference between succinate dehydrogenase subunit A-mutant gastrointestinal stromal tumors and KIT/PDGFRA-mutant or KIT/PDGFRA wild-type non-succinate dehydrogenase deficient gastrointestinal stromal tumors was significant considering different analyses (P = 0.007 and P = 0.033, respectively, from diagnosis of gastrointestinal stromal tumor for the whole study population; P = 0.005 and P = 0.018, respectively, from diagnosis of metastatic disease for the whole study population; P = 0.007 for only patients who were metastatic at diagnosis).
We analyzed 53 PDGFRA-mutated GISTs (including 2 with corresponding metastases) for chromosomal imbalances by conventional comparative genomic hybridization and compared them with a historical collective of 122 KIT-mutated GISTs.
Nuclear FGFR2 expression was associated with increased risk of metastasis (odds ratio (OR)=7.61, P=0.008), as was membranous PDGFRα (OR=13.71, P=0.015), membranous VEGFR1 (OR=8.01, P=0.037), nuclear MIB1 (OR=1.26, P=0.008), and cytoplasmic p27 (OR=1.037, P=0.030).
Mutational analysis (quantitative polymerase chain reaction) for KIT exons 9, 11, 13 and 17 and PDGFRa exon 18 was performed on paraffin-embedded tissue (40 primary tumours and three metastases).
Specifically, PDGF-Rα and PDGF-Rβ expressions documented in breast cancer tissue specimens as well as breast cancer cell lines are correlated with tumor aggressiveness and metastasis.
Only a single (3%) GIST was amplified for MDM2. p53 protein expression, mitotic index, and KIT/PDGFRA mutations did not correlate with recurrence or metastasis (P=0.20, 0.50, and 0.08, respectively) but tumor size did (P=0.04).
The importance of KIT and PDGFRA mutations in the oncogenesis of gastrointestinal stromal tumors (GIST) is well established, but the genetic basis of GIST metastasis is poorly understood.
Tumors with PDGFRA mutations were small, with a low MI and Ki67 score, and were associated with a very low rate of symptoms at diagnosis, invasion into adjacent organs and distant metastasis.