Dysregulated PDGFR alpha expression and novel somatic mutations in colorectal cancer: association to RAS wild type status and tumor size

Abstract

Background Platelet derived growth factor receptor alpha (PDGFRα) has been considered as a relevant factor in tumor proliferation, angiogenesis and metastatic dissemination. It was a target of tyrosine kinase (TK) inhibitors emerged in the therapy of diverse cancers. In colorectal cancer, the commonly used therapy is anti-epithelial growth factor receptor (EGFR). However, both RAS mutated and a subgroup of RAS wild type patients resist to such therapy. The aim of this study is to investigate PDGFRα protein expression and mutational status in colorectal adenocarcinoma and their association with clinicopathological features and molecular RAS status to provide useful information for the identification of an effective biomarker that might be implicated in prognosis and treatment prediction. Methods Our study enrolled 103 formalin fixed paraffin-embedded (FFPE) colorectal adenocarcinoma. PDGFRα expression was investigated by immunohistochemistry (IHC). Hotspot exon 18 of PDGFRA was studied by PCR followed by Sanger sequencing and RAS status was determined by real time quantitative PCR. Thirteen normal colon tissues were used as negative controls. Results PDGFRα staining was detected in the cytoplasm of all tissues. Low expression was observed in all normal colon mucosa. In adenocarcinoma, 45% (45/100) of cases showed PDGFRα overexpression. This overexpression was significantly associated with mutations in exon 18 (P = 0.024), RAS wild type status (P < 10–3), tumor diameter (P = 0.048), whereas there was no association with tumor side (P = 0.13) and other clinicopathological features. Conclusion Overexpression of PDGFRα in adenocarcinoma suggests its potential role in tumor cells growth and invasion. The association between PDGFRα overexpression in both tumor and stromal adenocarcinoma cells with RAS wild type status suggests its potential role in anti-EGFR therapy resistance and the relevance of using it as specific or adjuvant therapeutic target.

DIAPH3 is a prognostic biomarker and inhibit colorectal cancer progression through maintaining EGFR degradation

“…PFN2 17 and LIMK1 18 are implicated in EMT, whereas PDGFRA is a therapeutic target in young CRC patients, 19 and its mutations may contribute to the development of CRC. 28 Furthermore, we concentrated on DIAPH3 and concluded that DIAPH3 acts as a cancer suppressor in CRC. The depletion of DIAPH3 is also related to tumor progression and poor prognosis.…”

“…This study revealed four predictive biomarkers: LIMK1, PFN2, PDGFRA, and DIAPH3. PFN2 17 and LIMK1 18 are implicated in EMT, whereas PDGFRA is a therapeutic target in young CRC patients, 19 and its mutations may contribute to the development of CRC 28 …”