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

Nadia Ben Jemii (1, 2, 3) , Haifa Tounsi-Kettiti (1, 2, 3) , Hamza Yaiche (1, 2, 3) , Najla Mezghanni (1, 2, 3) , Amira Jaballah Gabteni (1, 2, 3) , Emna Fehri (1, 2) , Chayma Ben Fayala (1, 2) , Sonia Abdelhak (3) , Samir Boubaker (1, 2, 3)

1 Laboratoire d’Anatomie Pathologique Humaine et Expérimentale
2 UTM - Université de Tunis El Manar
3 LR11IPT05 - Laboratoire de Génomique Biomédicale et Oncogénétique - Biomedical Genomics and Oncogenetics Laboratory

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.

Mots clés: Platelet derived growth factor receptor alpha; Colorectal cancer; RAS status; Mutations exon 18; Immunohistochemistry

Domaines: Sciences du Vivant [q-bio]

Nadia Ben Jemii, Haifa Tounsi-Kettiti, Hamza Yaiche, Najla Mezghanni, Amira Jaballah Gabteni, et al.. Dysregulated PDGFR alpha expression and novel somatic mutations in colorectal cancer: association to RAS wild type status and tumor size. Journal of Translational Medicine, 2020, 18 (1), pp.440. ⟨10.1186/s12967-020-02614-3⟩. ⟨pasteur-03561537⟩