PDGFRA (platelet-derived growth factor receptor, alpha polypeptide)

Alias_names	platelet-derived growth factor receptor, alpha polypeptide
Alias_symbol (synonym)	CD140a
	PDGFR2
	GAS9
Other alias	CD140A
	PDGFR-2
	RHEPDGFRA
HGNC (Hugo)	PDGFRA
LocusID (NCBI)	5156
Atlas_Id	143
Location	4q12  [Link to chromosome band 4q12]
Location_base_pair	Starts at 54229089 and ends at 54298247 bp from pter ( according to hg19-Feb_2009)  [Mapping PDGFRA.png]
	PDGFRA (platelet-derived growth factor receptor, alpha polypeptide) Hybridization with Vysis 4q12 Tri-Color break apart rearrangement probe (Abbott Molecular, US) showing PDGFRA on 4q12 (red-green-aqua signal) - Courtesy Adriana Zamecnikova.

Note
Entity	Gastrointestinal stromal tumor (GIST)
Note	Activating mutations of PDGFRA are found in 5-8% of patients with gastrointestinal stromal tumors (GISTs) but their frequency increases to 30% to 40% in gastric GISTs lacking KIT mutations (Corless et al., 2005; Lasota et al., 2008). The majority of these mutations are "substitution missense", that can arise by various mechanisms (Figure 1). These include mutation hot spots in exon 18 of the PDGFRA gene such as the Asp-to-Val substitution at codon 842 (D842V) encoding the activation loop. Other activating mutations are less frequent such as mutations in exons 12 encoding the juxtamembrane domain and in exon 14 encoding the tyrosine kinase 1 domain of PDGFRA (Chompret et al., 2004; Heinrich et al., 2003). PDGFRA mutations except for D842V in exon 18 are sensitive to imatinib inhibition. However, despite initial clinical responses to tyrosine kinase inhibitors (imatinib, nilotinib, sorafenib and sunatinib), the majority of these patient develops resistance to the drug limiting the long-term benefit of tyrosine kinase inhibitors in this group of patients (Gramza et al., 2009; Pierotti et al., 2011). The D842V mutation results in an amino acid substitution at position 842 in PDGFRA, from an aspartic acid (D) to a valine (V). This mutation occurs within the TK2 domain (Figure 1). PDGFRA D842V mutation has been found in a distinct subset of GIST, typically from the stomach. The D842V mutation is known to be associated with tyrosine kinase inhibitor resistance.
	Figure 1. Schematic representation of the most frequent activating mutations of the homologous platelet-derived growth factor receptor alpha (PDGFRA) kinase in patients with gastrointestinal stromal tumors. Most common mutations are in exon 18, such as the D842V substitution that shows resistance to imatinib. Mutations in the juxtamembrane domain (exon 12; V561D most common) and in exon 14 tyrosine kinase 1 (TK1) domain (e.g., N659K) are less common. Abbreviations: JM, juxtamembrane; TK, tyrosine kinase. Adopted and modified from Pierott et al., 2011).
Entity	Hematologic disorders with primary eosinophilia
Note	Several chromosomal rearrangements generating fusion genes causing PDGFRA activation have been described in a variety of uncommon hematologic disorders that are often accompanied with a related condition called hypereosinophilic syndrome. These rearrangements activate PDGFRA by fusion to various partner genes: STRN (2p24) in the t(2;4)(p22;q12), FIP1L1 (interstitial 4q12 deletion), CDK5RAP2 (9q33) in the ins(9;4)(q33;q12q25), KIF5B (10p11) in the t(4;10)(q12;p11), ETV6 (12p13) in the t(4;12)(q12;p13), and BCR (22q11) in the t(4;22)(q12;q11). In each of these rearrangements, the breakpoints in PDGFRA partner genes are variable, but the breakpoints in PDGFRA invariably involve exon 12 encoding a portion of the juxtamembrane domain with autoinhibitory function (Baxter et al., 2002; Gotlib et al., 2008); the disruption of which activates the fusion protein (Figure 2). The most investigated of these fusion genes is FIP1L1-PDGFRA that arise as a result of a cryptic interstitial deletion on chromosome 4q12. FIP1L1-PDGFRA fusion protein is involved in the pathogenesis of uncommon hematologic disorders with primary eosinophilia like chronic eosinophilic leukemia (CEL) hyperseosinophilic syndrome (HES) and systemic mastocytosis (SM). Similar to other fusion tyrosine kinases, FIP1L1-PDGFRA is a constitutively active tyrosine kinase that was shown to be sensitive to kinase inhibitors (Cools et al., 2003; Jain et al., 2013).
	Figure 2. The structure and mechanism of activation of PDGFRA fusions in hematological disorders. In the fusion oncogene, the partner gene always replaces the 5 part of exon 12 of PDGFRA creating an in frame fusion. As the 5 part of exon 12 of PDGFRA containing the inhibitory domain is truncated, its expression is controlled by the partner gene promoter resulting in constitutive activation of the PDGFRA kinase domain. NH2: N-terminal site; COOH: C-terminal site; TM: transmembrane domain; JM: juxtamembrane domain. Adopted and modified from Cools et al., 2003 and Gotlib et al., 2008).
Entity	Lung adenocarcinoma
Cytogenetics	A t(4;12)(q12;q12) was found in a case of lung adenocarcinoma (Seo et al., 2012).
Hybrid/Mutated Gene	SCAF11/PDGFRA

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