mardi 17 juillet 2012

Mutated genes in cancer (76) – PDGFRA





PDGFRA

In databases:

● Entrez (http://www.ncbi.nlm.nih.gov/sites/gquery): 5156 or PDGFRA
● Ensembl (http://www.ensembl.org/index.html): ENSG00000134853
● UniProt (http://www.uniprot.org/): P16234
● GeneCards (http://www.genecards.org/): PDGFRA
● HGNC (http://www.genenames.org/): 8803 or PDGFRA
● Enzyme Number (IUBMB): EC 2.7.10.-, EC 2.7.10.1

Gene locus:

4q12

Protein name:

Platelet-derived growth factor receptor, alpha polypeptide

Protein Size:

1089 amino acids; about 123 kDa

Function :

PDGFRA encodes a cell surface tyrosine kinase receptor for members of the platelet-derived growth factor family. These growth factors are mitogens for cells of mesenchymal origin. The identity of the growth factor bound to a receptor monomer determines whether the functional receptor is a homodimer or a heterodimer, composed of both platelet-derived growth factor receptor alpha and beta polypeptides. Activation of PDGFRA kinase activity initiates intracellular signaling through the MAPK, PI 3-K and PKCγ pathways.

Cancer-related alterations:

Somatic PDGFRA mutations have been found in tumors of small intestine (about 50% of cases), stomach and soft tissue. Two-thirds of these mutations are “substitution missense”, for which a mutation hot spot exists, corresponding to amino acid 842.

Gastrointestinal stromal tumors (GISTs) are rare neoplasms of mesenchymal origin arising in the gastrointestinal tract. These tumors are characterized by activating mutations of either receptor tyrosine kinase KIT or PDGFRA, which are found in 85% of cases.

Fusion genes involving PDGFRA and various other genes (FIP1L1, CDK5RAP2, STRN, KIF5B, ETV6, BCR is the cause of diseases accompanied by eosinophilia (see below):

del(4)(q12q12)                       FIP1L1-PDGFRA                 ● CEL
ins(9;4)(q33;q12q25) CDK5RAP2-PDGFRA         ● CEL
t(2;4)(p22;q12)                       STRN-PDGFRA                   ● MPD with eosinophilia
t(4;10)(q12;p11)                     KIF5B-PDGFRA                  ● MPS  with hypereosinophilia
t(4;12)(q12;p13)                     ETV6-PDGFRA                    ● MPD with hypereosinophilia
t(4;22)(q12;q11.2)                  BCR-PDGFRA                     ● MPD and atypical CML

CEL: chronic eosinophilic leukemia ; MPD : myeloproliferative disorder ; MPS : myeloproliferative syndrome ; CML : chronic myeloid leukemia

The most investigated of these fusion genes is FIP1L1-PDGFRA (see, among others, Fukushima et al. 2009).

Therapies:

The introduction of imatinib mesylate, which targets the kinases presenting with PDGFRA or KIT alterations, has dramatically changed the management of GISTs, which were resistant to conventional cytotoxic chemotherapy, both in advanced and localized phases. However, although the majority of GISTs show an initial clinical response to imatinib, the development of resistance to this tyrosine kinase inhibitor as well as to the alternative kinase inhibitor sunitinib is problematic (Downs-Kelly & Rubin, 2011).
Rare cases of mutant FIP1L1-PDGFRA that are resistant to imatinib mesylate (eg, T674I, D842V) have been reported. In vitro, the T674I, but not the D842V, mutant was shown to be sensitive to other kinase inhibitors, including nilotinib, sorafenib, and PKC412 . Also, there are reported instances of interferon alfa–induced complete clinical remissions in FIP1L1-PDGFRA–positive clonal eosinophilia (Tefferi et al. 2010)

References (open access):

Gastrointestinal stromal tumors: molecular mechanisms and targeted therapies. Downs-Kelly E, Rubin BP. Patholog Res Int. 2011 Apr 14;2011:708596.

Hypereosinophilic syndrome and clonal eosinophilia: point-of-care diagnostic algorithm and treatment update. Tefferi A, Gotlib J, Pardanani A. Mayo Clin Proc. 2010 Feb;85(2):158-64.

FIP1L1-PDGFRalpha imposes eosinophil lineage commitment on hematopoietic stem/progenitor cells. Fukushima K, Matsumura I, Ezoe S, Tokunaga M, Yasumi M, Satoh Y, Shibayama H, Tanaka H, Iwama A, Kanakura Y. J Biol Chem. 2009 Mar 20;284(12):7719-32.


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