title: Sequence mutations of the substrate binding pocket of stem cell factor and multidrug resistance protein ABCG2 in renal cell cancer: a possible link to treatment resistance.
abstract: ABCG2 is a multidrug cellular transport protein that is associated with resistance to certain treatments in patients, particularly anticancer treatment. The tumor-protective properties of ABCG2 expression are reported to be a feature of a subset of stem cell-like tumor cells. While protection against chemotherapy has been well analyzed, the role of ABCG2 in the treatment with tyrosine kinase inhibitors is only partially understood. Tyrosine kinase inhibitors are currently the main treatment option in irresectable renal cell carcinomas. To investigate possible underlying sequence variations in the ABCG2 gene with relevance to the functional properties of the protein, 36 patient samples were analyzed. Using sequence analysis and single-nucleotide polymorphism databases, sequence variations in the highly conserved domains of the binding pocket of ABCG2 were analyzed. The resulting variations were used for computational protein prediction algorithms to identify conformational alterations. A relevant shift from A to G at position 1376 (resulting in Y→C at 459 aa) was identified and found to be present in 8.3% of the patients. These patients are currently in follow-up after resection, thus, further analysis will reveal whether this mutation has relevance to treatment efficacy.
authors: Department of Medical Oncology, National Center for Tumor Diseases, University of Heidelberg, D-69120 Heidelberg, Germany.
authors: Inka
authors: I
authors: Zoernig
authors: Claudia
authors: C
authors: Ziegelmeier
authors: Bernd
authors: B
authors: Lahrmann
authors: Niels
authors: N
authors: Grabe
authors: Dirk
authors: D
authors: Jäger
authors: Niels
authors: N
authors: Halama
mesh_terms: D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000235:genetics* / Q000378:metabolism; D000595:Amino Acid Sequence; D002292:Carcinoma, Renal Cell / Q000188:drug therapy* / Q000235:genetics* / Q000378:metabolism; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D006801:Humans; D007680:Kidney Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000378:metabolism; D008969:Molecular Sequence Data; D009154:Mutation; D009363:Neoplasm Proteins / Q000235:genetics* / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D011485:Protein Binding; D017510:Protein Folding; D019089:Stem Cell Factor / Q000235:genetics* / Q000378:metabolism
chemical_list: C116614:ABCG2 protein, human; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D009363:Neoplasm Proteins; D019089:Stem Cell Factor