title: Characterization of the Methylthioadenosine Phosphorylase Polymorphism rs7023954 - Incidence and Effects on Enzymatic Function in Malignant Melanoma.
abstract: Deficiency of methylthioadenosine phosphorylase (MTAP) supports melanoma development and progression through accumulation of its substrate 5'-methylthioadenosine (MTA), which leads amongst others to a constitutive inhibition of protein arginine methyltransferases (PRMTs) and activation of the transcription factor AP-1 via the receptor ADORA2B. Genetic association studies have also suggested that genetic polymorphism in MTAP may modulate the risk of melanoma. Here, we investigated the only globally common non-synonymous single nucleotide polymorphism (SNP) reported to date for MTAP. The SNP rs7023954 is located in exon 3 (c.166G>A), and leads to the conservative substitution of one branched-chain amino acid residue (valine) for another (isoleucine) at position 56 (p.Val56Ile). Whereas genotype frequencies in normal and primary melanoma tissues or cell lines were in Hardy-Weinberg equilibrium based on cDNA amplicon sequencing, a marked (P = 0.00019) deviation was observed in metastatic melanoma tissues and cell lines due to a deficit of heterozygotes. Enzyme assays conducted on the co-dominantly expressed alleles revealed no difference in the conversion rate of MTA to adenine and 5-methylthioribose-1-phosphate, indicating that this known enzymatic activity does not modulate the tumor suppressive function of MTAP.
authors.affiliation: Institute of Biochemistry, Friedrich-Alexander University of Erlangen-Nürnberg, Erlangen, Germany.
authors.forename: Katharina
authors.initials: K
authors.lastname: Limm
authors.affiliation: Institute of Functional Genomics, University of Regensburg, Regensburg, Germany.
authors.forename: Katja
authors.initials: K
authors.lastname: Dettmer
authors.affiliation: Institute of Functional Genomics, University of Regensburg, Regensburg, Germany.
authors.forename: Jörg
authors.initials: J
authors.lastname: Reinders
authors.affiliation: Institute of Functional Genomics, University of Regensburg, Regensburg, Germany.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Oefner
authors.affiliation: Institute of Biochemistry, Friedrich-Alexander University of Erlangen-Nürnberg, Erlangen, Germany.|Comprehensive Cancer Center Erlangen, CCC Erlangen-EMN, Friedrich-Alexander University of Erlangen-Nürnberg, Erlangen, Germany.
authors.forename: Anja-Katrin
authors.initials: AK
authors.lastname: Bosserhoff
mesh_terms: D000483:Alleles; D004789:Enzyme Activation / Q000235:genetics; D005091:Exons; D005787:Gene Frequency; D056726:Genetic Association Studies; D005838:Genotype; D006801:Humans; D015994:Incidence; D007700:Kinetics; D008545:Melanoma / Q000201:enzymology* / Q000453:epidemiology / Q000235:genetics* / Q000473:pathology; D020641:Polymorphism, Single Nucleotide; D011683:Purine-Nucleoside Phosphorylase / Q000235:genetics* / Q000378:metabolism; D012313:RNA / Q000737:chemistry / Q000302:isolation & purification / Q000378:metabolism; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000737:chemistry / Q000302:isolation & purification; D017423:Sequence Analysis, RNA; D021241:Spectrometry, Mass, Electrospray Ionization; D014407:Tumor Cells, Cultured
chemical_list: D011994:Recombinant Proteins; D012313:RNA; D011683:Purine-Nucleoside Phosphorylase; C021784:5'-methylthioadenosine phosphorylase