Dataset Information

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.

SUBMITTER: Limm K

PROVIDER: S-EPMC4968798 | biostudies-literature | 2016

REPOSITORIES: biostudies-literature

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Characterization of the Methylthioadenosine Phosphorylase Polymorphism rs7023954 - Incidence and Effects on Enzymatic Function in Malignant Melanoma.

Limm Katharina K Dettmer Katja K Reinders Jörg J Oefner Peter J PJ Bosserhoff Anja-Katrin AK

PloS one 20160801 8

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 global ...[more]

PMID: 27479139

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Project description:Identification of cancer-associated genes by genomic profiling contributes to the elucidation of tumor development and progression. The methylthioadenosine phosphorylase (MTAP) gene, located at chromosome 9p21, plays a critical role in tumorigenicity and disease progression in a wide variety of cancers. However, the prognostic impact of MTAP in patients with nasopharyngeal carcinoma (NPC) remains obscured. Through data mining from published transcriptomic database, MTAP was first identified as a differentially downregulated gene in NPC. In this study, our aim was to evaluate the expression of MTAP in NPC and to clarify its prognostic significance.MTAP immunohistochemistry was retrospectively performed and analyzed in biopsy specimens from 124 NPC patients who received standard treatment without distant metastasis at initial diagnosis. The immunoexpression status was correlated with the clinicopathological variables, disease-specific survival (DSS), distant metastasis-free survival (DMFS), and local recurrence-free survival (LRFS). Real-time quantitative polymerase chain reaction (PCR) was used to measure MTAP gene dosage. In some cases, we also performed methylation-specific PCR and pyrosequencing to assess the status of promoter methylation.MTAP deficiency was significantly associated with advanced tumor stages (P?=?0.023) and univariately predictive of adverse outcomes for DSS, DMFS, and LRFS. In the multivariate comparison, MTAP deficiency still remained prognostically independent to portend worse DSS (P?=?0.021, hazard ratio?=?1.870) and DMFS (P?=?0.009, hazard ratio?=?2.154), together with advanced AJCC stages III to IV. Homozygous deletion or promoter methylation of MTAP gene were identified to be significantly associated with MTAP protein deficiency (P?<?0.001).MTAP deficiency was correlated with an aggressive phenotype and independently predictive of worse DSS and DMFS, suggesting its role in disease progression and as an independent prognostic biomarker of NPC, which potentially offers new strategy of targeted treatment for patients lacking MTAP expression.

Dataset Information

Characterization of the Methylthioadenosine Phosphorylase Polymorphism rs7023954 - Incidence and Effects on Enzymatic Function in Malignant Melanoma.

Publications

Characterization of the Methylthioadenosine Phosphorylase Polymorphism rs7023954 - Incidence and Effects on Enzymatic Function in Malignant Melanoma.

Similar Datasets

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