title: Independent Loss of Methylthioadenosine Phosphorylase (MTAP) in Primary Cutaneous T-Cell Lymphoma.
abstract: Methylthioadenosine phosphorylase (MTAP) and the tumor suppressor genes CDKN2A-CDKN2B are frequently deleted in malignancies. The specific role of MTAP in cutaneous T-cell lymphoma subgroups, mycosis fungoides (MF) and Sézary syndrome (SS), is unknown. In 213 skin samples from patients with MF/SS, MTAP copy number loss (34%) was more frequent than CDKN2A (12%) in all cutaneous T-cell lymphoma stages using quantitative reverse transcription PCR. Importantly, in early stage MF, MTAP loss occurred independently of CDKN2A loss in 37% of samples. In peripheral blood mononuclear cells from patients with SS, codeletion with CDKN2A occurred in 18% of samples but loss of MTAP alone was uncommon. In CD4(+) cells from SS, reduced MTAP mRNA expression correlated with MTAP copy number loss (P < 0.01) but reduced MTAP expression was also detected in the absence of copy number loss. Deep sequencing of MTAP/CDKN2A-CDKN2B loci in 77 peripheral blood mononuclear cell DNA samples from patients with SS did not show any nonsynonymous mutations, but read-depth analysis suggested focal deletions consistent with MTAP and CDKN2A copy number loss detected with quantitative reverse transcription PCR. In a cutaneous T-cell lymphoma cell line, promoter hypermethylation was shown to downregulate MTAP expression and may represent a mechanism of MTAP inactivation. In conclusion, our findings suggest that there may be selection in early stages of MF for MTAP deletion within the cutaneous tumor microenvironment.
authors.affiliation: St John's Institute of Dermatology, Division of Genetics and Molecular Medicine, Faculty of Life Sciences & Medicine, King's College London, London, UK.
authors.forename: Wesley J
authors.initials: WJ
authors.lastname: Woollard
authors.affiliation: St John's Institute of Dermatology, Division of Genetics and Molecular Medicine, Faculty of Life Sciences & Medicine, King's College London, London, UK.
authors.forename: Nithyha P
authors.initials: NP
authors.lastname: Kalaivani
authors.affiliation: St John's Institute of Dermatology, Division of Genetics and Molecular Medicine, Faculty of Life Sciences & Medicine, King's College London, London, UK.
authors.forename: Christine L
authors.initials: CL
authors.lastname: Jones
authors.affiliation: St John's Institute of Dermatology, Division of Genetics and Molecular Medicine, Faculty of Life Sciences & Medicine, King's College London, London, UK.
authors.forename: Catherine
authors.initials: C
authors.lastname: Roper
authors.affiliation: St John's Institute of Dermatology, Division of Genetics and Molecular Medicine, Faculty of Life Sciences & Medicine, King's College London, London, UK.
authors.forename: Lam
authors.initials: L
authors.lastname: Tung
authors.affiliation: St John's Institute of Dermatology, Division of Genetics and Molecular Medicine, Faculty of Life Sciences & Medicine, King's College London, London, UK.
authors.forename: Jae Jin
authors.initials: JJ
authors.lastname: Lee
authors.affiliation: St John's Institute of Dermatology, Division of Genetics and Molecular Medicine, Faculty of Life Sciences & Medicine, King's College London, London, UK.
authors.forename: Bjorn R
authors.initials: BR
authors.lastname: Thomas
authors.affiliation: St John's Institute of Dermatology, Division of Genetics and Molecular Medicine, Faculty of Life Sciences & Medicine, King's College London, London, UK.
authors.forename: Isabella
authors.initials: I
authors.lastname: Tosi
authors.affiliation: Viapath, Skin Tumour Unit, St John's Institute of Dermatology, Guy's Hospital, London, UK.
authors.forename: Silvia
authors.initials: S
authors.lastname: Ferreira
authors.affiliation: Viapath, Skin Tumour Unit, St John's Institute of Dermatology, Guy's Hospital, London, UK.
authors.forename: Carl Z
authors.initials: CZ
authors.lastname: Beyers
authors.affiliation: St John's Institute of Dermatology, Division of Genetics and Molecular Medicine, Faculty of Life Sciences & Medicine, King's College London, London, UK.
authors.forename: Robert C T
authors.initials: RCT
authors.lastname: McKenzie
authors.affiliation: St John's Institute of Dermatology, Division of Genetics and Molecular Medicine, Faculty of Life Sciences & Medicine, King's College London, London, UK.
authors.forename: Rosie M
authors.initials: RM
authors.lastname: Butler
authors.affiliation: Transformational Bioinformatics, NIHR Research Biomedical Research Center at Guy's and St Thomas' Hospital Foundation Trust and Kings College London, London, UK.
authors.forename: Anna
authors.initials: A
authors.lastname: Lorenc
authors.affiliation: St John's Institute of Dermatology, Division of Genetics and Molecular Medicine, Faculty of Life Sciences & Medicine, King's College London, London, UK.
authors.forename: Sean J
authors.initials: SJ
authors.lastname: Whittaker
authors.affiliation: St John's Institute of Dermatology, Division of Genetics and Molecular Medicine, Faculty of Life Sciences & Medicine, King's College London, London, UK. Electronic address: tracey.mitchell@kcl.ac.uk.
authors.forename: Tracey J
authors.initials: TJ
authors.lastname: Mitchell
mesh_terms: D000328:Adult; D015331:Cohort Studies; D019175:DNA Methylation / Q000235:genetics; D005260:Female; D017353:Gene Deletion; D015972:Gene Expression Regulation, Neoplastic; D019942:Genes, p16; D006801:Humans; D016410:Lymphoma, T-Cell, Cutaneous / Q000235:genetics* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009361:Neoplasm Invasiveness / Q000473:pathology; D009367:Neoplasm Staging; D011683:Purine-Nucleoside Phosphorylase / Q000235:genetics*; D060888:Real-Time Polymerase Chain Reaction / Q000379:methods; D012878:Skin Neoplasms / Q000235:genetics* / Q000473:pathology; D014407:Tumor Cells, Cultured; D059016:Tumor Microenvironment / Q000235:genetics
chemical_list: D011683:Purine-Nucleoside Phosphorylase; C021784:5'-methylthioadenosine phosphorylase