title: Multi-step aberrant CpG island hyper-methylation is associated with the progression of adult T-cell leukemia/lymphoma.
abstract: Aberrant CpG island methylation contributes to the pathogenesis of various malignancies. However, little is known about the association of epigenetic abnormalities with multistep tumorigenic events in adult T cell leukemia/lymphoma (ATLL). To determine whether epigenetic abnormalities induce the progression of ATLL, we analyzed the methylation profiles of the SHP1, p15, p16, p73, HCAD, DAPK, hMLH-1, and MGMT genes by methylation specific PCR assay in 65 cases with ATLL patients. The number of CpG island methylated genes increased with disease progression and aberrant hypermethylation in specific genes was detected even in HTLV-1 carriers and correlated with progression to ATLL. The CpG island methylator phenotype (CIMP) was observed most frequently in lymphoma type ATLL and was also closely associated with the progression and crisis of ATLL. The high number of methylated genes and increase of CIMP incidence were shown to be unfavorable prognostic factors and correlated with a shorter overall survival by Kaplan-Meyer analysis. The present findings strongly suggest that the multistep accumulation of aberrant CpG methylation in specific target genes and the presence of CIMP are deeply involved in the crisis, progression, and prognosis of ATLL, as well as indicate the value of CpG methylation and CIMP for new diagnostic and prognostic biomarkers.
authors.affiliation: Departments of Pathology & Oncology, Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama University, Okayama 700-8558, Japan.
authors.forename: Hiaki
authors.initials: H
authors.lastname: Sato
authors.forename: Takashi
authors.initials: T
authors.lastname: Oka
authors.forename: Yoko
authors.initials: Y
authors.lastname: Shinnou
authors.forename: Takami
authors.initials: T
authors.lastname: Kondo
authors.forename: Kana
authors.initials: K
authors.lastname: Washio
authors.forename: Masayuki
authors.initials: M
authors.lastname: Takano
authors.forename: Katsuyoshi
authors.initials: K
authors.lastname: Takata
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Morito
authors.forename: Xingang
authors.initials: X
authors.lastname: Huang
authors.forename: Maiko
authors.initials: M
authors.lastname: Tamura
authors.forename: Yuta
authors.initials: Y
authors.lastname: Kitamura
authors.forename: Nobuya
authors.initials: N
authors.lastname: Ohara
authors.forename: Mamoru
authors.initials: M
authors.lastname: Ouchida
authors.forename: Koichi
authors.initials: K
authors.lastname: Ohshima
authors.forename: Kenji
authors.initials: K
authors.lastname: Shimizu
authors.forename: Mitsune
authors.initials: M
authors.lastname: Tanimoto
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Takahashi
authors.forename: Masao
authors.initials: M
authors.lastname: Matsuoka
authors.forename: Atae
authors.initials: A
authors.lastname: Utsunomiya
authors.forename: Tadashi
authors.initials: T
authors.lastname: Yoshino
mesh_terms: D000328:Adult; D000368:Aged; D001483:Base Sequence; D018899:CpG Islands / Q000235:genetics*; D019175:DNA Methylation / Q000235:genetics*; D018450:Disease Progression; D020868:Gene Silencing; D052138:Genes, Neoplasm / Q000235:genetics; D006801:Humans; D053208:Kaplan-Meier Estimate; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000235:genetics* / Q000473:pathology*; D008875:Middle Aged; D008957:Models, Genetic; D008969:Molecular Sequence Data; D009363:Neoplasm Proteins / Q000378:metabolism; D016133:Polymerase Chain Reaction
chemical_list: D009363:Neoplasm Proteins