Multi-step aberrant CpG island hyper-methylation is associated with the progression of adult T-cell leukemia/lymphoma.
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.
Sato
Hiaki
H
Departments of Pathology & Oncology, Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama University, Okayama 700-8558, Japan.
Oka
Takashi
T
Shinnou
Yoko
Y
Kondo
Takami
T
Washio
Kana
K
Takano
Masayuki
M
Takata
Katsuyoshi
K
Morito
Toshiaki
T
Huang
Xingang
X
Tamura
Maiko
M
Kitamura
Yuta
Y
Ohara
Nobuya
N
Ouchida
Mamoru
M
Ohshima
Koichi
K
Shimizu
Kenji
K
Tanimoto
Mitsune
M
Takahashi
Kiyoshi
K
Matsuoka
Masao
M
Utsunomiya
Atae
A
Yoshino
Tadashi
T
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
D009363:Neoplasm Proteins