TY - JOUR
T1 - Multi-step aberrant CpG island hyper-methylation is associated with the progression of adult T-cell leukemia/lymphoma
AU - Satou, Hiaki
AU - Oka, Takashi
AU - Shinnou, Yoko
AU - Kondo, Takumi
AU - Washio, Kana
AU - Takano, Masayuki
AU - Takata, Katsuyoshi
AU - Morito, Toshiaki
AU - Huang, Xingang
AU - Tamura, Maiko
AU - Kitamura, Yuta
AU - Ohara, Nobuya
AU - Ouchida, Mamoru
AU - Ohshima, Koichi
AU - Shimizu, Kenji
AU - Tanimoto, Mitsune
AU - Takahashi, Kiyoshi
AU - Matsuoka, Masao
AU - Utsunomiya, Atae
AU - Yoshino, Tadashi
N1 - Funding Information:
Supported by the Ministry of Education, Culture, Sports, Science and Technology of Japan (T.O.) (#12670161, #09470051).
PY - 2010/1
Y1 - 2010/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=73949141500&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=73949141500&partnerID=8YFLogxK
U2 - 10.2353/ajpath.2010.090236
DO - 10.2353/ajpath.2010.090236
M3 - Article
C2 - 20019193
AN - SCOPUS:73949141500
SN - 0002-9440
VL - 176
SP - 402
EP - 415
JO - American Journal of Pathology
JF - American Journal of Pathology
IS - 1
ER -