Multi-step aberrant CpG island hyper-methylation is associated with the progression of adult T-cell leukemia/lymphoma

Hiaki Sato, Takashi Oka, Yoko Shinnou, Takami Kondo, Kana Washio, Masayuki Takano, Katsuyoshi Takata, Toshiaki Morito, Xingang Huang, Maiko Tamura, Yuta Kitamura, Nobuya Ohara, Mamoru Ouchida, Koichi Ohshima, Kenji Shimizu, Mitsune Tanimoto, Kiyoshi Takahashi, Masao Matsuoka, Atae Utsunomiya, Tadashi Yoshino

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53 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)402-415
Number of pages14
JournalAmerican Journal of Pathology
Volume176
Issue number1
DOIs
Publication statusPublished - Jan 2010

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

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    Sato, H., Oka, T., Shinnou, Y., Kondo, T., Washio, K., Takano, M., Takata, K., Morito, T., Huang, X., Tamura, M., Kitamura, Y., Ohara, N., Ouchida, M., Ohshima, K., Shimizu, K., Tanimoto, M., Takahashi, K., Matsuoka, M., Utsunomiya, A., & Yoshino, T. (2010). Multi-step aberrant CpG island hyper-methylation is associated with the progression of adult T-cell leukemia/lymphoma. American Journal of Pathology, 176(1), 402-415. https://doi.org/10.2353/ajpath.2010.090236