Analysis of genome-wide DNA methylation profile according to Chlamydophila psittaci infection and the response to doxycycline treatment in ocular adnexal MALT lymphoma of Korean
한국인의 안구부속조직 점막기원 림프종에서 Chlamydophila psittaci 감염 여부와 독시사이클린 치료의 반응에 따른 전체 유전자 메틸화 양상의 비교 분석

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의과대학 의학과
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서울대학교 대학원
학위논문 (박사)-- 서울대학교 대학원 : 의학과, 2014. 2. 곽상인.
Background and purpose: Lymphomas of the ocular adnexa are the most common malignant tumor arising from the ocular adnexa. In Korea, extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue (MALT) accounts for a higher proportion than in western countries. Chlamydophila psittaci (Cp) is suggested to be a possible etiologic agent for ocular adnexal MALT lymphoma and Cp-eradicating treatment using doxycycline antibiotics has been attempted as a first-line targeted therapy in South Korea. Epigenetic alterations in association with aberrant promoter hypermethylation are also observed in MALT lymphomas, but genome-wide screening of DNA methylation profiles has not been performed. In this study, we compared genome-wide DNA methylation profiles according to Cp infection status and the response to doxycycline treatment in a Korean ocular adnexal MALT lymphoma patients.

Methods: Twelve ocular adnexal MALT lymphoma cases were classified into two groups (6 Cp-positive cases and 6 Cp-negative cases). Among the 12 cases, 8 were treated with doxycycline as a first-line therapy, and they were divided into 2 groups according to their response to the treatment (4 Doxy-responders and 4 Doxy-nonresponders). The differences in the DNA methylation states of 27,578 methylation sites in 14,000 genes were evaluated using Illumina bead assay technology. We also validated the top-ranking differentially methylated genes (DMGs) by bisulfite direct sequencing or pyrosequencing.

Results: The Infinium Methylation chip assay revealed 180 DMGs in the Cp-positive group (74 hypermethylated genes and 106 hypomethylated genes) compared to the Cp-negative group. Among the 180 DMGs, DUSP22, which had 2 significantly hypomethylated loci, was validated, and the correlation was significant for one CpG site (Spearman coefficient = 0.6478, p = 0.0262). With regard to the response to doxycycline treatment, a total of 778 DMGs were revealed (389 hypermethylated genes and 336 hypomethylated genes in the Doxy-responder group). In a subsequent replication study for representative hypomethylated (IRAK1) and hypermethylated (CXCL6) genes, the correlation between the bead chip analysis and pyrosequencing was significant (Spearman coefficient = 0.8961 and 0.7619, respectively, p < 0.05).

Conclusions: Ocular adnexal MALT lymphoma showed distinct methylation patterns according to Cp infection and the response to doxycycline treatment in this genome-wide methylation study. Among the candidate genes, DUSP22 has a methylation status that was likely attributable to Cp infection. Our data also suggest that the methylation statuses of IRAK1 and CXCL6 may reflect the response to doxycycline treatment.
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College of Medicine/School of Medicine (의과대학/대학원)Dept. of Medicine (의학과)Theses (Ph.D. / Sc.D._의학과)
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