TY - JOUR

T1 - MicroRNA profiling in ocular adnexal lymphoma

T2 - a role for MYC and NFKB1 mediated dysregulation of microRNA expression in aggressive disease

AU - Hother, Christoffer

AU - Rasmussen, Peter Kristian

AU - Joshi, Tejal

AU - Reker, Ditte

AU - Ralfkiær, Ulrik

AU - Workman, Christopher T

AU - Heegaard, Steffen

AU - Ralfkiær, Elisabeth

AU - Grønbæk, Kirsten

PY - 2013/8

Y1 - 2013/8

N2 - PURPOSE: Ocular adnexal lymphoma (i.e., lymphoma with involvement of the orbit, eyelids, conjunctiva, lacrimal gland, and lacrimal sac), although rare, is common among malignant tumors involving the ocular adnexal region. The main subtypes are low-grade extranodal marginal zone lymphoma (EMZL) and aggressive diffuse large B-cell lymphoma (DLBCL). In rare cases, low-grade EMZL are reported to transform to DLBCL. It is unclear, however, which genetic events distinguish low-grade disease from aggressive, potentially fatal disease.METHODS: Using LNA-based arrays from Exiqon, we performed global microRNA (miRNA) expression profiling of 18 EMZLs and 25 DLBCLs involving ocular adnexal sites to investigate changes in the miRNA expression in low- versus high-grade disease. Findings were confirmed by real-time quantitative PCR (RTq-PCR).RESULTS: Our analysis revealed 43 miRNAs with altered expression profiles in DLBCL compared to EMZL. Seven of the miRNAs down-regulated in DLBCL relative to EMZL showed enrichment for a direct transcriptional repression by the oncoprotein MYC. We also report a possible loss-of-regulation of NFKB1 and its downstream miRNAs. In addition, our analysis identified a group of DLBCLs whose expression profiles resembled that of EMZL. Although transformation of EMZL to DLBCL in the ocular adnexal region is rare, we hypothesize that the intermediate group potentially may derive from transformation of EMZL that was not recognized by histology.CONCLUSIONS: We conclude that fundamental differences in miRNA expression exist between ocular adnexal EMZL and DLBCL, mainly due to differences in MYC and NF-ĸB regulatory pathways.

AB - PURPOSE: Ocular adnexal lymphoma (i.e., lymphoma with involvement of the orbit, eyelids, conjunctiva, lacrimal gland, and lacrimal sac), although rare, is common among malignant tumors involving the ocular adnexal region. The main subtypes are low-grade extranodal marginal zone lymphoma (EMZL) and aggressive diffuse large B-cell lymphoma (DLBCL). In rare cases, low-grade EMZL are reported to transform to DLBCL. It is unclear, however, which genetic events distinguish low-grade disease from aggressive, potentially fatal disease.METHODS: Using LNA-based arrays from Exiqon, we performed global microRNA (miRNA) expression profiling of 18 EMZLs and 25 DLBCLs involving ocular adnexal sites to investigate changes in the miRNA expression in low- versus high-grade disease. Findings were confirmed by real-time quantitative PCR (RTq-PCR).RESULTS: Our analysis revealed 43 miRNAs with altered expression profiles in DLBCL compared to EMZL. Seven of the miRNAs down-regulated in DLBCL relative to EMZL showed enrichment for a direct transcriptional repression by the oncoprotein MYC. We also report a possible loss-of-regulation of NFKB1 and its downstream miRNAs. In addition, our analysis identified a group of DLBCLs whose expression profiles resembled that of EMZL. Although transformation of EMZL to DLBCL in the ocular adnexal region is rare, we hypothesize that the intermediate group potentially may derive from transformation of EMZL that was not recognized by histology.CONCLUSIONS: We conclude that fundamental differences in miRNA expression exist between ocular adnexal EMZL and DLBCL, mainly due to differences in MYC and NF-ĸB regulatory pathways.

KW - Adult

KW - Aged

KW - Aged, 80 and over

KW - Conjunctival Neoplasms

KW - Eye Neoplasms

KW - Female

KW - Follow-Up Studies

KW - Gene Expression Regulation, Neoplastic

KW - Humans

KW - Lacrimal Apparatus

KW - Lymphoma, Large B-Cell, Diffuse

KW - Male

KW - MicroRNAs

KW - Middle Aged

KW - NF-kappa B p50 Subunit

KW - Orbital Neoplasms

KW - Protein Array Analysis

KW - Proto-Oncogene Proteins c-myc

KW - RNA, Neoplasm

KW - Real-Time Polymerase Chain Reaction

U2 - 10.1167/iovs.13-12272

DO - 10.1167/iovs.13-12272

M3 - Journal article

C2 - 23821202

VL - 54

SP - 5169

EP - 5175

JO - Investigative Ophthalmology & Visual Science

JF - Investigative Ophthalmology & Visual Science

SN - 0146-0404

IS - 8

ER -