title: Distinctive patterns of BCL6 molecular alterations and their functional consequences in different subgroups of diffuse large B-cell lymphoma.
abstract: Gene expression profiling of diffuse large B-cell lymphoma (DLBCL) has revealed biologically and prognostically distinct subgroups: germinal center B-cell-like (GCB), activated B-cell-like (ABC) and primary mediastinal (PM) DLBCL. The BCL6 gene is often translocated and/or mutated in DLBCL. Therefore, we examined the BCL6 molecular alterations in these DLBCL subgroups, and their impact on BCL6 expression and BCL6 target gene repression. BCL6 translocations at the major breakpoint region (MBR) were detected in 25 (18.8%) of 133 DLBCL cases, with a higher frequency in the PM (33%) and ABC (24%) subgroups than in the GCB (10%) subgroup. Translocations at the alternative breakpoint region (ABR) were detected in five (6.4%) of 78 DLBCL cases, with three cases in ABC and one case each in the GCB and the unclassifiable subgroups. The translocated cases involved IgH and non-IgH partners in about equal frequency and were not associated with different levels of BCL6 mRNA and protein expression. BCL6 mutations were detected in 61% of DLBCL cases, with a significantly higher frequency in the GCB and PM subgroups (>70%) than in the ABC subgroup (44%). Exon-1 mutations were mostly observed in the GCB subgroup. The repression of known BCL6 target genes correlated with the level of BCL6 mRNA and protein expression in GCB and ABC subgroups but not with BCL6 translocation and intronic mutations. No clear inverse correlation between BCL6 expression and p53 expression was observed. Patients with higher BCL6 mRNA or protein expression had a significantly better overall survival. The biological role of BCL6 in translocated cases where repression of known target genes is not demonstrated is intriguing and warrants further investigation.
authors.affiliation: Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE 68198, USA.
authors.forename: J
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authors.forename: T C
authors.initials: TC
authors.lastname: Greiner
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authors.lastname: Patel
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authors.lastname: Smith
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authors.lastname: Wright
authors.forename: W G
authors.initials: WG
authors.lastname: Sanger
authors.forename: D L
authors.initials: DL
authors.lastname: Pickering
authors.forename: S
authors.initials: S
authors.lastname: Jain
authors.forename: D E
authors.initials: DE
authors.lastname: Horsman
authors.forename: Y
authors.initials: Y
authors.lastname: Shen
authors.forename: K
authors.initials: K
authors.lastname: Fu
authors.forename: D D
authors.initials: DD
authors.lastname: Weisenburger
authors.forename: C P
authors.initials: CP
authors.lastname: Hans
authors.forename: E
authors.initials: E
authors.lastname: Campo
authors.forename: R D
authors.initials: RD
authors.lastname: Gascoyne
authors.forename: A
authors.initials: A
authors.lastname: Rosenwald
authors.forename: E S
authors.initials: ES
authors.lastname: Jaffe
authors.forename: J
authors.initials: J
authors.lastname: Delabie
authors.forename: L
authors.initials: L
authors.lastname: Rimsza
authors.forename: G
authors.initials: G
authors.lastname: Ott
authors.forename: H K
authors.initials: HK
authors.lastname: Müller-Hermelink
authors.forename: J M
authors.initials: JM
authors.lastname: Connors
authors.forename: J M
authors.initials: JM
authors.lastname: Vose
authors.forename: T
authors.initials: T
authors.lastname: McKeithan
authors.forename: L M
authors.initials: LM
authors.lastname: Staudt
authors.forename: W C
authors.initials: WC
authors.lastname: Chan
mesh_terms: D004252:DNA Mutational Analysis; D004268:DNA-Binding Proteins / Q000096:biosynthesis*; D005091:Exons; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D007438:Introns; D016403:Lymphoma, Large B-Cell, Diffuse / Q000235:genetics* / Q000378:metabolism; D008957:Models, Genetic; D009154:Mutation; D011379:Prognosis; D051560:Proto-Oncogene Proteins c-bcl-6; D012333:RNA, Messenger / Q000378:metabolism; D013997:Time Factors; D014178:Translocation, Genetic; D016896:Treatment Outcome
chemical_list: C084103:BCL6 protein, human; D004268:DNA-Binding Proteins; D051560:Proto-Oncogene Proteins c-bcl-6; D012333:RNA, Messenger