Primary mediastinal B-cell lymphoma: hypermutation of the BCL6 gene targets motifs different from those in diffuse large B-cell and follicular lymphomas.
OBJECTIVE
Somatic hypermutation of the BCL6 gene and its expression in lymphoma represent specific markers for B-cell transit through the germinal center. Thus, analysis of BCL6 may aid in clarifying the relationship between primary mediastinal B-cell lymphoma (PMBL) and other non-thymic diffuse large cell lymphomas (DLCL).


METHODS
Twenty-four PMBL were analyzed for BCL6 status, including first intron mutations, by quantitative reverse transcription polymerase chain reaction (RT-PCR), and immunohistochemistry. We also performed a meta-analysis of reported BCL6 mutations in PMBL (n=141), DLCL (n=233), and follicular lymphoma (n=120).


RESULTS
Thirteen PMBL (54%) showed hypermutation of BCL6. All cases showed bcl6 mRNA and immunohistochemical expression. Meta-analysis demonstrated that the preferentially altered sequence motifs of BCL6 in PMBL were TA (p=0.002) and AT (p=0.0008) dinucleotides and TAT trinucleotides (p=0.001). GC and RGYW/WRCY motifs were a target in DLCL and FL but not in PMBL. Moreover, the DNA stretch spanning nucleotides 150-270 was highly targeted only in PMBL.


CONCLUSIONS
The consistent expression of bcl6 protein and occurrence of hypermutation indicate that PMBL should be considered of germinal center origin. The fact that the hypermutation sites and mutational spectrum of BCL6 in PMBL differ from those found in FL and DLCL might suggest that the maturation block of the transforming cells differs among these tumor types, and that the characteristic mutational pattern is present before neoplastic transformation. Thus, our findings strengthen the hypothesis that PMBL originate from an already defined sub-population of B-cells, which are different from those leading to either DLCL or FL.
Malpeli
Giorgio
G
Dipartimento di Patologia, Sezione di Anatomia Patologica Università di Verona, Strada Le Grazie I-37134 Verona, Italy.
Barbi
Stefano
S
Moore
Patrick S
PS
Scardoni
Maria
M
Chilosi
Marco
M
Scarpa
Aldo
A
Menestrina
Fabio
F
D000328:Adult; D000368:Aged; D020816:Amino Acid Motifs / Q000235:genetics; D019943:Amino Acid Substitution; D016175:B-Lymphocyte Subsets / Q000473:pathology*; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D004252:DNA Mutational Analysis; D004273:DNA, Neoplasm / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics*; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D018858:Germinal Center / Q000473:pathology; D006801:Humans; D016393:Lymphoma, B-Cell / Q000235:genetics* / Q000473:pathology; D008224:Lymphoma, Follicular / Q000235:genetics* / Q000473:pathology; D016403:Lymphoma, Large B-Cell, Diffuse / Q000235:genetics* / Q000473:pathology; D008297:Male; D008479:Mediastinal Neoplasms / Q000235:genetics* / Q000473:pathology; D008875:Middle Aged; D008957:Models, Genetic; D016296:Mutagenesis; D016254:Mutagenesis, Insertional; D020125:Mutation, Missense; D009363:Neoplasm Proteins / Q000235:genetics*; D018807:Polymorphism, Single-Stranded Conformational; D051560:Proto-Oncogene Proteins c-bcl-6; D012333:RNA, Messenger / Q000096:biosynthesis; D012334:RNA, Neoplasm / Q000096:biosynthesis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017422:Sequence Analysis, DNA; D017384:Sequence Deletion
C084103:BCL6 protein, human; D004273:DNA, Neoplasm; D004268:DNA-Binding Proteins; D009363:Neoplasm Proteins; D051560:Proto-Oncogene Proteins c-bcl-6; D012333:RNA, Messenger; D012334:RNA, Neoplasm