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MYC/BCL2 protein coexpression contributes inferior outcome in DLBCL
R4 簡聖軒 指導老師 : 高志平大夫
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Outline
Maturation of B lymphocyte DLBCL classification Double hit DLBCL MYC/BCL-2 co-expression DLBCL Conclusion and take home message
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DLBCL, NOS
Common morphologic variants Centroblastic/immunoblastic/anaplastic
Rare morphologic variants Molecular subgroups
Germinal centre B cell like(GCB) Activated B cell like (ABC)
Immnuohistochemical subgroup CD-5 (+) DLBCL Germinal centre B cell like (GCB) Non-germinal centre B cell like (non-GCB)
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Distinct type of DLBCL by gene expression profiling
Nature 2000, 403:503-511
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Germinal center/ activated B cell GCB: BCL6, CD 10 ABC: MYC, MUM1, CD44, FLIP, cyclin
D2
Nature 2000, 403:503-511
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Double hit lymphoma
•16 case •From 1998-2006 •CD20, CD10, Bcl-6, Mum-1, Bcl-2 CD138, MIB1, CD19, CD5, CD38 •DLBCL with a germinal center (GC) profile.•Progression free survival : 4 months •Over all survival : 5 months
Haematologica :92; 10, 1335-1342, 2007
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Double hit lymphoma
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Double hit lymphoma
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Double hit in DLBCL
Chromosome breaks targeting the MYC gene located at the 8q24 in combination with additional rearrangement, such as BCL2,BCL6
MYC/BCL2 double hit lymphoma extremely poor prognosis Most GCB type
Haematologica :92; 10, 1335-1342, 2007
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Co-expression MYC/BCL-2
•307 cases (167 in training /140 in validation center)• Detected MYC, BCL-2 by IHC •MYC correlated with high MYC mRNA and MYC translocation •Co expression of MYC and BCL-2 protein had inferior outcome
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MYC/BCL-2 VS others VS DHIT
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Method
Reviewed 893 cases Tissue microarray
immunohistochemical stain FISH for MYC, BCL-2 and sequencing
TP53 Gene expression profiling COO classification: combined with
GEP+IHC
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Result
64% MYC(+), 50% BCL-2(+) 34% MYC(+) + BCL-2(+) 19% MYC(-) + BCL-2(-)
MYC+BCL2
Others P
5-yr OS 30% 75% <0.0001
5-yr PFS 27% 73% <0.0001
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All VS subgroup comparsion
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COO type result
GCB
ABC
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IPI + DP result
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MYC/BCL-2 vs COO
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MYC/BCL-2 vs COO
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GEP for MYC/BCL-2(+) ABC VS GCB
•208 genes express differentially P<0.001•GCB: CD10 BCL-6 MYBL1 PI3KCG •ABC: MUM1 cyclin D2 FLIP CD44 SLAP
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GEP for MYC/BCL-2(-) ABC VS GCB
•No significant difference as P <0.001 •20 gene express differentially as P <0.01 •13/20 gene also express in MYC/BCL-2(+) COO differentially
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MYC/BCL2(+) VS MYC/BCL2(+)
Total 153 genes were differentially expressed (P<0.001) 65 genes up-regulated 88 genes down-regulated
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Discussion
5-yrs OS/PFS <30 % in MYC/BCL co- expression
Correlated with poor prognosis factor: older age, advanced stage, extra-nodal, high IPI
29% DLBCL, expand the spectrum of aggressive DLBCL via IHC VS 3% double hit via genetic level
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Discussion
MYC/BCL-2 co-expression is more frequently observed in ABC subtype
MYC/BCL-2 co-expression contributes to the overall poor prognosis of this patient subset
1. Excluded MYC/BCL-2 (+), ABC ≒GCB 2. In MYC/BCL-2 (+), ABC ≒GCB 3. Difference in gene signatures
between 2 subtypes was minimal in MYC/BCL-2 (-)
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Take home message
DLBCL is heterogeneous group MYC/BCL-2 co-expression identified
by IHC: poor prognosis, expand the spectrum of MYC/BCL-2 double hit in gene rearrangement
Assessment for MYC and BCL-2 protein expression more reliably predicts prognosis than COO classification
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Thanks