MYC/BCL2 protein coexpression contributes inferior outcome in DLBCL 指導老師: 高志平大夫

Outline Maturation of B lymphocyte DLBCL classification Double hit DLBCL MYC/BCL-2 co-expression DLBCL Conclusion and take home message

DLBCL, NOS Common morphologic variants Rare 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)

Distinct type of DLBCL by gene expression profiling Nature 2000, 403:503-511

Germinal center/ activated B cell GCB: BCL6, CD 10 ABC: MYC, MUM1, CD44, FLIP, cyclin D2 Nature 2000, 403:503-511

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

Double hit lymphoma

Double hit lymphoma

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

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

MYC/BCL-2 VS others VS DHIT

Characters in cell origin

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

Result 64% MYC(+), 50% BCL-2(+) 34% MYC(+) + BCL-2(+) Others P 5-yr OS 30% 75% <0.0001 5-yr PFS 27% 73%

All VS subgroup comparsion

COO type result GCB ABC

IPI + DP result

MYC/BCL-2 vs COO

MYC/BCL-2 vs COO

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

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

MYC/BCL2(+) VS MYC/BCL2(+) Total 153 genes were differentially expressed (P<0.001) 65 genes up-regulated 88 genes down-regulated

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

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 Excluded MYC/BCL-2 (+), ABC ≒GCB In MYC/BCL-2 (+), ABC ≒GCB Difference in gene signatures between 2 subtypes was minimal in MYC/BCL-2 (-)

Discussion Down regulation of ECM, lack of cell-cell and cell-matrix adhesion may play a role in the high frequency of advanced stage and extra-nodal involvement Inferior prognosis of patients with the ABC-DLBCL has been attributed to constitutive NF-kB activities

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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