MYC/BCL2 protein coexpression contributes inferior outcome in DLBCL

R4 簡聖軒 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 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

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(+) 19% MYC(-) + BCL-2(-)

MYC+BCL2

Others P

5-yr OS 30% 75% <0.0001

5-yr PFS 27% 73% <0.0001

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

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 (-)

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

Thanks