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

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

4. 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)

5. Distinct type of DLBCL by gene expression profiling
Nature 2000, 403:

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

10. 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, , 2007

11. Double hit lymphoma

13. Double hit lymphoma

14. 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, , 2007

15. 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

16. MYC/BCL-2 VS others VS DHIT

17. Characters in cell origin

19. 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

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

21. All VS subgroup comparsion

22. COO type result
GCB
ABC

23. IPI + DP result

25. MYC/BCL-2 vs COO

26. MYC/BCL-2 vs COO

28. 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

29. 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

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

31. 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

32. 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 (-)

33. 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

34. 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

35. Thanks