MYC/BCL2 protein coexpression - PowerPoint Presentation

Slide1

MYC/BCL2 protein coexpression contributes inferior outcome in DLBCL

R4

簡聖軒

指導老師

:

高志平大夫

Slide2

Outline Maturation of B lymphocyte

DLBCL classification

Double hit DLBCL

MYC/BCL-2 co-expression DLBCL

Conclusion and take home message

Slide3

Slide4

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)

Slide5

Distinct type of DLBCL by gene expression profiling

Nature 2000, 403:503-511

Slide6

Slide7

Germinal center/ activated B cell GCB: BCL6, CD 10

ABC: MYC, MUM1, CD44, FLIP,

cyclin

D2

Nature 2000, 403:503-511

Slide8

Slide9

Slide10

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

Slide11

Double hit lymphoma

Slide12

Slide13

Double hit lymphoma

Slide14

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

Slide15

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

Slide16

MYC/BCL-2 VS others VS DHIT

Slide17

Characters in cell origin

Slide18

Slide19

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

Slide20

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

Slide21

All VS subgroup comparsion

Slide22

COO type result

GCB

ABC

Slide23

IPI + DP result

Slide24

Slide25

MYC/BCL-2 vs COO

Slide26

MYC/BCL-2 vs COO

Slide27

Slide28

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

Slide29

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

Slide30

MYC/BCL2(+) VS MYC/BCL2(+)

Total 153 genes were differentially expressed (P<0.001)

65 genes up-regulated

88 genes down-regulated

Slide31

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

Slide32

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 (-)

Slide33

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

Slide34

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

Slide35

Thanks