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MYC/BCL2 protein coexpression contributes inferior outcome in DLBCL

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 .

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MYC/BCL2 protein coexpression contributes inferior outcome in DLBCL

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  1. MYC/BCL2 protein coexpression contributes inferior outcome in DLBCL R4 簡聖軒 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

  3. 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)

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

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

  6. Double hit lymphoma • 16case • 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

  7. Double hit lymphoma

  8. Double hit lymphoma

  9. 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

  10. Co-expression MYC/BCL-2 • 307 cases (167 in training /140 in validation center) • Detected MYC, BCL-2by IHC • MYC correlated with high MYC mRNA and MYC translocation • Co expression of MYC and BCL-2 protein had inferior outcome

  11. MYC/BCL-2 VS others VS DHIT

  12. 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

  13. Result • 64% MYC(+), 50% BCL-2(+) • 34% MYC(+) + BCL-2(+) • 19% MYC(-) + BCL-2(-)

  14. All VS subgroup comparsion

  15. COO type result GCB ABC

  16. IPI + DP result

  17. MYC/BCL-2 vs COO

  18. MYC/BCL-2 vs COO

  19. 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

  20. 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

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

  22. 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

  23. 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 (-)

  24. 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

  25. Thanks

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