Cytogenetic Analysis in Hematological Malignancies

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  • 1. Cytogenetic Analysis in Hematological Malignancies Hwei-Fang Tien, National Taiwan University Hospital
  • 2. Cytogenetics in Hematological Malignancies • Most patients with hematological malignancies have clonal chromosomal abnormalities. • Some recurrent chromosomal abnormalities are tumor- and even subtype-specific, so are good for diagnosis and classification. • The pattern of chromosomal aberrations may predict treatment response and clinical outcome and is good for risk stratification. • Genes located at the breakpoints of the recurrent abnormalities play an important role in the process of tumorigenesis and can be the target of treatment.
  • 3. Purpose of Cytogenetic Study in Hematological malignancies 1. Diagnosis and classification 2. Risk stratification 3. Selection of proper treatment 4. Follow-up of the response
  • 4. Recurrent chromosomal abnormalities in Hematological malignancies CML t(9;22) AML t(8;21), t(15;17), inv(16), t(9;11), inv(3), t(6;9), t(1;22), -5/5q-, -7/7q- ALL t(4;11), t(1;19), t(v;11q23), t(12;21) MDS -5/del(5q), del(20q); -7/del(7q), +8 Lymphoma DLBCL t(3q27) Burkitt t(8;14) and variant Follicular t(14;18) Mantle cell t(11;14) Marginal zone t(11;18), t(1;14), t(14;18)
  • 5. Case Demonstration Diagnosis
  • 6. BM smears in a patient with bleeding tendency NTUH, Gene Chromosome Cancer, 1995,12:161 23Y/O, male , PB plt, 3000/μL; Hb, 9.2 gm/dL; WBC, normal Plt count increased to 533x103/μL after steroid treatment, but dropped again 1 mo later. BM smears
  • 7. BM smears
  • 8. Cytogenetic Abnormalities NTUH, Gene Chromosome Cancer, 1995,12:161 The pt received splectomy. Final dignosis: hepatosplenic Tγ/δ lymphoma A new cytogentc- clinicopathological entity of NHL
  • 9. NK-cell large granular lymphocytosis NTUH, Br J Haematol, 1998, 103:1124 Cytogenetic Abnormalities Diagnosis: NK-cell large granular lymphocyte leukemia PB smears
  • 10. Differential diagnosis of hypoplastic MDS with AA BM smears
  • 11. Name: 林X榮, 46, XY, -7 [20] Chromosomal abnormality Diagnosis: hypoplastic MDS NTUH, Leukemia, 2008, 22:544
  • 12. Case Demonstration For Lymphoma Staging
  • 13. BM study for staging in a patients with DLBCL Pathol exam. of the BM biopsy specimen: no lymphoma involvement BM smears
  • 14. BM smears
  • 15. Same clonal chromosomal abnormalities in bone marrow as in lymph node Lymph node Bone marrow DLBCL stage IV with BM involvement is confirmed
  • 16. Risk Stratification
  • 17. AML: Impact of Cytogenetics based on 2008 WHO Classification Medical Research Council , United Kingdom Blood. 2010;116(3):354 , Blood Rev, 2011; 25:39 t(9;22) -7/7q- -5/5q- Inv(3), t(3;3) t(9;11) t(3;5) t(6;9) MDS-related other t(11q23) t(15;17) t(8;21) Inv(16) 5876 patients Normal
  • 18. MDS: New Cytogenetic Scoring System (n=2,754) Abnormality Overall survival AML transformation Prognostic Subgroup No. of Pts % Single Double Cplx Median (months) Median (months) Very good 81 2.9 del(11q), -Y ― ― 60.8 NR Good (reference) 1,809 65.7 Normal, del(5q) del(12p), del(20q) Including del(5q) ― 48.6 NR Intermediate 529 19.2 del(7q), +8, i(17q) +19, any other Independent clones Any other ― 26.0 78.0 Poor 148 5.4 Inv(3)/t(3q)/del(3q), -7 Including -7/del(7q) 3 15.8 21.0 Very poor 187 6.8 ― ― > 3 5.9 8.2 Abbreviations: AML, acute myeloid leukemia; NR, not reached. Schanz et al, J Clin Oncol, 2012
  • 19. MM: Impact of genomic aberrations on OS Avet-Loiseau et al, Blood. 2007;109:3489
  • 20. Implication of cytogenetics on survival in MM overall survival (month) 2001000 CumulativeSurvival 1.0 .8 .6 .4 .2 0.0 Hyperdipolidy (n=19) Non-hyperdiploid (n=25) p=0.025 overall survival (month) 2001000 CumulativeSurvival 1.0 .8 .6 .4 .2 0.0 Normal karyotype (n=106) Abnormal karyotype (n=44) P=0.029 NTUH, Ann Oncol 16:1530, 2005
  • 21. overall survival (month) 2001000 1.0 .8 .6 .4 .2 0.0 FISH_∆13 only, N=23 Without abnormality, N=57 p=0.013 CG_∆13 N=8 Survival Analysis: Combined cytogenetics & FISH NTUH, Ann Oncol 16:1530, 2005
  • 22. Prognostic relevance of chromosome aberrations in CLL Zenz & Dohner, Best Pract Res Clin Haematol. 2007 20:439 17p- 11q- +12 13q- sole normal
  • 23. Implications of 17p-/11q- on OS in CLL Cytogenetics FISH NTUH, Ann Hema, 2013, in press
  • 24. Follow Up the Clinical Course
  • 25. Chronic Myeloid Leukemia, Chronic Phase
  • 26. CML in blast crisis
  • 27. Indication of Cytogenetic Study • Unknown cause of cytopenia • Fever of unknown origin • WHO classification of AML and ALL • MDS diagnosis and classification (IPSS, IPSS-R) • Lymphoma diagnosis, classification and staging work up • Risk stratification of CLL and MM • Follow-up of treatment response
  • 28. 台灣藍鵲( Formosan Blue Magpie )
  • 29. Cytogenetics in Hematological Malignancies • Most patients with hematological malignancies have clonal chromosomal abnormalities. • Some recurrent chromosomal abnormalities are tumor- and even subtype-specific, so are good for diagnosis and classification. • The pattern of chromosomal aberrations may predict treatment response and clinical outcome and is good for risk stratification. • Genes located at the breakpoints of the recurrent abnormalities play an integral role in the process of tumorigenesis.
  • 30. Burkitt lymphoma
  • 31. t(8:14)(q24:q32)
  • 32. Relationship between Chromosomal Alterations and Pathogenesis of Cancer Nonrandom nature of chromosomal alterations in cancer CML : t(9;22) AML : t(8;21), t(15;17), inv(16) ALL : t(4;11), t(1;19) Lymphoma : t(8;14), t(14;18), t(11;14) Constitutional chromosomal deletions predispose to the development of cancer 13q14 deletion  retinoblastoma 11p13 or 11p15  Wilms’ tumor
  • 33. Hypoplastic MDS