Cytogenetic Analysis in Hematological Malignancies

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Cytogenetic Analysis in Hematological Malignancies

  1. 1. Cytogenetic Analysis in Hematological Malignancies Hwei-Fang Tien, National Taiwan University Hospital
  2. 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. 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. 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. 5. Case Demonstration Diagnosis
  6. 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. 7. BM smears
  8. 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. 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. 10. Differential diagnosis of hypoplastic MDS with AA BM smears
  11. 11. Name: 林X榮, 46, XY, -7 [20] Chromosomal abnormality Diagnosis: hypoplastic MDS NTUH, Leukemia, 2008, 22:544
  12. 12. Case Demonstration For Lymphoma Staging
  13. 13. BM study for staging in a patients with DLBCL Pathol exam. of the BM biopsy specimen: no lymphoma involvement BM smears
  14. 14. BM smears
  15. 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. 16. Risk Stratification
  17. 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. 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. 19. MM: Impact of genomic aberrations on OS Avet-Loiseau et al, Blood. 2007;109:3489
  20. 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. 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. 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. 23. Implications of 17p-/11q- on OS in CLL Cytogenetics FISH NTUH, Ann Hema, 2013, in press
  24. 24. Follow Up the Clinical Course
  25. 25. Chronic Myeloid Leukemia, Chronic Phase
  26. 26. CML in blast crisis
  27. 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. 28. 台灣藍鵲( Formosan Blue Magpie )
  29. 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. 30. Burkitt lymphoma
  31. 31. t(8:14)(q24:q32)
  32. 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. 33. Hypoplastic MDS

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