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Tumor Cytogenetics and Chromosome Aberrations in Cancer

This reference material provides an overview of tumor cytogenetics, discussing the role of chromosome abnormalities in transformation and their association with various types of cancer. It covers methods of chromosome preparations and the recognition of chromosome aberrations. The consequences of major chromosome changes, such as translocations and fusion genes, are also explored. Case studies of chronic myelogenous leukemia (CML) and myelodysplastic syndrome (MDS) are included to illustrate the clinical significance of chromosomal changes.

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Tumor Cytogenetics and Chromosome Aberrations in Cancer

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  1. Tumor CytogeneticsVundavalli MurtyDepartment of Pathology & Cell Biology&Institute for Cancer GeneticsSept 18, 2017

  2. Reference Material • 1. Cancer Cytogenetics: Text Book: Heim S and Mitelman F, 2015 • 2. Recurrent Chromosome Aberrations in Cancer • Web site http://cgap.nci.nih.gov/Chromosomes/RecurrentAberrations • 3. Atlas of Genetics and Cytogenetics in Oncology and Haematology • Web site: http://atlasgeneticsoncology.org//

  3. Overview • - Chromosomes in human tumors are widely abnormal: • Davidvon Hansemann 1890: nuclear and mitotic abnormalities in tumors • Boveri 1914: Chromosome abnormalities play a central role in transformaton • - Controversy: Early 1950s • Whether the chromosome changes are primary events or merely secondary phenomena? • - Changed view: • Recurring chromosome aberrations associated with leukemia, lymphoma, sarcoma, carcinoma • Proto-oncogenes identified at the breakpoints • Experimental evidence for these genes in transformation • Targeted drugs that inhibit gene product: e.g. STI571 for BCR-ABL

  4. Methods of Chromosome Preparations • Actively dividing cells can be arrested at metaphase or prometaphase stages using mitotic arresting agegns (eg. Colcemid) • Direct preparations or short-term cultures to represent in vivo conditions • Hypotonic treatment & fixation • A variety of methods: Giemsa-banding • FISH (Fluorescence in situ hybridization) • Probes to detect translocations, inversions, deletions, amplification • Chromosomal CGH, SKY, array CGH, Microarray

  5. Methods Employed in Recognizing Chromosome Aberrations • Banding methods: Trypsin-Giemsa • Chromosome painting: • FISH: • Comparative Genomic Hybridization CGH): • Spectral Karyotyping (SKY): Ref. Rao PH et al. Molecular cytogenetic applications in analysis of the cancer genome. Methods Mol Biol. 2007;383:165-85.

  6. Region • Band Number • e.g., 1p34.1 • p • Centromere • q Idiograms of G-band for normal Human ChromosomesNomenclature

  7. Important designations to describe cancer karyotype • cen centromere • del deletion • der derivative chromosome • dic dicentric chromosome • dmin double minute chromosome • dup duplication • hsr homogeneously staining region • i isochromosome • ins insertion • inv inversion • mar marker chromosome • minus (-) loss • plus (+) gain • p short arm • parenthesis()surround structurally altered • chromosoems and breakpoints • ph Philadelphia chromosome • q long arm • r ring chromosome • semicolon(;)separates altered chromosomes • t translocation • A translocation between chromosomes • 9 and 22 in CML at bands 9q34 • and 22q11.2 • 46,XX,t(9;22)(q34;q11.2)[20] • A deletion of long arm of chromosome 5 at band 5q31 in a leukemia patient • 46,XY,del(5)(q31)[10]/46,XY[10] Symbols and Abbreviated Terms: ISCN, 2009

  8. Ploidy (e.g., haploid, triploid, tetraploid): Unclear Aneuploidy (e.g.,tri-,tetra-, monosomy): Increased or decreased expression of set of genes Reciprocal or non-reciprocal translocations (inversions): Overexpression/fusion gene Deletions: Loss of expression Duplications and Amplifications: Increased gene expression Insertions: Loss or gain of function of genes Types & Consequences of Major chromosome changes Ref. Mitelman, F et al.,The impact of translocations and gene fusions on cancer causation. Nat. Rev. Cancer 7, 233–245 (2007).

  9. Gain of function; BCR/ABL Chromosomal Translocations in Leukemia and LymphomaConsequences: Altered Expression and/or Fusion Proteins • Over a 420 genes associated with translocations have been identified in human cancer. Ref.Rowley JD. Chromosome translocations: dangerous liaisons revisited. Nature Reviews Cancer 1, 245-250, 2001.

  10. Cancer is a Genetic (Chromosomal) Disease • Tumor cells exhibit non-random chromosome abnormalities • Recurrent in specific types of malignancies • Have been used as diagnostic and prognostic markers • Have lead to the understanding of biology of cancer

  11. BCR/ABL fusion Chronic Myelogenous Leukemia (CML) • t(9;22)(q34;q11.2) Ref.Goldman JM1, Melo JV. Chronic myeloid leukemia--advances in biology and new approaches to treatment. N Engl J Med. 2003 Oct 9;349(15):1451-64.

  12. CML: Karyotyping and FISH • 05-1363 • t(9;22)(q34;q11.2) • 06-174 • t(9;22)(q34;q11.2) • 02-15 • t(9;22)(q22;q11.2) • t(9;22) partial karyotype BCR/ABL FISH

  13. Chromosome changes in CML progression • A: Karyotype: 47,XX,t(9;22)(q34;q11.2),+8,i(17)(q10) • B: FISH--BCR/ABL • C: FISH--CEP 8 (green) and D20S108 (red) • D: FISH– TP53 (red) and ATM (green)

  14. Chromosomal changes in Myelodysplatic Syndrome(MDS): Clinical significance • Heterogenous group • Primary and secondary MDS • Cytogenetic changes have prognostic implications • The classification of MDS is based on clinical data (previous history, age) and biologic characteristics (morphology, cytochemistry, immunophenotype, cytogenetic and molecular alterations)

  15. >85% karyotypic abnormalities Translocations, deletions, and inversions Diagnostic and classification of risk groups Acute Myeloid Leukemia (AML) • The classification of acute myeloid leukemia (AML) similar to myelodysplasic syndromes (MDS) is based on clinical data (previous history, age) and biologic characteristics (morphology, cytochemistry, immunophenotype, cytogenetic and molecular alterations)

  16. Recurring Chromosome Abnormalities in AML • Many other categorized, Uncategorized, and Treatment-related

  17. Inversion 16 in AML: Good prognostic AML

  18. t(15;17) is a charcteristic chromosome change in APML

  19. Therapy Related MDS and AML

  20. An AML patient with complex karytoype and MLL amplification predicts poor prognosis • Diagnosis: AML • Age: 74 years (Female) • Karyotype: 45,XX,-4,der(5)t(5;17)(q11.2-q21;q11.2),+6,+8,der(11)dup(11)(q13q23)ins(11;4)(q23;q22q28)hsr(11)(?23),-17,-18[cp35] • Amplification: MLL, ATM: Deletion: EGR1, TP53 • Treatment: Mylotarg, ATRA • Survival: 5 days after diagnosis • MLL gene amplified

  21. A patient of P. vera transformed to AML with complex karytoype • Diagnosis: tAML • Age: 70 years (Male) • Karyotype: 61-63,<3N>,XY,-2,-3,-4,-5,-7,der(8)t(2;8)(?;p21),-9,+der(9)(?)x6,-10,-12,-13,-14,-15,-17,-18,+der(18)t(11;18)(q13;p11.2),+21[25] • Treatment: No data • Survival: No data

  22. Myeloid neoplasms with complex karyotypes predict poor prognosis

  23. Probabilities of 5-year survival according to cytogenetic stratifications in children with advanced primary or secondary MDS • Gohring G et al., Blood 116: 3766, 2010

  24. Cytogenetic abnormalities in therapy-related myeloid neoplasms (t-MN) vs. de novo acute myeloid leukaemia (AML) • *Can co-occur in various combinations • From: McNerney ME, Godley LA, & Le Beau MM. Nature Reviews Cancer 17, 513–527 (2017) 

  25. Somatic gene mutations in therapy-related myeloid neoplasms (t-MN) • vs. de novo acute myeloid leukaemia (AML) • from: • McNerney ME, Godley LA, & Le Beau MM. • Nature Reviews Cancer 17, 513–527 (2017) 

  26. Acute Lymphoblastic Leukemia (ALL): Cytogenetics Diagnostic and prognostic significance • Accumulation of malignant and immature lyphoid cells in marrow

  27. Chromosomal abnormalities in ALL: T-CellDiagnostic and prognostic significance

  28. Cytogenetic Subsets in Pediatric ALL • Excellent prognosis • Poor outcome • Poor outcome • Favorable outcome • Poor prognosis • Mullighan CG. J. Clin Invest. 122; 3407, 2012

  29. Karyotype showing near haploid chromosomes in an ALL patient • Karyotype: 27<1N>,XY,+14,+18,+21

  30. t(4;11)(q21;q23) in ALL • A: Karyotype--46,XY,t(2;19)(q23;q13.4),t(4;11)(q21;q23) • B: FISH: MLL break apart probe

  31. Prognostic Impact of Diagnostic Karyotypes in Pediatric ALL • Heim and Mitelman, 1995

  32. Cytogenetics: Mature B- and T-Cell Lympoma

  33. Chromosome Translocations: Lymphocyte Development • Translocations are considered to arise as errors during intragenic physiologic rearrangements that assemble productive copies of IG and TCR genes during normal B- and T-cell development • Translocations tend to be specific for breakpoints and show a high degree of association with histologic subsets • Three Main Subsets of NHLs: • -- B-Cell • -- T-Cell/Natural Killer (NK) Cell • -- Hodgkin’s Lymphoma (HL) • First description of karyotype in BL in 1963 (Jacobs et al., 1963) • Identified as t(8;14)(q24;q32) in 1972 (Manolov and Manolova, 1972) • t(8;14) was shown that MYC rearranges with IGH (Dalla-Favera et al., 1987)

  34. Burkitt’s Lymphoma • Primary Chromosome change: • --t(8;14)(q24;q32) MYC/IgH • Variant translocations: • -- t(8;22)(q24;q11) (MYC/IgL) • -- t(2;8)(p11;q24) (IgK/MYC) • Duplication 1q: progression

  35. Follicular Lymphoma • Primary Chromosome Change: • t(14;18)(q32;q21) (IgH/BCL2)(>75%) • variant translocations involving 18q21 break point (BCL2) • 3q27 rearrangements (BCL6) • 6q21 deletions • t/der(1q), +7, del(6q), del(17p): Progression/transformation • t(14;18) negative tumors do exist, which exhibit complex and heterogeneous breakpoints (3q27; 8q24, ect)

  36. Diffuse Large B-Cell Lymphoma (DLBCL) • Generally complex, hyperdiploid • t(14;18)(q32;q21) (IgH/BCL2) • followed by • 3q27 rearrangements (BCL6)(many partners) • t(8;14)(q24;q32) (MYC/IgH) • Correlations with chromosome changes contradictory • -- der(1)(q21), +7, del(6q), del(17p) Associate with progression/transformation; predict adverse outcomes --Chromosome amplifications frequent

  37. Mantle Cell Lymphoma (MCL) t(11;14)(q13;q32): The cytogenetic hallmark found in 70% of cases (CCND1/IgH) • Monosomy 13/del(13q)

  38. del (17p13) (TP53) (v) del(11q22-q23) (ATM) (iv) Trisomy 12 (ii) Normal (iii) del(13q14.3)(sole) (i) Adverse Progression Intermediate Intermediate Favorable Chronic lymphocytic leukemia (CLL/SLL) • A chronic lymphoproliferative disorder of mature B-lymphocytes • Tumor cells are inert with only a small proliferative compartment • 50-60% abnormal by karyotype (>80% by FISH) • Chromosome change Prognosis OS (mo) • 30 • 80 • 115 • 110 • 135 • FISHpanel targeting all the above changes • Absence of IGHV mutation: Aggressive course

  39. Prognosis of deletions in CLL • Dal Bo M et al. GENES, CHROMOSOMES & CANCER (2011)

  40. Multiple Myeloma (MM) • Karyotype detects only 30-50% cases with abnormalities

  41. Overall survival according to chromosome abnormality in multiple myeloma • Hervé Avet-Loiseau etal., J Clin Oncol: 30 (16): 1949-52, 2012

  42. Mature T-cell Neoplasms

  43. Chromosome change in Anaplastic Large Cell Lymphoma (ALCL) Ref. Amin HM, Lai R. Pathobiology of ALK+ anaplastic large-cell lymphoma. Blood. 110(7):2259-67, 2007.

  44. Genetic hallmark of T-PLL is inv(14)(q11.2q32) or t(14;14)(q11.2;q32) TCL1 gene at 14q32 juxtapose next to TCRA/D locus at 14q11.2 resulting in up regulation of the TCL1 expression. The TCR-associated translocations are regarded as the primary oncogenic events in T-PLL. T-PLL are generally very aggressive tumors among T-cell lymphomas and poorly responsive to chemotherapy.

  45. Karyotype Changes in NHL: diagnostic and prognostic significance • Chromosome abnormalities of 1, 6, and 17 are virtually seen in all lineage NHLs: • Associated with poor clinical outcome

  46. Solid Tumor Cytogenetics

  47. Ewing sarcoma/Primitive neuroectodermal tumor • Heterogeneous group of distinct histologic types • 90% cases with t(11;22)(q24;q12); in all histologic types • Translocation results in the fusion of the EWS with FLI1, forming a chimeric protein • variant translocations: t(21;22)(q12;q12)[EWS-ERG] and t(7;22)(p22;q12) [EWS-ETV1 in 5% cases • EWSR1 is also rarely rearranged in other soft tissue tumors (Myxoid chondrosarcoma, Desmoplastic small round cell tumor, malignant melanoma of soft parts) Ref. Crompton BD. et al. The genomic landscape of pediatric Ewing sarcoma. Cancer Discov. 4(11):1326-41, 2014.

  48. Other soft tissue tumors- Karyotypic Changes

  49. Neuroblastoma • Sympathetic neuronal precursor: Embryonic origin • Common Extracranial pediatric tumor of infancy • Classified as low, intermediate, and high-risk groups • Two major types of Cytogenetic abnormalities: • Segmental chromsome aberrations 1p and 11q deletion (LOH)—High-risk • Amplification of NMYC is the most robust prognostic factor in NB

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