Atlas of Genetics and Cytogenetics in Oncology and Haematology

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Chromosomes, Leukemias, Solid Tumors, Hereditary Cancers

 

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I- Haematologic malignancies

II- Solid Tumours

III- Cancer-prone diseases

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Haematologic malignancies

Introduction

I- Myeloproliferative Syndromes (MPD)

    1. Chronic myelogenous leukaemia (CML)
    2. Polycytemia vera (PV)
    3. Idiopathic myelofibrosis
    4. Essential thrombocythemia (ET)
    5. Atypical chronic myelogenous leukemia (aCML)

II- Myelodysplastic Syndromes (MDS)

    1. Introduction
    2. Del(5q) and myeloid malignancies

III- Acute Myeloid Leukemias (AML)

    1. Introduction
    2. First group: AML with recurrent cytogenetic translocations
    3. Second group: Multilineage AML (mAML)
    4. Third group: Secondary AML
    5. Fourth group: others AML, Morpholocical and Immunophenotyping classification

IV- Acute Lymphoblastic Leukemias (ALL)

    1. Introduction
    2. t(4;11)(q21;q23)
    3. Others 11q23 (MLL)
    4. t(9;22)(q34;q11)
    5. t(12;21)(p12;q22)
    6. t(8;14)(q24;q32) and t(2;8)(p12;q24) and t(8;22)(q24;q11) variants
    7. 14q11 rearrangements
    8. B Cell/ T Cell
    9. Others
    10. Domino game

V- Non Hodgkin's Lymphomas / Chronic Lymphoproliferative Diseases

    1. B-cell chronic lymphoproliferative disorders
    2. B-cell Non Hodgkin Lymphomas
    3. T Cell

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INTRODUCTION

Malignant blood diseases may be classified:

Leukaemias are classified according to cytogenetics, cytology and pathology, and immunophenotype of the malignant cells. The WHO (World Health Organization) classification has replaced the FAB classification of leukaemias.

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I- MYELOPROLIFERATIVE SYNDROMES


Myeloproliferations : quantitatives anomalies of the myeloid lineage.

I.1. Chronic myelogenous leukaemia (CML)

  • Malignant monoclonal process involving a pluripotent hematopoietic progenitor (therefore, most of the lineages are implicated).
  • Splenomegaly, high leukocyte count, basophilia, immature cells in the peripheral blood, low leucocyte alkaline phosphatase, bone marrow expansion with increased neutrophil lineage.
  • Prognosis: chronic phase, followed by blast crises, ending in an acute transformation; median survival was about 4 yrs before the recently introduced antityrosine kinase (imatinib mesylate) therapies.

  • Chromosome anomalies:

    Clonal evolution concept

    Other myeloproliferative syndromes:

    I.2. Polycytemia vera (PV)

    I.3. Idiopathic myelofibrosis (or agnogenic myeloid metaplasia)

    I.4. Essential thrombocythemia (ET):


    I.5. Atypical chronic myelogenous leukemia:

    Hybrid genes, with the involvement of : +/- Non Hodgkin Lymphoma in the case of FGFR1 involvement --> indicating that a stem-cell is likely to be implicated.

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    II- MYELODYSPLASTIC SYNDROMES (MDS)

    II.1. Introduction

    Myelodysplasia: cells look "bizarre", dysplastic.

    II.2. Del(5q) and myeloid malignancies

    It is the most common structural rearrangement in myelodysplastic syndromes (MDS) and in acute myeloid leukemias (AML); del (5q) is accompanied with given clinical and haematological features.
    We herein summarize these three pictures as:
    Clinics:

    RPS14 (5q33), encoding for a ribosomal protein, was recently discovered (Jan 2008) has having a major role in the 5q- syndrome.

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    III- ACUTE MYELOID LEUKAEMIAS (AML)
    (or Acute Non Lymphocytic Leukaemias (ANLL))


    III.1. Introduction

    Massive proliferation of myeloid precursors; with a hiatus aspect in the maturation pyramid and entry of immature cells into the bloodstream.

    The new WHO/OMS classification replaces and completes the FAB classification (M1 to M7).

    FAB:

    WHO:

    Prognostic value of the chromosomal anomaly +++.

    III.2. First group: AML with recurrent cytogenetic translocations

    III.3. Second group: Multilineage AML

    This category is defined by the presence of multilineage dysplasia (in contrast with the t(15;17), for example, which affects only promyelocytes).

    III.4. Third group: Secondary AML

     

    III.5. Fourth group: others AML, classified by Morphology and Immunophenotyping of the cells


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    IV- ACUTE LYMPHOBLASTIC LEUKEMIAS (ALL)

    IV.1. Introduction

    Chromosomes anomalies:

    IV.2. t(4;11)(q21;q23)

    IV.3. Other 11q23 rearrangements in leukemias

    IV.4. t(9;22)(q34;q11)

    IV.5. t(12;21)(p12;q22)

    IV.6. t(8;14)(q24;q32) and t(2;8)(p12;q24) and t(8;22)(q24;q11) variants

    IV.7. 14q11 rearrangements

    ex: t(11;14)(p13;q11), t(8;14)(q24;q11) and t(10;14)(q24;q11)

    IV.8. B Cell/ T Cell

    t(8;14)(q24;q11) MYC/TCR
    T Cell

    t(8;14)(q24;q32) / t(2;8)(p12;q24) / t(8;22)(q24;q11)
    MYC/Ig
    B Cell

    IV.9. Others:

    IV.10. Domino game

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    V- NON HODGKIN'S LYMPHOMAS / CHRONIC LYMPHOPROLIFERATIVE DISEASES


    V.1. B-cell chronic lymphoproliferative disorders (CLD)


    V.2. B cell Non Hodgkin's lymphomas (NHL)


    V.3. T Cell:

    Solid Tumours (short summary)

    I- Sarcomas

    II- Carcinomas with translocations

    III- Carcinomas: colorectal cancer

    IV- Carcinomas: breast cancer/ hereditary breast cancer

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    I- SARCOMAS


    Sarcomas: it is an heterogeneous group, of many benign or malignant tumours, often the diagnostic is hard to reach; however, a number of these tumours present a specific translocation; which can be of great help for diagnostic ascertainement.

    I-1. Lipoma: rearrangement of HMGA2 (12q15), high mobility group gene, , non histone protein, architectural factor, preferential binding to AT rich sequences in the minor groove of DNA helix.

    I-2. Liposarcoma: MDM2 amplification (NO translocation, NOR stimulation by a gene enhancer as for MYC) ; (located in 12q15, MDM2 interacts with TP53 and RB1, inhibits the cell cycle arrest in G1 phase and apoptosis); Often, neighbouring genes too, CDK4 and HMGA2, may be amplified and over-expressed.

    I-3. Inflammatory myofibroblastic tumor (see above).

    I-4. Embryonal rhabdomyosarcoma: loss of heterozygoty in 11p15 (function of IGF2, H19, CDKN1C ??); complex karyotype.

    I-5. Alveolar rhabdomyosarcoma: specific translocation t(2;13)(q35;q14); PAX3 (2q35, transcription factor implicated in proliferation, differentiation, apoptosis) and FKHR (13q14). Variant translocation: t(1;13)(p36;q14): PAX7(1p36) / FKHR.

    I-6. Ewing's tumors / Primitive neurectodermal tumours (PNET): small round-cell tumours (difficult to diagnose) deriving from neural crests cells.

     

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    II- CARCINOMAS


    Carcinomas:

    II-1. There can be specific translocations, e.g.:


    II-2. Most often, karyotypes are complex, and still poorly understandable; comparative genomic hybridization (CGH) and CGH array are particularly useful..

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    III- COLORECTAL CANCER model


  • The diploid form, RER+ (Replication Error +), sporadic, without loss of heterozygoty (LOH), with few TP53 and APC, mutations, in the right-sided colon.
  • The polyploid form, RER-, with LOH 5q, 17p, 18q, p53 mutations, more often in left-sided colon, with a poorer prognosis.


    … Colorectal cancers can also be related to given cancer-prone diseases:

    III-1. Familial adenomatous polyposis (FAP): characterized by the development of hundreds of polyps at a very early age, due to mutations in APC (5q21); CTNNB1 is phosphorylated by a complex including APC, which leads to CTNNB1 degradation by the ubiquitin-proteasome; CTNNB1 is assumed to transactivate genes which may stimulate cell proliferation or inhibit apoptosis.

    III-2. Hereditary nonpolyposis colon cancer (HNPCC) or Lynch syndrome: due to germline mutations in genes intervening in the repair of DNA mismatches occurring during replication (MSH2 and MLH1).

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    IV- BREAST CANCER model / HEREDITARY BREAST CANCER

    Karyotype:

    Genes Implicated:

    … 5-10% of breast cancers are due to hereditary predisposition, with germinal mutations in:

    … Others hereditary conditions with predisposition to breast cancers:

    Cancer prone diseases

    I- Hereditary Breast Cancer, Colorectal Cancer, etcÖ (see above)

    II- Chromosome Instability Syndromes

      1. Fanconi Anemia (FA)
      2. Ataxia telangiectasia (AT)
      3. Bloom Syndrome (BS)
      4. Xeroderma pigmentosum (XP)

    III- Retinoblastoma / Li-Fraumeni Syndrome

      1. Retinoblastoma
      2. Li-Fraumeni Syndrome and TP53

    IV- Hamarto-Neoplastic Syndromes

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    II- CHROMOSOME INSTABILITY SYNDROMES


    Some rare genetic diseases:
      - Fanconi Anaemia (FA)
      - Ataxia Telangiectasia (AT)
      - Bloom Syndrome (BS)
      - Xeroderma pigmentosum (XP)
    are defined by:         These diseases are defined by a high level of breaks or chromosomal rearrangements and/or a high sensibility to mutagen reagents.
    If DNA lesions are not properly repaired, mutations and genes rearrangements fast accumulate, leading to oncogene activation or antioncogene inactivation, by chance, at a time or another.

    II.1. Fanconi Anemia (FA)

    II.2. Ataxia Telangiectasia (AT)

    II.3. Bloom Syndrome (BS)

    Micro nuclei
    SCE (sister chromatid exchange)

    II.4. Xeroderma Pigmentosum (XP)

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    III- RETINOBLASTOMA and LI-FRAUMENI SYNDROME

    III.1. Retinoblastoma

    Cancer prone disease at increased risk of the cancer of the retina called retinoblastoma.

    These features are unusual, and some appear contradictory...let's tell the story:

    Therefore, the gene is a recessive gene; however it seems to be transmitted with an autosomal dominant pattern in the hereditary forms; How?:

    RB1 (13q14)


    III.2. Li-Fraumeni Syndrome and TP53

  • How to suspect an hereditary cancer predisposition:
  • In 1969 FP Li and JF Fraumeni define a syndrome:

  • Mutation of various genes can lead to Li-Fraumeni Syndrome:

    ...on the other hand, somatic mutations of P53 are found in about 50% of all cancers.

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    IV- HAMARTO-NEOPLASTIC SYNDROMES


  • Hamartomas are localized tissue proliferations with faulty differenciation and mixture of component tissues;
  • hamartomas are benign proliferations that have a potential towards neoplasia;
  • patients are at increased risk of benign and malignant tumors of various tissues and organs.
  • these diseases are heritable;
  • The genes known so far are tumor suppressor genes, but no common fonction has yet been established.

    … Example: NF1:

    Neurofibromatosis Type 1

    Contributor(s)

    Written06-2000Jean-Loup Huret
    Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers, France
    Updated02-2008Jean-Loup Huret
    Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers, France

    Citation

    This paper should be referenced as such :
    Huret JL . Chromosomes, Leukemias, Solid Tumors, Hereditary Cancers. Atlas Genet Cytogenet Oncol Haematol. June 2000 .
    URL : http://AtlasGeneticsOncology.org/Educ/Hempat_e.html
    Huret JL . Chromosomes, Leukemias, Solid Tumors, Hereditary Cancers. Atlas Genet Cytogenet Oncol Haematol. February 2008 .
    URL : http://AtlasGeneticsOncology.org/Educ/Hempat_e.html

    © Atlas of Genetics and Cytogenetics in Oncology and Haematology
    indexed on : Wed Sep 24 20:48:13 2008

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