Recurring Abnormalities

Overview of Recurring Cytogenetic Abnormalities in Hematologic Malignancies

Definition: Recurring cytogenetic abnormalities are specific chromosomal changes (translocations, deletions, inversions, etc.) that are frequently observed in certain types of hematologic malignancies
Importance in WHO Classification:
- Diagnostic: The presence of certain recurring cytogenetic abnormalities is used as a defining criterion for specific subtypes of leukemia, lymphoma, and myeloproliferative neoplasms in the WHO classification
- Prognostic: Many recurring cytogenetic abnormalities have prognostic significance, meaning they can help predict the likely outcome of the disease
- Therapeutic: Some genetic abnormalities are targets for specific therapies
Testing Methods:
- Cytogenetic Analysis (Karyotyping): Traditional method for identifying chromosomal abnormalities
- Fluorescence In Situ Hybridization (FISH): Used to detect specific chromosomal abnormalities more rapidly and sensitively
- Molecular Testing (PCR, NGS): Can detect gene mutations and fusion genes that result from chromosomal rearrangements

Recurring Cytogenetic Abnormalities by WHO Classification

Here, we’ll break down the key cytogenetic abnormalities associated with different types of myeloid and lymphoid neoplasms according to the WHO classification. Please note that the WHO classification is updated periodically, so it’s important to consult the most recent version for the most current information.

Myeloid Neoplasms

Acute Myeloid Leukemia (AML) with Recurrent Genetic Abnormalities
- t(8;21)(q22;q22.1); RUNX1-RUNX1T1 (AML1-ETO):
  - Favorable prognosis
  - Morphology: AML with maturation, often showing Auer rods
  - Immunophenotype: Expresses myeloid markers (CD13, CD33, CD117), often co-expresses CD19
- inv(16)(p13.1q22) or t(16;16)(p13.1;q22); CBFB-MYH11:
  - Favorable prognosis
  - Morphology: AML with abnormal eosinophils in the bone marrow
  - Immunophenotype: Expresses myeloid markers, CD11b, and CD2; eosinophil markers
- t(15;17)(q24.1;q21.1); PML-RARA (Acute Promyelocytic Leukemia - APL):
  - Favorable prognosis with appropriate treatment
  - Morphology: Abnormal promyelocytes with Auer rods
  - Clinical Significance: Associated with disseminated intravascular coagulation (DIC)
  - Treatment: All-trans retinoic acid (ATRA) and arsenic trioxide (ATO)
- t(9;11)(p21.3;q23.3); MLLT3-KMT2A:
  - Poor prognosis
  - Morphology: Acute monocytic leukemia or acute myelomonocytic leukemia
  - Immunophenotype: Expresses monocytic markers (CD14, CD11b, CD4, CD36, CD64)
- inv(3)(q21.3q26.2) or t(3;3)(q21.3;q26.2); GATA2, MECOM (EVI1):
  - Unfavorable prognosis
  - Associated with increased blasts and multi-lineage dysplasia
Myelodysplastic Syndromes (MDS)
- del(5q):
  - MDS with Isolated del(5q):
    - Anemia
    - Normal or elevated platelet count
    - Hypolobated megakaryocytes in the bone marrow
    - Good response to lenalidomide
- Trisomy 8 (+8):
  - Common in MDS and AML
  - May be associated with dysplasia in multiple cell lines
  - Variable prognosis
- del(20q):
  - Often associated with isolated anemia and a relatively indolent course
- del(7q) or Monosomy 7 (-7):
  - Associated with poor prognosis and a high risk of transformation to AML
Myeloproliferative Neoplasms (MPNs)
- t(9;22)(q34.1;q11.2); BCR-ABL1 (Chronic Myeloid Leukemia - CML):
  - Diagnostic hallmark of CML
  - Results in a fusion protein with constitutive tyrosine kinase activity
- JAK2 V617F Mutation:
  - Present in >95% of Polycythemia Vera (PV) cases and in approximately 50-60% of Essential Thrombocythemia (ET) and Primary Myelofibrosis (PMF) cases
  - A gain-of-function mutation that activates the JAK-STAT signaling pathway
- CALR Mutations:
  - Mutations in the calreticulin (CALR) gene are found in approximately 25% of ET and PMF cases that are JAK2-negative
  - Involve insertions or deletions in exon 9 of CALR, leading to a frameshift and altered protein function
- MPL Mutations:
  - Mutations in the thrombopoietin receptor gene (MPL) are found in approximately 5-10% of ET and PMF cases that are JAK2-negative and CALR-negative

Lymphoid Neoplasms

Precursor B-Cell Neoplasms (B-Lymphoblastic Leukemia/Lymphoma):
- t(9;22)(q34.1;q11.2); BCR-ABL1:
  - Seen in ~25% of adult B-ALL cases
  - Associated with poor prognosis
- t(12;21)(p13.2;q22.1); ETV6-RUNX1:
  - Most common translocation in childhood B-ALL
  - Associated with favorable prognosis
- t(v;11q23.3); KMT2A (MLL) rearranged:
  - Seen in infants and adults with B-ALL
  - Associated with poor prognosis
- t(1;19)(q23;p13.3); TCF3-PBX1:
  - Seen in ~25% of childhood B-ALL cases
  - Associated with increased risk of relapse
  - Hyperdiploidy:
    - Gain of multiple chromosomes (more than 50 chromosomes)
    - Associated with favorable prognosis in childhood B-ALL
- Hypodiploidy:
  - Loss of multiple chromosomes (less than 46 chromosomes)
  - Associated with poor prognosis in childhood B-ALL
Mature B-Cell Neoplasms:
- t(14;18)(q32;q21); IGH-BCL2 (Follicular Lymphoma):
  - Diagnostic hallmark of follicular lymphoma
  - Results in overexpression of BCL2, an anti-apoptotic protein
- t(11;14)(q13;q32); CCND1-IGH (Mantle Cell Lymphoma):
  - Diagnostic hallmark of mantle cell lymphoma
  - Results in overexpression of cyclin D1, a cell cycle regulator
- t(8;14)(q24;q32); MYC-IGH (Burkitt Lymphoma):
  - Diagnostic hallmark of Burkitt lymphoma
  - Results in overexpression of MYC, a transcription factor that promotes cell growth
- del(13q14.3) (Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma): *Good Prognosis

Molecular Testing (PCR and NGS)

Molecular testing plays an increasingly important role in the diagnosis, classification, and monitoring of hematologic malignancies

PCR-Based Assays:
- Used to detect gene mutations and fusion genes that are not visible by cytogenetic analysis
- Example: JAK2 V617F mutation in MPNs
Next-Generation Sequencing (NGS):
- Allows for the simultaneous sequencing of multiple genes, providing a comprehensive analysis of the genetic landscape of the tumor cells
- Used to identify gene mutations, insertions, deletions, and copy number variations
- Provides valuable information for diagnosis, prognosis, and treatment planning

Reporting and Interpretation

Karyotype: Describe the karyotype using the ISCN nomenclature and indicate the presence or absence of any chromosomal abnormalities
FISH Results: Report the percentage of cells with the specific chromosomal abnormality
Molecular Testing Results: Report the presence or absence of specific gene mutations or fusion genes
Integrate the Cytogenetic and Molecular Findings with the Patient’s Clinical, Morphologic, and Immunophenotypic Data
Prognostic Interpretation: When reporting results, it’s important to convey the prognostic significance of the findings to the clinician

Key Terms

Cytogenetic Analysis (Karyotyping): The study of chromosomes and their abnormalities
FISH (Fluorescence In Situ Hybridization): A technique that uses fluorescent probes to detect specific DNA sequences on chromosomes
Molecular Testing: Techniques to detect gene mutations and fusion genes
Mutation: A change in the DNA sequence of a gene
Translocation: The transfer of genetic material from one chromosome to another
Deletion: The loss of a portion of a chromosome
Inversion: The reversal of a segment of a chromosome
Fusion Gene: A gene formed by the fusion of two separate genes due to a chromosomal translocation or deletion
Myeloid Neoplasm: A hematologic malignancy arising from myeloid progenitor cells
Lymphoid Neoplasm: A hematologic malignancy arising from lymphocytes
Leukemia: A malignant disorder of blood-forming cells
Lymphoma: A malignant disorder of lymphocytes that typically arises in lymph nodes

Molecular/Cytogenetic

BCR/ABL1