Haematological Malignancies: Aetiology & Genetics

Haematological Malignancies: Aetiology and Genetics

• Haematological malignancies are clonal diseases affecting the haemopoietic tissues.
• They originate from a single cell in the bone marrow or peripheral lymphoid tissues.
• Often, the tissue of origin has pre-existing genetic alterations.
• Common types include leukaemias, lymphomas, myelodysplastic syndrome (MDS), and myeloproliferative neoplasms (MPN).

Synopsis

• The presentation covers introduction, epidemiology, aetiology, genetics, diagnostic techniques in haemato-oncology, and conclusion.

Introduction: Haematologic Malignancies

• Haematologic malignancies are clonal disorders of haemopoietic tissues.
• They arise from a single transformed cell in bone marrow or peripheral lymphoid tissues.
• Often, the cells of origin have pre-existing genetic alterations.
• Types include various leukaemias, lymphomas, MDS and MPN.

Epidemiology: Haematologic Malignancies

• Haematological malignancies account for roughly 7% of all cancers.
• Incidence varies by age, sex, and geographical location.
• These factors influence the disease's progression.
• Charts show variation in incidence by cancer type among males and females (pie charts). Cancer types are shown, with percentage breakdowns for each gender.

Aetiology: Genetic Factors

• Genetic conditions significantly increase haematological malignancy risk.
• These include Down's syndrome, Bloom's syndrome, Fanconi anaemia, ataxia telangiectasia, neurofibromatosis, Klinefelter's syndrome, and Wiskott-Aldrich syndrome.
• These conditions often predispose to leukaemia development.
• Lymphomas (CLL and AML) also demonstrate a weak familial tendency.

Aetiology: Environmental Factors

• Exposure to certain chemicals (e.g., aromatic hydrocarbons like benzene, industrial solvents) increases malignancy risk.
• Exposure to radiation and specific drugs (alkylating agents like chlorambucil, melphalan, procarbazine) are also related to malignancy development.
• Infective agents such as viruses (HTLV-1, EBV, HHV8, HIV) and bacteria (Helicobacter pylori) and protozoa (Malaria) are associated with haematological malignancies.

Genetics: Oncogenes

• Oncogenes have the potential to induce cancer.
• They develop from proto-oncogenes that are normal genes regulating critical cellular processes.
• Activation or mutation of these proto-oncogenes can transform them into oncogenes (like a good cop becoming a bad cop).
• Translocation and duplication are key processes in proto-oncogene mutation leading to oncogene development.
• Translocation: Exchange of genetic material between non-homologous chromosomes can form a chimeric fusion gene or lead to gene overexpression, creating oncogenes.
• Duplication: Leads to extra genetic activity on a duplicated chromosome part, sometimes resulting in chromosome abnormalities like trisomy.

Genetics: Tumour Suppressor Genes

• Tumour suppressor genes usually regulate the cell cycle (G1 to S, S to G2).
• These genes act as primary cellular control mechanisms.
• A common example of a tumour suppressor gene is p53.
• Loss-of-function mutations within these genes can lead to uncontrolled cell growth and cancer.
• Mutations can take the form of point mutations (single base change in DNA) or deletions (loss of a chromosome part).

Diagnostic Techniques in Haemato-oncology

• Karyotyping: Direct morphological analysis of chromosomes from tumour cells, often using cell cultures and colchicine induced metaphase arrest.
• Polymerase Chain Reaction (PCR): Amplifies specific DNA segments (sometimes mRNA via reverse transcriptase), used for diagnosis and detecting minimal residual disease.
• Flow cytometry: Uses surface-specific antigens (protein markers) to differentiate normal vs abnormal (tumour) cells based on unique profiles of expression. Uses fluorescently labelled antibodies.
• Immunohistochemistry: Antibody staining of tissue sections (using fluorescent markers) to visually assess tissue characteristics (and tumour cell properties), performed by histopathologists.
• Fluorescence in situ hybridization (FISH): Genetic probes (with fluorescent labels) are hybridized with patient samples to detect extra copies, gene rearrangements (translocations).
• DNA microarray platform: Enables study of transcription by using known DNA probes on a solid base to assess specific sequences and expression patterns (including those of interest relating to malignant vs normal cells).
• Gene Sequencing (NGS): Advanced techniques used to detect genetic mutations for malignancy; can study single or multiple genes of interest, or the whole genome.

Management of Haematological Malignancies: An Overview

• An approach to treating haematologic malignancies includes multiple steps: history, physical examinations, diagnostic investigations, treatment, follow up, and prognosis stages.

Diagnostic Investigations

• A battery of tests is used, including: full blood counts and differentials, peripheral blood film, bone marrow aspiration/biopsy, cytochemistry, immunophenotyping, cytogenetics, and molecular genetics.

Supportive Investigations

• Important supportive investigations include clotting profiles, serum analyses (renal/liver function, electrolytes), blood glucose, virus/bacteria serology, sepsis assessments, and imaging like X-ray, ultrasound, CT and PET scan.

Treatment

Treatment: Supportive

• Supportive strategies during haematological malignancy treatment include counselling, reproductive health management, nutritional support, central venous catheter insertion, intravenous fluids, blood products, antimicrobial therapy (prophylaxis), anti-uricogenic medicines, and pain relief.

Treatment: Definitive

• Definitive treatments often include multi-drug chemotherapy regimens, radiation therapy, and surgical interventions (where appropriate).

Conclusion

• Understanding the etiology and genetics of haematological malignancies is important for early diagnosis, treatment choices, and patient monitoring and follow up. Key diagnostic methods for malignancies include karyotyping, PCR, flow cytometry, immunohistochemistry, FISH, microarray and NGS.

This quiz explores haematological malignancies, focusing on their aetiology and genetics. You'll learn about common types like leukaemias and lymphomas, along with their origins and genetic background. Test your understanding of these clonal diseases and their impact on haemopoietic tissues.