Lecture 13 - Intro to malignancy Flashcards
Haematological malignancies: what type of diseases are they, what are they caused by, and what features do they have?
Clonal diseases
Cell - undergone genetic changes (somatic mutation) leading to malignant transformation usually caused by a combination of genetic predisposition and environmental factors including:
* Infection
* Ionizing radiation
* Chemicals
* Drugs
These factors lead to mutations occurring - mostly point mutations/gene and chromosomal deletions/chromosomal duplication (e.g. trisomy 12 in CLL)/ gene amplification (not common)
Excessive proliferation
Resistance to apoptosis
Decreased differentiation
Clonal diseases: where do they originate from?
Derived from a single cell that has undergone genetic alteration
Pathogenesis of haematological malignancy
Cause - random, genetic predisposition, or the cell’s environment
Pathogenesis - altered gene expression: oncogenes, tumour suppressor gene
Phenotype - increased proliferation and decreased differentiation and apoptosis
What are the causes of haematological malignancies?
- Genetic predisposition - Downs syndrome
- Infection - Viruses/bacteria: human T-lymphotropic virus type-1 (HTVP1), adult T-cell leukaemia/lymphoma (ATLL), Epstein-Barr virus (Burkitt’s lymphoma), Heliobacter pylori infection (gastric lymphomas)
- Ionizing radiation - Hiroshima/Nagasaki
- Chemicals - benzene (chronic abnormalities in leukaemia)
- Drugs - Alkalyting agents, e.g.chlorambucil -> myeloid leukaemia
ALL: what is it, when does it occur, what is it caused by, which people have a lower incidence, and what happens with the second transforming event?
Acute lymphoblastic leukaemia
Initiated by genetic mutations that occur during development in utero
- Primary event occurs in utero - possibly by environmental exposure during pregnancy
- Secondary event occurs at a later date (varies) as possibly an abnormal response of the immune system to infection - unclear mechanism
Decreased incidence in those with young exposure to diseases (nurseries/daycares)
Occurs within tumour cells after birth. Twin studies – both may be born with the same chromosomal abnormality but the second transforming event may differ for both twins, ie one develops ALL at ~5, and the other remains well until 14
Oncogenes: what are they, where do they come from, what do they do,
Genes that can transform a normal cell into a tumour cell
Derived from proto-oncogenes, gain of function mutation - amplification, point mutations or chromosomal translocations
- Uncontrolled proliferation
- Blockage of differentiation
- Prevention of apoptosis
TSGs: what are they, what do they do, how do they form, and what is the most significant one in human cancers?
Tumour suppressor genes - genes that prevent tumour formation
Commonly involved in cell-cycle, promotes malignant transformation, encodes for proteins that negatively regulate proliferation
Deletion/mutation, typically loss of function mutations
p53 most significant TSG in human cancers (~50% of malignant disease)
How do oncogenes and tumour suppressor genes interact with one another?
Proliferation of normal cells depends on a balance between proto-oncogenes and tumour suppressor genes
Cellular oncogenes and tumour-suppressor genes implicated in human leukaemias and lymphomas: FMS/KIT, RAS, retinoic acid, ABL/FGFR1, p53/ATM, Bcl-2, and Bcl-1/Rb
Feline McDonough Sarcoma (oncogene) and KIT - Membrane-associated tyrosine kinases (including growth factor receptors)
Intracellular signal transducers (?)
RAS - GTP-binding
Retinoic acid - hormone receptor receptor α (RARα)
Abelson murine leukaemia viral oncogene homolog 1 (ABL) and fibroblast growth factor receptor (FGFR1) - tyrosine kinase
p53 and ataxia telangiectasia mutated (ATM) - signalling of DNA damage and apoptosis
B cell lymphoma 2 (Bcl-2) - Inhibitor of apoptosis
B cell lymphoma 1 (Bcl-1) and Rb - control of cell cycle
AML, CML, ALL, and CLL; what are they, what is the difference, and what do they mean?
Acute myeloid leukaemia - cancer involving monocytes/granulocytes, rapid progression
Chronic myeloid leukaemia - cancer involving monocytes/granulocytes, slow progression
Acute lymphoblastic leukaemia - cancer involving lymphocytes, rapid progression
Chronic lymphoblastic leukaemia - cancer involving lymphocytes, slow progression
Acute leukaemia - new/immature cells (blasts) remain very immature and cannot perform their functions. The blasts increase in number rapidly, and the disease progresses quickly.
Chronic leukaemia: There are fewer blast cells present, and they are more mature and can perform some of their functions. The cells grow more slowly, and the number increases less quickly, so the disease progresses gradually.
What is the treatment for APML?
All trans-retinoic acid (ATRA) treatment for acute promyelocytic leukaemia (t15;17)
How good is PCR at detecting malignant cells?
Capable of detecting 1 malignant cell in up to 106 normal cells
How useful are translocations in prognostics?
Disease-specific - very useful for MRD monitoring
MRD: what is it and how can it be useful for patients?
The term used to describe the small number of cancer cells in the body after cancer treatment
If the MRD result is positive, there is a high risk of relapse allowing the potential of additional therapy before relapse
Malignant cell detection: what are the main methods used?
- Karyotype analysis
- Fluorescent in situ hybridisation
- PCR
