Haematological malignancies Flashcards
What are the ways in which tumour suppressor genes and oncogenes can be aberrantly affected in cancer? (6)
- Gain/loss of whole/parts of chromosomes (aneuploidy)
- Gene deletion/duplication/amplification
- Genomic rearrangements
- Epigenetic changes
- Pathogenic variants
- Small insertions/deletions
What is an example of aneuploidy in cancer?
- Trisomy 8 in myeloid leukaemia
- Results in upregulation of c-MYC proto-oncogene
Which gene is amplified in neuroblastoma?
n-MYC
What is an example of loss of large chromosomal regions in cancer?
- Isodicentric chromosome 17 resulting in the loss of 17p and the deletion of TP53
- del5q
-del7q
What are examples of genomic rearrangement in cancer? (3)
- Translocation, inversion and insertion resulting in generation of fusion-oncogenes or the silencing of tumour suppressor genes
- TMPRSS2-ERG in prostate cancer
- IGH-BCL2 in follicular lymphoma
What are the features of fusion genes? (2)
- They can be specific to a disease and therefore useful diagnostic markers and therapeutic targets
- Some fusion genes are sufficient to cause disease so abnormalities don’t need to be accumulated to cause the cancer as it can be done in ‘1 hit’ (mostly childhood cancers)
What is chromothripsis? (3)
- Complex chromosomal rearrangement where major levels of DNA damage result in genome fragmentation
- Usually causes apoptosis but cancer cells can evade this and end up with a highly complex and abnormal genome
- Results in more genetic diversity and increased likelihood of competitive clones being produced
How are epigenetic changes involved in cancer? (2)
- Methylation of upstream regulatory elements of genes often results in transcriptional suppression
- Methylation status of tumour suppressor genes and oncogenes can be modified to alter expression
How are pathogenic variants involved in cancer? (2)
- Point mutations can inactivate tumour suppressor gene function
- E.g. isodicentric 17 results in loss of one copy of TP53, an inactivating point mutation/frameshift mutation in the other copy would worsen patient prognosis
What is the prognosis for trisomy 8? (3)
- Intermediate/poor
- cMYC amplification which is a transcription factor for cell cycle progression and inhibition of anti-proliferation genes
- Seen in myeloid disease rather than lymphoid
How often is c-MYC constitutively active in cancer?
Approx 70%
What is the prognosis for del5q? (2)
- Good is seen as the sole abnormality in MDS as linked to low risk progression to AML
- Poor if consistent with progression as common marker of therapy-related leukaemia
What is the prognosis for trisomy 7? (3)
- Poor/very poor
- Highly complex set of candidate genes present on chromosome 7
- Associated with likely progression to acute leukaemia
What is an example of epigenetic changes in cancer?
Barrett’s oesophagus
What are examples of point mutations seen in AML? (2)
- NPM1
- FLT3
What are the 3 major strategies for cancer treatment?
- Surgery (removal)
- Radiotherapy (DNA damage)
- Chemotherapy (DNA damage)
What are the haematological malignancies? (2)
- Cancers of the blood or blood forming tissues (bone marrow, lymphatic system, peripheral blood)
- Account for approximately 3% of all cancers
What is the most common haematological malignancy seen in children?
Acute lymphoblastic leukaemia (ALL)
Which haematological malignancies are more common in the elderly? (2)
- Acute myeloid leukaemia (AML)
- Myelodysplastic syndrome (MDS)
How rare are haematological malignancies?
Approximately 63 new cases per 100 000 individuals per year
What are the 3 major disease classes of haematological malignancy?
- Leukaemia
- Lymphoma
- Multiple Myeloma
(- Myelodysplastic syndromes (MDS) are precancerous disorders that can progress to AML)
What makes haematological malignancies clonal?
The disease develops from a single cell and the descendants inherit the abnormalities
What makes haematological malignancies progressive? (2)
- Progression of the cancer is driven by accumulation of abnormalities in the genome
- Type, number and distribution of abnormalities can help determine the nature of the disease and be used for monitoring
What are markers of disease progression? (2)
- Clonal expansion (proportion of the tissue involved increases)
- Clonal evolution (abnormal clones accumulate more abnormalities)
What is clonal expansion? (2)
- Proliferation of a cancerous clone
- An indication of disease progression
What is clonal evolution? (3)
- When an abnormal clone accumulates further abnormalities
- Consistent with poor prognosis
- Likely that the second more complex clone will proliferate more rapidly than the first
What is disease load?
The proportion of bone marrow which is thought to be cancerous
What is remission? (3)
- The point at which the cancer is no longer detected
- Doesn’t mean the cancer is gone
- Split into cytogenetic remissions and molecular genetic remissions (molecular being a deeper remission as these techniques are more sensitive)
What genomic technologies are used to detect relapses quickly? (2)
- FISH (down to 1% of the bone marrow)
- Quantitative PCR (1000 times more sensitive than FISH)
What are the 2 ways in which relapse can occur?
- Original cancer comes back
- Cancer with a new genotype emerges
How can relapse occur as a new genotype? (2)
- Therapy related disease: therapy to destroy the original cancer causes DNA damage to normal cells which can become new malignant clones
- The new cancer may have always been present but at undetectable levels but able to proliferate once the major clones have been destroyed by therapy
How are haematological malignancies classified? (2)
- Histology
- Cytology and haematology
What is histology? (2)
- Identifying abnormal tissue morphology
- Density of chromosome staining and nucleus morphology are likely to be altered
What is cytology/haematology? (2)
- Reporting on the morphology of stem cells and the derivatives in the bone marrow, lymph nodes and peripheral blood
- Malignancies change the proportions of cells in the blood which can be characterised by unique morphology
How can haematological malignancies affect immature stem cells in the bone marrow? (2)
- Enhancing proliferation
- Restricting differentiation
What are blast cells? (3)
- Immature blood cells
- Should only be found in the bone marrow but start to appear in peripheral blood as bone marrow becomes more hypercellular
- The proportion of blast cells in the peripheral blood is important in prognosis
What is cytosis?
Hypercellularity due to over proliferation of malignant cells
What is cytopenia?
Too few cells
How does cytopenia occur in cancer? (3)
- Organisation of the bone marrow is destroyed in cancer which alters the spaces allowed for each cell type to function normally
- Filling up of space with abnormal stem cells reduces the space for normal cells to divide resulting in lower number of these lineages (cytopenia) and adds to malfunction of the blood
- A failure of immature stem cells to fully differentiate results in cytopenia of their terminally differentiated daughters
What are the subtypes of lymphoma? (2)
- Hodgkin
- Non-Hodgkin
What is Hodgkin lymphoma? (3)
- Arises in the lymph nodes
- Characterised by presence of Reed Sternberg Cells
- Common in young adults
Which cell type is affected by lymphoma?
B-lymphocytes
What is non-Hodgkin lymphoma?
Largely re-designated as a leukaemia as they are now thought to arise in the bone marrow not the lymph nodes
What is multiple myeloma? (2)
- Characterised by clonal expansion of an abnormal plasma cell which produces an abnormal antibody called an M-protein
- Over proliferation may also disrupt normal haematopoiesis
Which cell type is affected by multiple myeloma?
Plasma cells (type of B-lymphocyte)
How is leukaemia classified? (4)
- Myeloid or lymphoid lineage
- Chronic or acute
How is leukaemia determined to be chronic or acute? (2)
- Chronic: blast cells account for less than 20% of nucleated cells in peripheral blood
- Acute: blast cells account for more than 20%
What are the characteristics of chronic myeloid leukaemias? (5)
- Referred to as the myeloproliferative neoplasms
- 8 types
- Less than 20% blast cells in PB
- Affecting myeloid lineage
- Capable of progression into acute myeloid leukaemia
What are myeloproliferative neoplasms?
Name for cancers that are chronic myeloid leukaemias
What are the characteristics of acute myeloid leukaemias? (2)
- Referred to as “acute myeloid leukaemias and related precursor neoplasms” (AML)
- Greater than 20% blast cells in PB
What are the characteristics of chronic lymphoid leukaemias? (4)
- CLL
- Affects B-lymphocyte lineage
- Less than 20% blast cells in PB
- Typically seen in old age
- Capable of progression into acute lymphoid leukaemia
What are the characteristics of acute lymphoid leukaemias? (3)
- ALL
- Lymphoid lineage
- Greater than 20% blast cells in PB
