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GOHD > Genetics of cancer > Flashcards

Genetics of cancer Flashcards

1
Q

What are the two main classes of change that drive cancer?

A

Inappropriate/overexpression of oncogenes
Reduced expression/down regulation of tumour suppressor gene expression/function.

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2
Q

What do these changes and abnormal levels of these products lead to?

A

abnormal levels of products of these genes help to bias cells towards uncontrolled growth and proliferation, protection from apoptosis

Are a permissive of mutator phenotype - allowingfor the accumulation of additional genetic changes - allowing cells to evolve and acquire additional characteristics that support the proliferation and spread of malignant clones throughout the body.

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3
Q

What is observed in patients with myeloid leukemia?

A

Trisomy for chromosome 8 - mechanism by which proto-oncogene c-MYC is upregulated.

Example of expression of oncogene resulting in aneuploidy

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4
Q

What is loss of chromosomal regions is thought to do?

A

Reduce the expression of tumour suppressors e.g isodicentric chromosome 17

Results in loss of one copy of 17p and deletion of the tumour suppressor gene TP53 which is located on this chromosome arm.

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5
Q

Example of cancer resulting from deletion, duplication and amplification altering the expression of oncogene and tumour supressors

A

high-stage neuroblastomoa (nMyc amplification)
metastatic breast cancer (Her2 amplification)

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6
Q

How are fusion-oncogenes generated?

A

Translocation, inversion and insertion mutations.

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7
Q

Where are fusion-oncogenes seen?
WHy are they unusual?

A

Leikaemia.
Some solid tumours (prostate cancer TMPR222-ERG).

Unusual as most cancers require the accumulation of many mutations over time – meaning that in most cases, cancer is a disease of old age. However fusion oncogenes break this rule, and helps to explain why leukaemia is the most common cancer seen in children.

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8
Q

How might genomic rearrangements disturb tumour supressor and oncogene expression?

A

For example, the translocation of enhancer elements can help to deregulate a proto-oncogene.

Juxtaposition of an insulator element may help to silence a tumour suppressor.

“chromothripsis” - a mechanism by which massive levels of DNA damage resulting in genome fragmentation. This would usually result in apoptosis, but if cells are protected from this (as many malignant cells are) – then the genome can be pieced back together again in a manner that generates lots of abnormalities – including complex rearrangements, duplications, amplifications and deletions.

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9
Q

How might epigenetic change lead to changes in expression of oncogene and tumour suppressor genes?

A

methylation of upstream regulatory elements of genes will often result in transcriptional repression. In cancer – changes to the methylation status of proto-oncogenes and tumour suppressors is not uncommon.

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10
Q

How might point mutations lead to changes in expression of oncogene and tumour suppressor genes?

A

Point mutations in the coding regions of genes – and particularly in the active sites of genes or at splice site – will often inactive gene function.

Common way cells lose tumour suppressor function

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11
Q

What would happen if isodicentric chromosome 17 identified by karyotyping and what does this mean?

A

. This abnormal chromosome would have resulted in the loss of one of the copies of the TP53 tumour suppressor. But this still leaves one other copy of the gene on the other apparently normal homolog. If we saw such an abnormality in the lab by G-Banding, we would need to check the copy number of the gene by FISH. Assuming that only one copy of the gene has been lost from the abnormal chromosome – we would then need to investigate the sequence of the other copy of the gene - as an inactivating point mutation or frameshift mutation [click] would drastically worsen the prognosis for the patient.

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12
Q

Read over second slide

A

How treatment of cancer really evolved from studying leukaemia

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13
Q

What is Leukaemia

A

Leukaemia is a group of diseases which are part of a much larger set of cancers that collectively are termed the Haematological Malignancies

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14
Q

Sporadic cancers of the blood or blood forming tissue:

A

Bone marrow (BM)
Lymphatic system
Peripheral blood (PB)

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15
Q

Which haematological malignancy is commonly observed in children?

A

Acute lymphoblastic keukaemia

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16
Q

Which haematological malignancy is commonly observed in adults/elderly?

A

Acute myeloid leukaemia and myeloproliferative neoplasms

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17
Q

WHich classes of lumphoma affect all ages equally?

A

Burkitt lymphoma, T-cell lymphoma, Hodgkin lymphoma

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18
Q

What are the three classes of Haematological malignancies?

A

Leukaemia
Lymphoma
Multiple myeloma

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19
Q

What are myelodysplastic syndromes?

A

technically not thought as of a full blown cancer.
However they are progressive disorders that originate in the bone marrow, and if they are left untreated they can develop into some particularly nasty types of leukaemia – so practically in the lab they are treated in the same way as other haematological malignancies..

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20
Q

What does clonal mean? what this mean

A

disease develops from a single cell - descendants of that cell will inherit the abnormalities in that original cell
Biomarkers of disease are inherited by daughter cell from mother cell

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21
Q

What kind of diseases are haematological malignancies?

A

Clonal and progressive

amenable to genetic analysis

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22
Q

HM cancers are progressive
what is cancer progression and state two marker for disease progression

A

Progression of cancer is driven by accumulation of abnormalities in the genome.

Proportion of tissue involved increases (clonal expansion)
Abnormal clones may change to become more abnormal (clonal evolution).

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23
Q

What is clonal expansion used to describe

A

how a single clone (i.e. a group of cells in a tissue with the same genotype) proliferates over time to occupy a greater proportion of a tissue.

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24
Q

What is disease load

A

Proportion of bone marrow which is thought to be cancerous

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25
Q

WHat are the two types of remission

A

Cytogenic remission
Molecular genetic remission

26
Q

What is consistant with poor prognosis

A

Clonal evolution - strong evidence of cancer progressing

27
Q

What is clonal evolution
What could happen in a later follow up?

A

Two different types of abnormal clones identified. Theres a larger proportion of clone 1 compared to clone 2. Clone 2 cell have orinigal abnormality from clone 1, and a additional abnormality.

This makes it likely that this new more complex clone 2 will grow and proliferate more rapidly than the original abnormal clone 1.

Possible that clone 2 will be the major clone and a further clonal evolution of a third clone.

(look at slide)

28
Q

What is the depletion of normal tissue a result from? and what is it not a result from?

A

Its NOT a result from normal cells becoming cancerous. But they are being out competed by abnormal tissue for space and nutrients.

29
Q

What do cancer treatments do?

A

Preferentially destroy malignant tissue which is then replaced with normal cells. HOPEFULLY!

30
Q

How do genetic technologies play important role in pateints who were in remission and then cancer comes back .

A

Genomic technologies are highly sensitive.
allows us to monitor abnormal clones using FISH down to about 1% of bone marrow.
Then quantitative PCR which is roughly 1000 fold more sensitive.

Capable of reporting patient samples quickly - within hour.

Ideal as can detect relapses incredibly quickly and early on - crucial to give patient best chance of acheving remission.

31
Q

Two ways cancer comes back after relapse.

A

Original cancer comes back- clone 1, 2 or 3
Replase defined by completely new genotype

32
Q

How does a new genotype occur?

A

Therapy related disease
New genotype was present as very low undetectable levels

33
Q

What is therapy related disease

A

Therapy used has damaged the DNA of some normal cells to such extent that these cells became new malignant clones.

34
Q

How could the genotype be at undetectable levels?

A

Clones 1,2 or 3 were so proliferative that they mopped up all the available nutrients and space – and thus suppressed the proliferation of other clones. Once the major clones have been destroyed by therapy – space is created for other clones to grow into. Our therapeutic strategy and hope – is that this space becomes occupied by normal tissue – but it can end up being a perfect environment for an even nastier cancer to grow into.

35
Q

Two ways to classify haematological malignancies (first phase)

A

Histology: Analysis of tissue structure

Cytology/Haematology: Analysis of haemtological cells and precursor cells in the PB, BM (aspirate) and from the lymphatic system. Proportion of different cells are reported along with cell morphology.

Immunology: Use of monoclonal antibodies for the automated immuno-detection of cell surface markers.

36
Q

Why is disease classification important?

A

Disease classification is essential to ensure that patients receive the most effective treatments, and are triaged with appropriate urgency.

37
Q

Aim of histology investigation

A

Histology investigations are intended to characterise the morphology of whole tissues. For many haematological malignancies the cellularity of the bone marrow is often abnormal.

38
Q

Aims of Cytology and haematology investigations

A

Cytology and haematology investigations report on the morphology of stem-cells in the bone marrow and lymph nodes and the terminally differentiated derivatives in the peripheral blood. Malignancies of these tissues often change the proportions of cells in the blood. These cells can be charaterised by their unique morphology.

39
Q

How to haematological malignancies affect immature stem cells in bone marrow?

A

either by enhancing their rate of proliferation, or by restricting their ability to differentiate (often both).

40
Q

What happens when the bone marrow becomes more hyper cellular?

A

– as the bone marrow becomes more hyper cellular – these blast cells start to appear in the peripheral blood – this is a poor prognostic marker – and the quantification of blasts in the bone marrow and in the peripheral blood is an important metric that is used to classify and prognose a patients disease. In any case when the number, differentiation potential and location of blood stem cells is altered – the function of blood is altered – and as you can imagine this leads to serious life threatening illnesses in patients.

41
Q

Aims of immunology investigation

A

To support the characterization and quantification of cells in peripheral blood and related tissues, monoclonal antibodies can be used to detect cell specific surface markers.

42
Q

Why is characterisation of type of cells invovled in cancer useful?

A

Because haematological malignancies are clonal, if a stem cells acquires genetic abnormality and becomes malignant then all descendants of that cell (cell lineage) will also be abnormal and contain the same GENETIC MARKERS

43
Q

What happens when a cancer progresses and what does this result in? Explain an example

A

Become more complex
Resulting in confusing phenotypes.

Example -
a hallmark of cancer is the over proliferation of malignant cells. In haematological disease we refer to this type of hyper cellularity as a cytosis, which means too many cells. The opposite term is cytopenia – which means that there are too few cells. Often haematological disease is characterized by cytosis of some lineages and cytopenia of others. This means that we are observing too many cells of one type and not enough of others..

44
Q

What does haematopoiesis require?

A

the process by which cells are produced in the bone marrow require space to function normally.

45
Q

What is normal bone marrow like and what happens when cancer arises? and how does this lead to cytopenia lineages

A

.Under normal circumstances the bone marrow is a highly ordered tissue, with defined spaces for various stem cells to differentiate into new blood cells.

But in cancer the organization of the bone marrow is destroyed, and often these crucial spaces are filled up with abnormal stem cells.

As a result of this, the space that is available to normal tissue becomes limited. This means that the non-malignant stem cells in the bone marrow simply don’t have enough physical space to divide – which means the descendants of these cells are produced in lower numbers – which is observed as cytopenia of that lineage – and adds to the malfunction of the blood.

46
Q

Life of a blast cell (stem cell)

A

Stem cells aka blast cells, are normally located in the bone marrow. When they divide they are capable of generating new copies of themselves (which is called self renewal) or they may differentiate into a one of the cell types that you can see at the bottom of the slide. The maturation process by which these functional units of the blood and related tissues are formed usually starts in the bone marrow and is completed in the blood or via lymph nodes.

47
Q

What are the two main lineages of blood

A

Myeloid lineage from myeloid stem cells
Lymphoid lineage - for immunity

48
Q

Mature myeloid cells

A

Thrombocytes (platelets) for blot clots

49
Q

How are red blood cells and immunity affected in blood cancer

A

The number of red blood cells is often reduced in blood cancer due to limited available space in the bone marrow. This leads to low oxygen levels in the blood, which is commonly observed in the patient as chronic fatigue and muscle weakness.

Some myeloid cells are also involved in immunity such as Macrophages which engulf pathogens by phagocytosis and Natural killer cells, which release powerful cytokines to that act as a sort of chemical stimulant to attract more cells to the site of an infection.

50
Q

What are lymphoid lineages important for

A

The lymphoid lineage shown on the right is also important for immunity – and so patients living with a haematological malignancy are often immuno-compromised and are highly susceptible to infectious disease.

51
Q

How are haematological diseases classified?

what are the three classes

A

by identifying the lineage of cells in the bone marrow, blood or lymphnodes that has acquired malignant characteristics.

Lymphoma, multiple myeloma, leukaemia

52
Q

Lymphomas

A

Affect B-lymphocytes
Two main classes - Hodgkin lymphoma and non-hodgkin lymphoma

53
Q

Where is Hodgkin-lymphoma thought to arise from

A

is thought to arise in the lymph nodes and is typically characterised by the observation of a particular cell type with distinct morphology – called Reed Sternberg Cells. This type of cancer is quite common in young adults.

54
Q

Multiple myeloma

A

Multiple myeloma affects a specific type of B-lymphocyte called a plasma cell – which secretes antibodies. This cancer is characterized by the massive clonal expansion of an abnormal plasma cell, which produces a very unique antibody called an M-protein.

55
Q

Where do Leukaemias arise

A

arise in the bone marrow and are characterised by the over proliferation of malignant cells. There are 4 main classes of leukaemia, which are generated by the characterization of 2 important parameters.

56
Q

When is leukaeia classed as chronic?

A

If the blast cells account for less than 20% of all nucleated cells in the blood, the leukaemia is classified as a chronic disease.

57
Q

When is leukaemia classed as acute

A

. If there are more than 20% blasts in the blood, the leukaemia is classified as acute.

58
Q

What are the four main classes of Leukaemia

A

Chronic myeloid leukaemia, Acute myeloid leukaemia, Chronic lymphoid leukaemia and Acute lymphoid leukaemia.

59
Q

What are chronic myeloid/lymphoid diseases capable of?

A

Transforming int acute leukemia

60
Q

What lineage is affected by Chronic lymphoid leukaemias

A

B lymphocyte lineage

61
Q

Do further reading

A

Gene fusion in prostate cancer:
https://www.nature.com/articles/nrc2402

Chromothripsis background reading
https://www.cell.com/action/showPdf?pii=S0960-9822(15)00202-X

Barrett’s Esophagus
https://gut.bmj.com/content/gutjnl/67/11/1942.full.pdf

GOHD (23 decks)

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