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Cellular And Molecular Pathology > Cancer > Flashcards

Cancer Flashcards

0
Q

Why are cancer trends changing?

A

Increase in lung cancer due to smoking
Increase in breast cancer due to delayed childbirth
Increasing obesity and diet changes affects risk of cancer

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1
Q

How are politics involved in cancer today?

A

Can’t afford to treat someone if it increase lifespans by 6months
Can afford to treat if it increases lifespan by 5 years
Circumstances- mother with 2 kids likely to get correct treatment compared to single middle aged male

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2
Q

If smoking was stopped how would cancer incidence change?

A

Incidence would reduce by 25% worldwide

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3
Q

Why are 90% of cancers of epithelial origin?

A

Proliferating tissues have increased risk of mutation

Exposure to uv light, diet and smoking which can enter blood and cause cancer anywhere

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4
Q

What factors increase the likelihood of a cell turning cancerous?

A

6-10 mutations in same cell
Live longer - more likely to accumulate mutations
Weak immune system
Changes in gene expression
Shape of nucleus changes with age - can have impact on gene expression
Genetic predisposition in young people

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5
Q

What gene is involved in bowel cancer?

A

Adenomatous polyposis coli APC gene
Tumour suppressor gene
Inherit one mutant copy - 100% risk bowel cancer

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6
Q

What are the key events in colorectal tumorigenesis?

A
  1. Mutated APC causes early adenoma
  2. Mutated K-ras proto-oncogene and overexpression of epidermal growth factor ….. Late adenoma
  3. Mutated p53 causes carcinoma
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7
Q

What is cancer?

A

Breakdown in the control of proliferation, differentiation and cell death Movement of cancerous cells to invade other tissues

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8
Q

What is the role of Bcl-2 in the colonic crypt?

A

Protects from apoptosis

Found in the base of the crypt

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9
Q

What is the role of TGFB in the colonic crypt?

A

Inhibits epithelial cell growth

Found at the top of the crypt

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10
Q

What is the role of Bax in the colonic crypt?

A

Gene involved in apoptosis

Found at the top of the crypt

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11
Q

As well as increased cell growth, what must there also be for tumours to develop?

A

Decreased cell death

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12
Q

What pathway is affected in colon cancer?

A

Apoptotic pathway
Bcl-2 overexpression
Baxmutated

Number of cells increases

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13
Q

How might some genetic changes that uncouple growth also confer resistance to current therapies for cancer?

A

Bcl-2 can protect against chemotherapy as it prevents programmed cell death

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14
Q

How does aspirin reduce the risk of bowel cancer?

A

Chronic inflammation increases risk

Aspirin is an NSAID so decreases inflammation

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15
Q

What do cancer cells behave like?

A

Embryonic cells

Display retrodifferentiation and revert back to embryonic phenotype

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16
Q

What behaviour do tumours acquire?

A 
Evading apoptosis
Self sufficiency in growth signal
Insensitivity to anti growth signals - resistance to TGFB
Tissue invasion and metastasis
Limitless replication potential
Sustained angiogenesis
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17
Q

How do carcinogens cause cancer?

A

Mutate growth control genes (TSG and Proto-oncogenes)

Alter gene expression

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18
Q

Does where you live affect your risk of developing cancer?

A

Yes
People who migrate from low to high incidence places, within one generation their cancer risk increases
Proof lifestyle is a factor in cancer development

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19
Q

What is a proto-oncogene?

A

Normal gene involved in normal growth control and differentiation.
Often involved in controlling the cell cycle- if they mutate or overexpress they become an oncogene
Single base change of c-ras turns it into oncogene
Overexpression of c-myc means it is an oncogene but still has normal function

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20
Q

What is an oncogene?

A

Gene whose product can act in a dominant fashion to make a normal cell cancerous
Mutant form of a proto-oncogene
2 alleles - mutate one - becomes oncogene

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21
Q

What are compete carcinogens?

A

Produce tumours on their own
Don’t need extra chemicals such as tumour promotors
E.g. Radiation at high dose

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22
Q

What is an incomplete carcinogen?

A

Sometimes called initiating agents
Require subsequent exposure of the treated cells to tumour promoting agents
Damage cells in such a way that if it comes into contact with another chemical it will turn cancerous

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23
Q

What is a papilloma?

A

Benign skin tumour caused by initiation followed by tumour promotion
Some undergo tumour progression
Most regress
(Similar to adenoma in colorectal cancer)

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24
Q

What do tumour promoting agents do?

A

Not mutagenic
Cause irritation and inflammation
Alter gene expression and inhibit metabolic cooperation
Prevents communication between cell gap junctions allowing clinal expansion
Prevents normal surrounding cells restraining mutant cell

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25
Q

Why is clonal expansion a key part in cancer?

A

Increase pool of benign cells
Increase risk of another mutation
Increase development of carcinoma

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26
Q

Example of an initiating agent

A

B(a)P found in tobacco

DMBA

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27
Q

Example of a tumour promoting agent

A

TPA
Phorbol ester that causes inflammation
Activates many signalling pathways

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28
Q

How is B(a)P a carcinogen?

A

Indirect
P450 inactivates it
Metabolic activation in the liver in order to damage DNA
Chemical itself does not damage DNA
Genetic variation in individuals - enzyme to activate may be more active in one person compared to another and vice versa

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29
Q

How does 7,8-diol-9,10-epoxide work as a carcinogen?

A

Direct

Bunds directly to guanine causing mutations

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30
Q

Can a tumour develop if exposed to promoter before cell is initiated?

A

No

Must be exposed to incomplete carcinogen first

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31
Q

How can mutations in proto-oncogenes be detected?

A

Direct DNA sequencing of whole gene to see if mutated
Direct DNA sequencing of the known hotspots to be mutated
DNA transfection assays

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32
Q

In mouse skin carcinogenesis how is the cellular proto-oncogene c-H-ras mutated?

A

Depends on carcinogen
B(a)P causes codon 12 mutations
DMBA causes codon 61 mutations
Single base change causes constituitive activation as growth factor can’t bind to receptor on surface

Different carcinogens leave different DNA fingerprints

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33
Q

At what stage is ras mutated in morse skin carcinogenesis?

A

Smallest papilloma had a ras mutation - is it the initiating event?
Specificity of the mutation depended on the initiating agent and not the tumour promoter - promoter could be swapped but ras had same mutation
Initiating agents target specific DNA bases consistent with codon 12 and 61 mutations in H-ras suggesting the carcinogens target c-H-ras in skin stem cells
Take active oncogene from virus and scrape into skin - tumour
Some papillomas merely require more mutations for them to become cancerous - p53 mutant or amplified ras mutation

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34
Q

What is the significance of viruses causing cancer?

A

10-20% cancers have a viral involvement
Viruses are relatively simple hence can understand mechanisms of cancer induction
Can reduce cancer incidence by screening, vaccines and avoiding risks of infection (prostitutes)
Changing trends of cancer incidence..increased sexual activity - cervical cancer

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35
Q

How does a proto-oncogene become an oncogene?

A

Single base pair point mutation - ras
Over expression of normal gene causing high levels of normal protein - c-myc
Knowing if a gene is switched on is just as important as knowing if it’s mutated or not.

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36
Q

What is the product of the ras oncogene?

A

p21 protein which has GTPase activity

The mutant form has reduced activity

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37
Q

How does the ras oncogene function?

A

As a G protein involved in signal transduction at the cell membrane

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38
Q

What do ras mutations do to the gene?

A

Constitutively switched on to continuously signal for growth
Usually dominant acting, gain of function mutations
Does not require growth factor binding to be activated

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39
Q

In what cancers is ras mutated?

A

60-80% pancreatic cancer
50% colorectal cancer
In some ras is not mutated but pathway is activated by mutations in receptors

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40
Q

What is the definition of a tumour virus?

A

Viruses which are capable either alone or in cooperation with other agents of converting normal cells to tumour cells.
Most viruses are not oncogenic

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41
Q

How is acute transforming virus oncogenic?

A 
p60src (rous sarcoma virus) oncoprotein
Dominant acting
Has protein kinase activity
Quick at inducing tumours
Virus can transform regardless of where it integrates in host DNA
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42
Q

How is it proven that acute virus and cellular transfections cause foci?

A

Isolate gene from virus and sheer it
Add calcium phosphate
Precipitate it onto normal cells in culture
DNA taken up into cells

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43
Q

How does avian leukosis virus cause cancer?

A

No oncogene
Integrates next to c-myc proto-oncogene
- insertional mutagenesis
Viral promotor drives over expression of c-myc

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44
Q

Why is integration site of non oncogenic viruses crucial?

A

Integration is random, can take a while for it to integrate into the right place in a cells DNA
Not as potent as viral oncogenes

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45
Q

Which two methods are a form of insertional mutagenesis?

A

Promoter insertion next to proto-oncogene

Viral insertion directly onto a growth control gene, mutating it. E.g. p53 or Rb TSGs and causing inactivation

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46
Q

What are the properties of slow transforming viruses?

A

No oncogene- don’t transform cells in culture
3-14months for tumour to appear
Specific integration site - KEY
Slow due to randomness of integration and time it takes
Direct effect of viral genome and not viral encoded proteins

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47
Q

What type of secretion do tumour cells respond to?

A

Autocrine secretion

Decreased growth factor requirement as produce their own

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48
Q

What are the requirements for growth factor action?

A

Specific receptors
Some secreted latent and require activation
Response to a GF may be determined by what other GF are present
More than one GF to a receptor
Can have a positive (EGF) or negative (TGFB) effect

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49
Q

Do all cells respond in the same way to GF?

A

No

TGFB stimulates normal fibroblasts but inhibits normal epithelial cells (G1arrest)

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50
Q

What are the domains of the receptor/growth factor?

A

Receptor has outer domain
Transmembrane domain
Inner cytoplasmic domain which associates with intrinsic tyrosine kinase cascade and activates it - autophosphorylation of the receptor and other cellular proteins for stimulation of DNA synthesis

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51
Q

What is platelet derived growth factor?

A

Blood serum supported growth of connective tissue cells
Released from platelets at wounded sites
Major mitogen in serum for cells of mesenchymal origin
Fibroblasts, smooth muscle, glial cells have receptors

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52
Q

What is the relationship between PDGF and role in transformation?

A

Viral transformed cells have reduced GF need. Cancer cells conditions medium by secreting GF to promote growth
Are viral oncogenes encoding growth factors?
PDGF sequence made and compared with p28sis of simian sarcoma virus oncogene - VERY SIMILAR 104 contiguous aa showed virtual identity
V-sis may have picked up mutant version of proto-oncogene

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53
Q

Properties of Epidermal Growth Factor?

A

Single polypeptide chain
All 3 germ layers
Not restricted to epidermis
Receptor has intrinsic tyrosine kinase activity - DNA synthesis
Structural similarity between receptor and v-erb B oncogene of avian erythroblastosis - viral encodes truncated receptor

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54
Q

How does the viral oncogene affect epidermal growth factor?

A

EGF receptor is truncated so that there is no outer domain

Receptor is constitutively activated with no need for GF binding

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55
Q

Why do tumours show reduced GF requirements?

A

Over expression of growth factors caused by viral genes (v-sis)
Abnormal GF receptors
Over expression of normal GF receptors - genes regulated by promoters
v-src encodes protein kinase activity, phosphorylating signalling pathways
Mutation of ras or overexpression of c-myc - don’t need GF

56
Q

How was the first oncogene-ras isolated?

A

Transfect in DNA from EJ bladder carcinoma onto mouse 3T3 cells (non tumourigenic)
Pick several tx foci and isolate the human DNA
Find common sequences on mouse background for all foci
Is there homologous gene in normal cells? Yes
Sequence it and compare

Control using normal DNA from normal bladder cells

57
Q

What is the difference between normal and viral c-h-ras?

A

Single point mutation

58
Q

When is a tumour considered malignant?

A

When tumour has invaded the basement membrane

59
Q

Can metastatic cancer be completely cured?

A

No

Once in blood stream not all cells can be removed, too small to find

60
Q

What is the pathology of benign tumours?

A 
Encapsulated
Noninvasive
Highly differentiated
Rare mitosis
Slow growth
Little/mild dysphasia - nucleus looks normal
Non metastatic
Often completely curable
61
Q

What is the pathology of malignant tumours?

A 
Non-encapsulated 
Invasive
Poorly differentiated
Mitosis common
Rapid growth
Dysplasia
Metastatic
Difficult to treat if spread
62
Q

What are benign and metastatic squamous epithelial tumours called?

A

Benign - squamous papilloma

Malignant - squamous carcinoma

63
Q

What are benign and metastatic glandular epithelial tumours called?

A

Benign- adenoma

Malignant - adenocarcinoma

64
Q

What are benign and metastatic connective tissue tumours called?

A

Fibrous tissue benign - fibroma
Malignant - fibrosarcoma

Fat benign - lipoma
Malignant - liposarcoma

Cartilage benign - Chondroma
Malignant - chondrosarcoma

Bone benign - osteoma
Malignant - osteosarcoma

Blood vessel benign - angioma
Malignant - angiosarcoma

65
Q

What are benign and malignant ovarian and testicular tumours called?

A

Benign - teratoma

Malignant - malignant teratoma

66
Q

What is a hydatidiform mole?

A

Growing mass of tissue in uterus that will not develop into a baby
Result of abnormal conception

67
Q

Why do large tumours require angiogenesis?

A

If a tumour becomes too large it becomes hypoxic, nutrient deficient and can’t get rid of waste products
Tumour secretes vasculoendothelium growth factor
Metastasis is influenced by angiogenesis

68
Q

What are examples of angiogenesis factors?

A 
Fibroblast growth factor
TGFA and B
Angiogenin
Heparin
Vascular endothelial growth factor - produced my nearly all cells
69
Q

How can Tumour Angiogenesis Factor (TAG) be used as treatment?

A

Induces new blood vessels

May be used to restimulate blocked vessels

70
Q

Why can’t radiation and chemotherapy be used in hypoxic tumour cells?

A

Radiation activates water and O2 molecules so won’t work in a cell lacking in O2
Chemo attacks dividing cells, tumour switches off growth and has low blood supply so drugs can’t reach

71
Q

What is hypoxia inducible factor (HIF-1)?

A

Heterodimeric transcription factor with two subunits
HIF-1A is inducible - produced all the time but degraded within minutes
HIF-1B is constitutive - all cells in body
Hypoxia stabilises HIF-1A so it can bind to B driving expression of VEGF

72
Q

What are two anti angiogenesis factors?

A

Thrombospondin
Angiostatin

Expressed in normal cells and reduced in tumours

73
Q

How are anti angiogenesis factors decreased in tumours?

A

Mutations in tumour suppressor genes

Mutant p53 decreases thrombospondin

74
Q

What is anoikis?

A

Type of programmed cell death induced by anchorage-dependent cells detaching from the surrounding extracellular matrix
Metastatic cells resistant - increase bcl-2 expression and are resistant to abnormal conditions

75
Q

What are the steps for a tumour to become metastatic?

A

Tumour greater than 1cm - bigger the tumour the more potential for mutation
Invasion and entry into blood vessels
Metastasis

76
Q

Why are metastatic tumours difficult to treat?

A

Scans pick up tumours greater than 1cm
Metastatic tumours can be smaller than this
Once in blood stream don’t know wherein body they are

77
Q

What is the 3 step hypothesis to describe biochemical events during tumour evasion of extracellular matrix?

A

Attachment to extracellular matrix
Local proteolysis - enzymes to destroy BM
Tumour cell locomotion into region of the matrix modified by proteolysis - Epithelial Mesenchymal Transition

78
Q

What is EMT?

A

Epithelial-mesenchymal transition
Loss of e-cadherin
Change in cell morphology to allow movement between cells and tissues

79
Q

What is e-cadherin?

A

Cell-cell adhesion
Can be a TSG
prevents movement of specific cells - breast tissue cells remain in breast tissue etc.

80
Q

Is metastasis random or are the cells distinct genetically from the mass of the primary tumour?

A

Inject primary melanoma SC into mouse - number of metastasis in lungs was small
Remove metastasis from mouse and inject into another SC - more metastatic and genetically different to primary tumour

Metastasis not random but a result of specific mutations

81
Q

How can you find metastatic genes?

A

cDNA libraries from metastatic and non metastatic tumours from same model and compare expression
NM23 gene lost in metastatic tumour - tumour suppressor gene
Metastatic cell + NM23 = non metastatic cell

82
Q

Why do less than 1% metastatic cells in circulation survive?

A

Killed by mechanical sheer forces
Loss of attachment and spreading as still anchorage dependent
Oxygen toxicity
Destruction by natural killer cells

83
Q

What is metastasis to a specific organ due to?

A

Easy access via circulation from primary site - colon goes direct to liver
Appropriate growth factors in some tissues but not others

84
Q

How is surgery used to treat cancer?

A

Remove primary
Avoid promoting spread during surgery
Main way

85
Q

How is radiotherapy used in treating cancer?

A

Shine primary or secondary tumour prior to surgery
Used for brain tumours
50% cancers treated with radiotherapy
Can’t treat disseminated disease

86
Q

How is chemotherapy used to treat cancer?

A

Can treat whole body
PO / IV
Designed to kill proliferating cells..will kill normal cells in renewing tissue -side effects
Toxic to normal bone marrow but some toxicity is tolerated
Target cells with monoclonal antibodies (magic bullet)
Drug resistance can develop - relapse

87
Q

What is fluorouracil?

A

Chemo drug
Bowel, breast, skin, stomach and gullet cancer
Pyrimidine analogue which inhibits DNA synthesis in rapidly growing cells - includes normal cells
IV over several months
Combine with radiation in colon cancer - attack in a way it can’t evolve resistance

88
Q

How are monoclonal antibodies used in cancer treatment?

A

Localisation of tumour and detecting metastasis
Cell type characterisation determines treatment
Drug target with specific antibodies to specific antigen on tumour surface
Target surface antigens
Iodine-labelled anti-CEA monoclonal so can detect it in body

89
Q

What is herceptin?

A

Human epidermal growth factor receptor 2 is overexpressed in breast cancer
Herceptin is a monoclonal antibody to the HER2 receptor
Blocks intrinsic kinase activity
Only effective in a subset of patients that over express the receptor

90
Q

What is tamoxifen?

A

Antagonist of oestrogen receptor in breast cancer tissue - some ER+ cells require oestrogen binding in order to grow “addicted to oestrogen”
Treats oestrogen receptor positive breast cancer and males rests cancer

Example of personalised treatment

91
Q

What is avastin?

A

Humanised monoclonal antibody
Angiogenesis inhibitor by inhibiting VEGF
Used in advanced bowel cancer treatment

92
Q

How does Ricin kill cancer cells?

A

B-chain binds the A-chain to specific receptors on sensitive cells
A-chain enters cytoplasm
Inhibits protein synthesis and kills the cells
If B-chain replaced by antibodies specific to tumour cells it will have a powerful cytotoxic effect against them
Eg. Use monoclonal antibody against CEA In colorectal tumours

93
Q

How is a ricin A-Immunotoxin constructed?

A

Introduce activated disulphides group to CEA Monoclonal antibody
Reduce and purify A-chain of ricin
Mix together and purify
Will only enter cell expressing CEA

94
Q

Why is cancer treatment of metastasis limited?

A

Toxicity to normal bone marrow cells as it’s highly proliferative
May not eradicate all cells - relapse
If higher doses of chemo and radiotherapy used, bone marrow must be reconstituted after treatment

95
Q

How can we reduce the limitation of chemotherapy?

A

Remove bone marrow before giving treatment
Keep in culture medium to retain haemopoietic material and prevent from differentiating
Replace bone marrow after treatment

96
Q

How could cancer in bone marrow be treated?

A

Treat cells outside of patient
Separate cancer cells
Label with magnetic beads

97
Q

What is autologous bone marrow transplantation?

A

Sample of bone marrow removed before high dose chemo
Re implanted afterwards
With leukaemia or lymphoma marrow is purged

98
Q

How is bone marrow purged when neuroblastoma cells are present?

A

Magic bullet
Tumour cells coated with mouse monoclonal anti-neuroblastoma antibodies then with sheep Ig antibodies bound to magnetic microspheres
Pass the marrow between magnets to remove cells
Removes 99.9% of tumour cells

99
Q

What is allogeneic bone marrow transplantation?

A

Bone marrow from another individual
Must be a match for histocompatibility antigens to reduce risk of graft vs. host disease - graft T cells attack host cells

100
Q

How can graft vs. host disease be prevented?

A

Remove or kill T cells in donor marrow before its infused into patient

101
Q

What does cytogenetics mean?

A

The study of the structure and function of chromosomes

102
Q

How is comparative genetic hybridisation done?

A

Label normal DNA red and the tumour green
Hybridise together, if balanced get grey colour
If green, more tumour sequences than normal
Red- deletions in tumour chromosome

103
Q

How are chromosomes recognised?

A

Size, position of the centromere and banding pattern

104
Q

What are telomeres?

A

Repeated sequences
Stop sequences getting lost during division
Work as replication clock once eroded
Telomeres normal, cell won’t divide

105
Q

How can chromosome instability accelerate tumour progression?

A

Defects in DNA repair may cause chromosomes to fuse
Defects in chromosome segregation

These cause further genetic changes - losing genes at break points leads to instability syndrome, become more and more abnormal
Don’t align properly - mitosis won’t separate properly

106
Q

What are the three types of chromosome abnormalities in neoplasticism cells?

A

Primary abnormalities drive initiation - establish the tumour
Secondary abnormalities increase profession of the tumour and occur after tumour has developed
Cytogenetic noise - background level of non consequential aberrations, chromosome instability where not every change is mutagenic

107
Q

What are primary abnormalities?

A

Genes whose mutation or alter expression relieves normal controls on cell division, death or lifespan, promoting the outgrowth of cancer cells
‘Gatekeepers’

108
Q

What are secondary abnormalities?

A

Those whose disruption causes genome instability increasing the frequency of alterations in gatekeeper genes
Work as caretakers

109
Q

How do cancer genes gain function?

A

Dominant effect
One allele is defective
Proto-oncogene

110
Q

How do cancer genes lose function?

A

Both alleles inactivated or deleted

Tumour suppressor gene

111
Q

When are genes associated with cancer?

A

Gene product is altered
Gene inappropriately expressed
Gene over expressed
Gene expression suppressed (TSG)

112
Q

How is an oncogene activated?

A

Point mutation in DNA sequence
Gene amplification
Chromosome translocations or rearrangements - may form new gene product
-may move proto-oncogene into a transcription ally active region so the protein is produced in excess

113
Q

What part of oncogene activation can not be seen at chromosome level?

A

Point mutation in DNA sequence

114
Q

What is an example of gene amplification?

A

Trisomy 12 - chronic lymphocytic leukaemia
Duplication of mutated chromosome

Duplication of part of chromosome to form an isochromosome - loos of sequences of p arm, duplication of q arm

Tandem repeats on same allele (many copies)

115
Q

What is a minisatellite?

A

10-60 nucleotides repeated

Relatively unstable

116
Q

What is a microsatellite?

A

Less than 10 nucleotides repeated
Won’t necessarily lead to tumorigenesis - depends on location
Can change gene expression of regulatory proteins
Background noise

117
Q

What are double minutes?

A

Small circular fragments of extra chromosomal DNA
Present in a large number of tumours
Sign of gene amplification

118
Q

How are TSGs inactivated?

A

Deletion after mutation of normal allele
Mutation in second allele
Aneuploidy

119
Q

What are haematopoietic tumours?

A

Rearrangements involving a few abnormal chromosomes
Many dividing cells
Normal diploid karyotype

120
Q

What are solid tumours?

A

Many chromosome rearrangements
Gross aneuploidy
Chromosome preparations difficult as few dividing cells - must be in metaphase

121
Q

What is the translocation in Burkitt’s lymphoma translocation?

A

C-myc oncogene translocated to Ig loci - very active
Overexpression of c-myc prevents cells exiting cell cycle as drives proliferation
Reciprocal translocation
t(8;14)(q24;q32)

122
Q

What is the translocation involved in follicular lymphoma?

A

Bcl-2 to IgH
Bcl-2 over expressed - protects against apoptosis
t(14;18)(q32;q21)

123
Q

What is the consequence of the translocation in follicular lymphoma?

A 
Entire coding sequence bcl-2 translocated
Same protein
Over expressed
Increased cell survival
Protects against apoptosis
Cooperates with c-myc in many tumours
124
Q

What is the translocation that causes CML?

A

C-abl to bcr
Enhanced tyrosine kinase activity which increases proliferation
t(9;22)(q34;q11)
First exon of c-abl stays on chr 9
First and second exons of bcr gene fused to remainder of c-abl gene
Now constitutively active kinase

125
Q

What are the biological effects of bcr-abl?

A

Constitutive activation of tyrosine kinase
Inhibits DNA repair leads to genomic instability - increased chance of further mutations
Increased cell cycle
Both lead to tumorigenesis

126
Q

What are examples of haematopoietic tumours?

A

Burkitt’s lymphoma
Follicular lymphoma
CML

127
Q

Why is it difficult to identify the important cancer related genes in solid tumours?

A

Aberrations often contain multiple genes

More than one may be important

128
Q

What is a circos plot?

A

Graph depicting Chromosomal translocations places chromosomes around a circle according to their number or letter
With fusions between previously unlinked chromosomes in purple
Short green ticks show intra chromosomal rearrangements including translocations, small amplifications, deletions and inversions

129
Q

What is chromothripsis?

A

When parts of chromosome explode
DNA repair mechanisms try and piece back together
Mutational mechanism behind this is unclear
Potential scrambling of DNA

130
Q

How is chromosomal instability involved in cancer?

A

General chaos that progressively envelopes cancer cells as they advance towards highly malignant States
Required for tumours to scramble their genomes to arrive at chromosomal configurations that are more favourable to neoplasticism growth
Rarely occurs in haematopoietic tumours

131
Q

What is chromosomal instability?

A

Changes in chromosomal number due to mis segregation of chromosomes during mitosis
M-phase checkpoint fails so sisters chromatids go to one pole causing nondisjunction
Chromosome my fail to attach to spindle and may be lost to a daughter cell
Hundreds of proteins involved in spindle assembly - many things that can go wrong to cause abnormalities

132
Q

What are multipolar mitotic apparatuses?

A

Spindle divides 3 ways instead of two
4 daughter cells
Chromosome scrambled
Viral oncogenes involved

133
Q

What are examples of genetic instability syndromes?

A

Ataxia telangiectasia
Bloom’s syndrome
Franconia anaemia

134
Q

What is Bloom’s syndrome?

A

Half patients have at least one cancer
First cancer at 25 years
Diagnosis on highly elevated sister chromatid exchange rate - 90 of these events per cell

135
Q

What do BRCA 1 and 2 do?

A

DNA repair
Encode large proteins
Significantly overlapping functions

136
Q

What is non-homologous end joining?

A

Simple religation of broken ends
High chance correct ends won’t be stuck together - may also lose some info
Resection of single stands by exonuclease
DNA strands brought together and strands filled in - joined by ligation
Double helix reconstruction
Several base pairs present in original wildtypes sequence are missing

137
Q

What is homologous recombination?

A

Involved BRCA genes
Complex but no info is lost at point of damage
Double strand break resected by exonuclease
Base pairing with unwound DNA or sister chromatid
Undamaged chromosome brought into close proximity and used as template
Fill in gaps and restore wildtype helix - complex process of enzymes

Cellular And Molecular Pathology (3 decks)

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