Cancer and Genes Flashcards
(116 cards)
1
Q
Carcinogenesis stages
A
INITIATION- interaction of carcinogen and DNA
PROMOTION- selective growth advantage (free radicals) + early pre-cancer (adenoma) reversible
PROGRESSION- enhanced cell division (additional mutations) + later pre-cancer (late adenoma) reversible
MALIGNANT CONVERSION- cancer, not reversible
2
Q
What is the first gene lost in colorectal cancer?
A
APC- adenomatous polyposis coli tumour suppressor gene
3
Q
What is progression?
A
Unlimited growth (not self-limited as in benign tumours) - as long as an adequate blood supply is available to prevent hypoxia.
4
Q
Invasiveness
A
Migration of tumour cells into the surrounding stroma where they are free to disseminate via vascular or lymphatic channels to distant organs.
5
Q
Metastasis
A
Spread of tumour cells from the primary site to form secondary tumours at other sites in the body.
6
Q
Mechanisms of cell invasion
A
Increased mechanical pressure caused by rapid cellular proliferation.
Hypoxia and blood supply.
Increased motility of the malignant cells (epithelial to mesenchymal transition- EMT).
Increased production of degradative enzymes by both tumour cells and stromal cells.
7
Q
What happens to malignant cells to increase their motility?
A
New transcriptional programme is activated to promote the mesenchymal fate.
Cells become:
Fibroblast like shape and motility
N-cadherin
Invasiveness
Vimentin intermediate filament expression
Mesenchymal gene expression (fibronectin, PDGF receptor, avB6 integrin)
Protease secretion (MMP2, MMP9)
Cells lose:
Epithelial shape and cell polarity
Cytokeratin intermediate filament expression
Epithelial adherent junction protein (E-cadherin)
8
Q
Hereditary cancer predisposition syndromes
A
Li-Fraumeni syndrome
Down syndrome
9
Q
Examples of chemical, physical and viral carcinogens?
A
Chemical- benzene, alkylating agents (chemotherapy)
Physical- X rays, UV light, alpha particles
Viral- hepatitis B, Human papilloma
10
Q
Ionising radiation vs non ionising radiation carcinogens and the damage they cause?
A
Ionising: gamma, X rays, particulate radiaiton
Non ionising: UV light
Cause: DNA breaks, pyrimidine dimers -> failed repair -> translocations and mutations
11
Q
Tumour suppressors and oncogenes in cell cycle
A
p53 in charge of maintaining cell checkpoints
Proto oncogenes like Myc, ras involved in cell proliferation
12
Q
Proto oncogene
A
normal cellular genes which regulate cell growth and/or division and differentiation.
13
Q
Oncogene
A
a proto-oncogene that has been activated by mutation or overexpression. (malignant)
14
Q
What are the 2 types of conversion from proto-oncogene to oncogene?
A
- Mutation in the gene results in a different oncoprotein to the normal protein within the cell.
- Oncoproteins are the same as the normal protein but expressed at higher levels. So LOADS of em
15
Q
Different ways to convert proto-oncogenes to oncogenes
A
Point Mutation: variant in proto-oncogene (KRAS in lung cancer) or in promoter/regulatory element
Gene Amplification (c-myc in breast cancer)
Chromosomal Translocation: creation of fusion protein (BCR-ABL in CML) or disruption of regulatory elements
16
Q
What is the bare minimum needed to promote an oncogene?
A
One pathogenic alteration on one copy of a proto oncogene is enough to cause an oncogene, ie a single copy of oncogene is sufficient to promote tumorigenesis
17
Q
Why are proto oncogene mutations rarely inherited?
A
Somatic mutations occurring in non-germline cell types
18
Q
Features of oncogene HER2
A
Growth factor receptor
- HER2/neu/ERBB2 gene encodes for part of the human epidermal growth factor receptor 2
Receptor dimerization is required for HER2 function
- Growth factors bind EGFR or HER3 and alter conformation of receptors that become active.
- HER2 protein has intracellular tyrosine kinase activity- can phosphorylate other proteins in signalling cascade
19
Q
What gene is amplified in 20% invasive breast cancers?
A
HER2
Associated w aggressive disease and poor prognosis
20
Q
What monoclonal antibodies therapeutically target HER2?
A
Trastuzumab and pertuzumab
- Only effective in HER2+ cancers
prevents dimerization of HER2 and 3
21
Q
What are Ras proteins?
A
Cellular signal transducers
activated by phosphorylation signal of growth factor receptor like HER2 -> Activation of receptor tyrosine kinases activate the Ras proteins.
22
Q
How is KRas switched on and off?
A
GDP (turned off) to GTP bound (on)
Ras gene products are involved in kinase signalling pathways that control the transcription of genes, which then regulate cell growth and differentiation
23
Q
Point mutations in what gene are observed in 30% of cancers?
A
Kras
codons 12, 13 (and 18,61,117,146)
Permanent “on” position → permanent cell growth and proliferation
24
Q
BCR-ABL1 oncogene
A
ABL resides on ch9
BCR on ch22
Involved in balanced translocation between small fragment of long arm of ch9 and long arm ch22 = Philadelphia chromosome
in 95% cases of chronic myeloid leukaemia
25
BCR function
ABL function
and joined BCR-ABL oncoprotein function
BCR: encodes a protein that acts as a guanine nucleotide exchange factor for Rho GTPase proteins
ABL encodes a protein tyrosine kinase whose activity is tightly regulated (auto-inhibition)
=
BCR-ABL protein has constitutive (unregulated) protein tyrosine kinase activity
BCR promoter starts controlling ABL gene = constant activation = lots of TK activity
26
Unregulated BCR-ABL leads to what?
Unregulated BCR-Abl= tyrosine kinase activity that causes:
- Proliferation of progenitor cells in the absence of growth factors
- Decreased apoptosis
- Decreased adhesion to bone marrow stroma
Abl is the oncogene
27
What drug specifically inhibits BCR-ABL1?
Imatinib
28
c-Myc oncogene
Encodes for transcription factors
Pathogenic alterations in c-myc involve gene retrovirus activation, amplifications and translocations.
Translocation between chromosome 8 (c-Myc proto-oncogene) and chromosome 14 (immunoglobulin heavy chain gene) are commonly observed in Burkitt’s lymphoma.
29
What do drugs for c-Myc oncoproteins do?
Can't directly target
| Inhibitors of its translation and Myc protein destabilizing drugs show great promise
30
Tumour suppressor genes
TSG encode proteins that maintain the checkpoints and control genome stability. Inhibit replication and proliferation of damaged cells by:
- Repair of DNA damage (e.g. MLH1, BRCA1/2)
- Apoptosis (TP53)
31
Knudson’s two-hit hypothesis
Most of loss-of-function mutations that occur in tumour suppressor genes are recessive in nature- Generally, one normal allele is sufficient for the cellular control.
A “second hit” affecting the normal allele is needed to disrupt gene’s function.
32
When do heritable cancers develop?
Heritable cancers develop after additional loss of the normal functional allele (loss of heterozygosity).
33
Functions of tumour suppressor genes
Oncogenes antagonists
DNA repair (eg BRCA1, 2)
Induce apoptosis (eg p53)
Block proliferation- cell cycle inhibitors, activate TFs, repress TFs
34
DNA repair genes: BRCA1/2
Knockout of the DNA repair function of one or more DNA repair genes leads to sequential acquisition of more mutations.
Defects in DNA repair genes cause genomic instability and accelerate the activation of oncogenes and the loss of tumour suppressors.
Tumours arising in patients as a result of inherited defects in DNA repair genes tend to have a very high mutational load.
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Synthetic lethality
When combination of deficiencies in 2 or more genes leads to cell death
36
Single strand breaks can be repaired by...
PARP
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Double strand breaks can be repaired by...
BRCA1/2
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PARP inhibitors
Olaparib
Rucaparib
Niraparib
Talazoparib
for breast cancers BRCA1/2
39
TP53
TP53 is the gene, p53 is the protein
active when phosphorylated
Detects cellular stress, especially DNA damage
Induces G2 cell cycle arrest
If failure to repair damage induces apoptosis
- Over 50% of cancers contain mutations in the TP53 gene.
- Most commonly affected tumour suppressor gene in human cancer.
- Missense mutations in hotspots (DNA binding domain).
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Li-Fraumeni syndrome and TP53
Approximately 70% of families with LFS will have a mutation (alteration) in the TP53
41
How to restore p53 functions?
Current advances suggest the use of small molecules (MIRA-1, PRIMA-1) that can restore wild-type p53 functions.
42
RB1 oncogene
'gatekeeper' girlboss. encodes Rb protein
Prevents cell growth by inhibiting cell cycle until cell is ready to divide
Phosphorylation = inactivation
Retinoblastoma:
- 90% present before 5 years of age
- Treatment: surgery & radiotherapy
- 98% of cases are cured
43
2 forms of retinoblastoma
44
Mendelian/monogenic disease
Disease caused by a single gene, with little or no impact from the environment (e.g. PKD)
45
Oligogenic/polygenic disease
Diseases or traits caused by the combined effect of:
* a few genes (oligogenic) each having a large effect, or
* many different genes (polygenic) each having only a small individual impact on the final condition (e.g. psoriasis)
46
Multifactorial disease
(= polygenic + environmental factors)
Diseases or traits resulting from an interaction between multiple genes and often multiple environmental factors (e.g. heart disease)
47
Autosomal recessive
Two faulty gene copies cause disease in an autosomal recessive inherited condition
eg cystic fibrosis
48
What chance do two parent carriers have of having a baby inheriting 1) the recessive allele and 2) the actual condition?
50% chance of inheriting a recessive allele from either of the parent.
Two carrier parents have 25% chance of having a child affected by the disorder.
Normal allele is denoted capital R. The mutant allele is denoted small r.
And as I said, in a recessive disease you need to inherit two copies of the mutant allele to be affected.
Imagine two parents who carry one normal allele capital R and one mutant allele small r which is the one that carries the mutation.
These two parents have the genotype of a carrier because they carry a copy of the mutated allele.
But their phenotype is unaffected because they'd need 2 copies for that
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Key points of an autosomal recessive pedigree
The condition is always expressed in homozygotes (individuals with two altered copies);
and carried by heterozygotes (individuals who carry one copy).
Males and females are equally affected.
Typically often no family history.
Consanguinity is frequent in autosomal recessive disorders.
50
Autosomal recessive disorders
```
Cystic Fibrosis
Sickle cell anaemia
Spinal Muscular Atrophy
Phenylketonuria (PKU)
Tay-Sachs disease
Meckel-Gruber Syndrome
```
51
Autosomal dominant
one faulty gene copy is enough to cause disease in an autosomal dominant inherited condition
eg achondroplasia- (heterozygous) genetic defect in the FGFR3 gene.
52
What happens if one parent has achondroplasia, and then what if both have it?
If one parent is affected with achondroplasia, there is a 50 percent risk that his offspring will also be affected. So the father’s genotype is small d, captial D and he is affected by the disease. If he has children with someone who has two fully functioning alleles, then there is 2 out of 4 chances that their offspring will be affected.
This number increases if both parents are affected. Then there is 3 out of 4 i.e. 75% chance that the child will be affected. There is a 25 percent chance that the offspring will inherit two faulty gene copies and in most autosomal dominant disease develop severe, life-threatening features. In for example achondroplasia a captial DD genotype usually leads to still birth.
You should note here, that with autosomal dominant conditions there are no carriers, you are either affected or unaffected.
53
Key points of an autosomal dominant pedigree
An autosomal dominant trait is expressed in heterozygotes.
Usually the homozygotes are lethal.
So an alteration in only one gene is sufficient to cause the disorder.
Males=females
Vertical pedigree
Often adult onset disorders
An affected heterozygote has a 1 in 2 chance of passing the trait on to his or her offspring.
54
Autosomal dominant conditions
```
Achondroplasia
Huntingtons
Familial hypercholesterolaemia
Marfan syndrome
Polycystic Kidney Disease
Polydactyly
```
55
X linked recessive
• In X-linked conditions the faulty gene copy is located on
Chromosome X.
• X-linked recessive traits are expressed in male hemizygotes
and carried by a female heterozygote.
• The son of a female heterozygote has a 1 in 2 chance of being
affected.
• The daughter of a female heterozygote has a 1 in 2 chance of
being a carrier.
• When an affected male has children all his daughters will be
carriers and none of his sons will be affected.
• It is important to remember that X-linked conditions cannot
be passed on from father to son- ffected fathers cannot pass on
the disease to a son, because any
son would get a Y-chromosome
from their father.
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Common situation with X linked recessive
* Only males are affected
* The females are carriers
* There is no male to male transmission
57
Rare situation in X linked recessive
Same situation as with autosomal recessive
inheritance, i.e. 1:4 chance both parents pass on their faulty chromosome X.
• The affected daughter will develop the disease as her affected brother.
58
X linked recessive disorders
Red green colour blindness
Duchenne Becker muscular dystrophy
Haemophilia A and B
X linked ichthyosis
59
X linked dominant
As with autosomal dominant disease, in X-linked dominant disease you only need one faulty gene copy to be affected.
• Therefore, women as well as men can be affected.
However, affected fathers still do not pass on the condition to their sons, but all their daugthers will be affected.
• If a male is affected, it is because he has inherited the faulty gene copy from his mother.
• An affected mother has a 50% chance of passing on the faulty gene to both sons and daughters.
60
X linked dominant disorders
Cranio fronto nasal dysplasia
| Hypophosphataemic rickets
61
X linked dominant passing onto offspring
With an affected female, on
average half her sons and half
her daughters will be affected.
An affected male will transmit
XLD trait to all his daughters
but NONE of his sons.
Remember, father to son
excludes any X-Linked
inheritance!!
62
X linked dominant/male lethal
Condition can be so bad that without normal X chromosome it's fatal
Living females outnumber living males two to one when mother is affected
63
Penetrance
Penetrance is the proportion of individuals carrying a particular genotype that also expresses the associated phenotype.I.e. if an individual carry the disease variant (or allele), they will also develop the disease.
64
# Define:
Complete penetrance
Highly penetrant
Reduced penetrance
Complete penetrance: 100%. Everybody in a family with the genotype will show clinical signs. 10 out of 10 will develop the disease
Highly penetrant: >90%; most of those with the mutation will show clinical signs, but a few will not.
Reduced levels of penetrance: smaller % family members with the genotype will show clinical signs. In a family with 60% penetrance, 6 out of 10 will develop the disease, while 4 will not show symptoms.
65
Reduced penetrance in an autosomal dominant condition
Family with familial Parkinson’s disease.
And we know this is a autosomal dominantly inherited condition. This affected male here would have received the mutated genecopy from his dad, but the dad is clinically normal, and doesn’t show any symptoms at all.
So this is an example of a pedigree showing a trait with incomplete penetrance.
And that of course can cause confusion when drawing out pedigrees.
66
Variable expression
The extent to which a genotype exhibits
its phenotypic expression
Everyone in a family with a mutation will show some clinical signs, but to a variable extent.
67
How is variable expression shown here?
Using different shadings you can indicate in a pedigree who in the family is affected and how severe. So the lighter shade indicates those in the family that have only minor clinical abnormalities, whereas the black shading indicates the most severe cases.
68
Mitochondrial inheritance
Transmission through females but without a consistent segregationally pattern
Both male and female affected
No transmission through males
The number of mutant mitochondia in an offspring is random.
If the number of mutant mitochondria exceeds the threshold disease develops
69
If you get a genogram that do not have a clear inheritance pattern – think...
Mitochondrial disease
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Mitochondrial diseases
• Mitochondrial myopathy
• Myoclonic epilepsy with ragged red fibres
(MERRF)
• Neuropathy, ataxia, retinitis pigmentosa and
ptosis (NARP)
• Kearns-Sayre syndrome
71
Mosaicism
Mosaicism is when not all the cells in the body harbours the genetic defect
This genetic defect is caused by a postzygotic mutational event
72
Gene associated with overgrowth
PIK3CA
73
Sporadic cancer occurs due to...
Postzygotic mutations
```
Late age at onset (60s or 70s)
No family history of cancer
So no inheritance pattern
Single or unilateral tumours
Genetic testing not beneficial
```
74
Inherited cancer due to germline mutation
Early age of onset (<50)
Family history of cancer
Multiple or bilateral tumours in the same individual
Genetic testing can be beneficial
75
How does inheritance of a germline mutation act as a risk factor for cancer?
Inheritance of a germline mutation acts as a risk factor for cancer by reducing the number of somatic mutations required to cause cancer.
The probability of the a 2nd mutation happening in an already mutated cell is much higher in a person with a germline mutation as all cells carry a mutation, than in a person with a sporadic mutation, because the 2nd mutation needs to happen in exactly that same cell to have an effect on disease risk
76
Heritable cancer syndromes
Hereditary breast-ovarian cancer (HBOC) – gene: BRCA1, BRCA2
Retinoblastoma – gene: RB1
Cowden syndrome – gene: PTEN
Lynch syndrome – gene: MSH2, MLH1 etc
77
What cancer increases risk of BRCA1/2 carriers?
Ovarian cancer risks also increases in BRCA1/2 carriers
78
BRCA1-related hereditary breast/ovarian cancer is what kind of inherited disease?
Autosomal dominant inheritance with high penetrance
AD inheritance =
50% chance of inheritance
Lifetime risk of cancer increased by 30-70%
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Hereditary cancers can show..
Reduced penetrance
just because the cancer skipped a generation, the mutation can still be passed on.
Penetrance = 5/6 = 83%
Cancer mutations can also vary in their expressivity. This means e.g. age of onset and type of cancer may vary from person to person even within same family
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Non-neoplastic alterations in cell growth
Hyperplasia / Hypoplasia (+ aplasia)
Hypertrophy / Atrophy
Metaplasia
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Permanent cells
Incapable of reproduction as adults
undergo:
Hypertrophy
Atrophy
82
Labile cells
Multiply constantly throughout life so can increase in number in response to stress
undergo:
Hyperplasia
Hypoplasia
83
Hyperplasia
Increase in tissue or organ size due to increase in cell number
Typically affects glandular tissue
• Can be normal physiological event, eg breast hyperplasia at puberty or pregnancy
• Pathological hyperplasia e.g. benign prostatic hyperplasia (BPH)
84
Physiological hypoplasia example
endometrial hypoplasia after the menopause
| accompanied by atrophy of endometrium and myometrium
85
Pathological hypoplasia example
– loss of stimulation, eg panhypopituitarism after pituitary infarct at parturition leads to atrophy of target organs
– pressure on organ from adjacent structures
– insufficient blood supply
– destruction of cells, eg autoimmune gastritis or thyroiditis
86
Hypoplasia
Decrease in organ or tissue size due to loss of cells
87
Hypertrophy
Enlargement because of increase in cell size
Generally affects muscle
• Can be physiological, as in skeletal muscle hypertrophy with exercise, or myometrial hypertrophy in pregnancy
• Pathological hypertrophy may occur when an increased load is placed on an organ or tissue, eg left ventricular hypertrophy in hypertension
• In pathological states there may be a combination of hypertrophy and hyperplasia
88
Atrophy
Shrinkage of tissue or organ due to loss of cells and a decrease in size
Physiological
– eg thymic atrophy at puberty
Pathological
– disuse, eg muscle wasting in an immobilized
fracture or following nerve severance
– response to pressure, eg renal atrophy in
ureteric obstruction
89
Metaplasia
Reversible replacement of one mature tissue type by another
• Squamous metaplasia at cervical
transformation zone
• Intestinal metaplasia at the gastrooesophageal junction
• Squamous metaplasia in the bronchus
as a consequence of smoking
90
Dysplasia
A premalignant state characterised by disordered maturation of cells within a tissue.
* Dysplasia can occurs in a background of metaplasia.
* Dysplastic cells show cytological features of malignancy but cannot metastasise (they have not broken through the basement membrane)
91
Roman signs of inflammation
Calor - heat
Dolar - pain
Tubor - redness
Tumor - swelling
92
Benign vs malignant
benign is not capable of metastases but malignant is
93
How do tumours develop?
Accumulation of mutations which over-ride the normal mechanisms which control cell proliferation.
• A number of forces can cause gene mutation, such as smoking, radiation, viruses, cancer-causing chemicals (carcinogens), obesity, hormones, chronic inflammation and lack of exercise
94
Features of benign tumours
Expansile growth
Bland cut surface
May be encapsulated
No lymph node or vascular invasion
95
Features of malignant tumours
Irregular infiltrating edge
Foci of necrosis and haemorrhage
Satellite nodules
Spread to adjacent organs, lymph nodes and distant sites via blood
96
Benign vs malignant microscopic features
97
Epithelial tumours
Epithelium:
– Covers surface of the body
– Lines all hollow organs
– Squamous, cuboidal and columnar, transitional
Benign and malignant tumours may arise
as a result of viral infection (eg HPV)
• Squamous cell carcinoma may arise at an
‘inappropriate’ site following squamous
metaplasia, eg bronchus of smokers
98
Glandular epithelium
• Covers entire GI tract from stomach to
rectum
• Lines ducts and acini of glands
• Forms tubular structures, such as renal
tubules
• Glandular tumours may arise at
‘inappropriate’ sites following metaplasia,
eg Barrett’s metaplasia in gastrooesophageal reflux disease
99
100
Colour appearance of tumour cells
Renal cell adenocarcinoma (clear cell carcinoma) : tumour cells
appear clear due to their high glycogen content
101
Urothelium (previously termed transitional epithelium)
Covers urothelial tract, ie renal pelvis,
| ureter, bladder and urethra
102
Classification of non-epithelial tumours
* connective tissue tumours
* embryonal tumours
* germ cell tumours
* lymphohaemopoeitic
* glial and neuronal tumours
103
Connective tissue types
104
Mature vs immature teratoma
105
Tamoxifen action
Tamoxifen blocks oestrogen
| receptor in ER+ tumours of breast
106
Herceptin action
Herceptin targets EGF-R in
| Her2Neu + tumours of breast
107
Imatinib action
```
Imatinib (Glivec) blocks tyrosine
kinase receptor in CD117+
tumours (chronic myeloid
leukaemia, gastrointestinal stromal
tumours)
```
108
Grade vs stage in tumour classification
* Grade = degree of differentiation
| * Stage = extent of tumour spread
109
Grade of a tumour
Degree of differentiation, ie similarity to tissue of origin, can only be assessed histologically
– well differentiated tumours (grade 1) resemble the tissue of origin and tend to behave less
aggressively than poorly differentiated tumours (grade 3)
– some tumours have specific grading systems ascribed to them, eg Ca breast (Bloom & Richardson)
110
Routes of spread for tumours
– directly into adjacent tissues (eg basal cell Ca of skin)
– via lymphatics (eg Ca breast, colon)
– blood vessels (eg renal cell Ca, small cell Ca lung, prostatic Ca, all sarcomas)
– along nerves (eg Ca pancreas, prostate)
– across coelomic cavities (eg Ca stomach, ovary)
111
Stage of a tumour
Extent of a tumour spread assessed by tissue biopsy/imaging
112
TNM
T= tumour, generally tumour size, eg Ca breast, T1 <2cm, T4 >5cm or tethered to skin
N= nodes. Regional lymph node involvement is N1, distant nodes N2
M=metastases: M0 none, M1 present, MX not known
113
When is TNM not applicable?
If primary tumour originates in a lymph node
then use another system eg ANN ARBOR STAGING FOR HODGKINS
114
Local effects of malignancy
effects of mass, eg ulceration of breast skin,
obstruction of lymphatics (peau d’orange);
recurrent laryngeal nerve infiltration by Ca
bronchus
115
Distant effects of malignancy
effects of metastases: eg lymph node
spread/lymphoedema; bone mets with
pain/fractures; liver failure due to massive
infiltration.
116
Systemic effects of malignancy
– Aberrant hormone secretion, eg Cushingoid
effects of small cell carcinoma
– Spontaneous thrombosis, eg Ca pancreas or lung
– Cachexia (cytokines, eg TNF)
