EMS Flashcards
1
Q
TSG in retinoblastoma
A
RB1 - retinoblastoma
2
Q
TSG in Li Fraumeni
A
TP53- sarcomas, breast tumour
3
Q
TSG in familial adenomatous polyposis
A
APC- colorectal tumours
4
Q
Caretaker gene mutation in familial breast cancer
A
BRCA1 BRCA 2- breast and ovarian tumours
5
Q
Caretaker gene mutation in HNPCC
A
hMLH1, hMSH2 (mismatch repair genes) - colon, endometrial cancer
6
Q
What are proto-oncogenes
A
Promote cell proliferation, survival, angiogenesis and negative regulation of apoptosis
7
Q
What is an oncogene
A
Activated mutated versions/increased expression of proto-oncogenes (caused by carcinogens), which causes their products to have increased/uncontrolled activity
8
Q
How many mutational hits does an oncogene need to be activated
A
Only 1 copy of the gene needs to be activated to induce a gain of function. This mutated gene is therefore said to be dominant to the remaining normal parental gene
9
Q
Mechanisms of oncogene activation
A
- Translocation of an oncogene from a low transcriptionally active site to an active site
- Point mutation - alters the amino acid sequence and production of an oncoprotein causing it to be hyperactive
- Amplification by insertion of multiple copies of an oncogene
- Insertion of a promoter or enhancing gene (by retroviruses) near an oncogene
10
Q
What is RAS oncogene
A
Cytoplasmic messenger. Activated by point mutation making it permanently active, allowing cell proliferation independent of GF
11
Q
What is HER2 oncogene
A
Growth factor receptor. Activated by gene amplification allowing cell proliferation independent of GF
12
Q
What is PI3K oncogene
A
Bladder cancer. cytoplasmic messenger. Activated by a point mutation making it permanently activated, allowing cell proliferation independent of GF
13
Q
Tumour Suppressor Genes
A
negative regulators of cell growth/survival, positive regulator of apoptosis.
- Caretakers- maintain genetic stability
- Gatekeepers- antioncogenes
14
Q
Inactivating TSGs
A
Both copies (2 hit) of a TSG have to be mutational or epigenetically inactivated for complete loss of function as the normal version is capable of doing the job of two genes
15
Q
Inherited TSG mutations in familial cancer
A
If inherited TSG with mutated/absent allele then only need 1 hit/loss of gene in any cell to induce tumour e.g. bilateral retinoblastoma
16
Q
How many genetic alterations needed to transform a normal cell into a neoplastic cell
A
Minimum of 3 genetic alterations :
- Telomerase expression- cell immortality
- Inactivation of TSG- removal of growth inhibition
- Activation of oncogene- autocrine growth stimulation
17
Q
Inactivating Rb growth factor
A
A key regulator of cell cycle by preventing progression from G1 to S phase (activated by negative GFs)
Inactivation of Rb gene is common event in tumours and results in resistance to -ve growth regulation
18
Q
What is TP53
A
TP53 induces cell cycle arrest to allow repair of DNA damage by caretaker genes, But also induces apoptosis if too much damage
TP53 inactivation leading to loss of apoptotic response is the most common genetic abnormality in human tumours (> 50% of tumours)
19
Q
How do tumours invade the basement membrane
A
Epithelial cells are held tightly together by adhesion molecule E-cadherin
Many tumours show loss of E-cadherin through mutation/hypermethylation of the gene
Results in epithelial-mesenchymal transition (EMT) – these mesenchymal cells are motile, secrete proteases, which allows them to break through basement membrane
20
Q
5 Features of poor differentiation
A
- Pleomorphism- variability in shape/size
- Tumour giant cells
- Abnormal nuclear features- high nucleus:cytoplasm ratio,, clumped chromatin, prominent nucleoli
- Increased mitotic activity
- Loss of cell polarity/order
21
Q
What are the 3 main types of carcinogens
A
- Genotoxic/Initiators- can chemically modify or damage DNA
- Non-genotoxic/Promoters- induce proliferation and DNA replication
- Complete- carcinogens can initiate and promote e.g. UV light
22
Q
2 methods of metabolically activating carcinogens
A
- Direct acting: interact directly with DNA, e.g. oxygen radicals, nitrosomines, UV light
- Procarcinogens: require enzymatic (metabolic) activation before they react with DNA, e.g. aromatic amines, PAHs (benzopyrene -> BPDE ultimate carcinogen)
23
Q
Repair process affected in inherited Xeroderma Pigmentosa
A
NER (nucleotide excision repair) - leading to skin cancer
24
Q
Repair process affected in inherited Ataxia Telangiectasia
A
ATM gene defect affecting Recombinational repair (HR, EJ) - leading to acute lymphocytic leukaemia or lymphoma in children and solid tumours in adults.
25
Repair process affected in inherited HNPCC
Mismatch repair (MLH, MSH) - leading to colorectal, ovarian, endometrial cancers
26
Main carcinogens in tobacco smoke (approx 19)
1. PAHs e.g. benzopyrene which is converted in vitro to BPDE
2. Acrolein- potent direct-acting mutagen
3. Nitrosamines- alkylating agents of bases of DNA changing coding properties
4. Radioactive lead and polonium
5. Heavy metals - cadmium, chromium, nickel
27
Carcinogenic effects of alcohol
1. converted into acetaldehyde (mutagen not that potent)- can cause DNA damage
2. Increases levels of oestrogen and testosterone
3. increases uptake of carcinogenic chemicals into cells within the upper GI e.g. benzopyrene
4. reduces levels of folate, needed for accurate DNA replication
5. can kill surface epithelium leading to unscheduled proliferation
28
Dietary genotoxins (mainly linked to GI cancers)
1. Nitrosamines- Reaction of nitrites with amino acids
2. Polycyclic aromatic hydrocarbons (PAH)- Combustion of organic material e.g. burnt toast, BBQ meat
3. Heterocyclic amines- Proteins heated to high temperatures
29
Viral carcinogens
1. HPV (cervix) - inhibits the activity of proteins encoded by tumour suppressor genes
2. HBV/HCV (liver)
3. Epstein-Barr virus (Burkitt’s lymphoma, nasopharyngeal)
30
Cancer caused by Helicobacter Pylori
Gastric cancer- H Pylori inhibits the activity of proteins encoded by tumour suppressor genes
31
Cancer caused by Schistosoma haematobium (parasite)
Bladder Cancer
32
How does HPV cause cervical cancer (HPV16, HPV18)
HPV expresses two oncoproteins, E6 & E7, that suppress two cellular TSGs, p53 (initiates apoptosis) & rb (halts cell cycle before s phase)
Results in abnormal proliferation and inhibition of apoptosis in affected stem cell
33
How is obesity linked to cancer
1. fat tissues in overweight people produce oestrogen and insulin
2. protective factors may be missing from unhealthy diets
3. Eating more meat etc
34
How does chronic inflammation cause cancer
Inflammatory response is a “complete” carcinogen i.e results in double whammy:
DNA damage from release of free radicals by immune cells - initiation
Growth factor induced cell division to repair tissue damage - promotion
e.g. Gallbladder carcinoma associated with gallstones
35
What are Tumour Associated Macrophages (TAMs)
The link between inflammation and cancer.
These cells are recruited by cytokines released by tumour cells and produce tumour necrosis factor- alpha (TNF-α), a cytokine that induces and maintains the inflammatory response
TAMs also release reactive oxygen and nitrogen species (ROS and RNS) that can be genotoxic, resulting in mutation directly or indirectly through stimulating proliferative regeneration
ROS secreted by TAMs and tumour cells can also induce fibroblasts to undergo autophagy, which releases important nutrients that tumour cells can “feed” on
36
What is a papilloma
Benign tumour of Surface (non-glandular / non-secretory) epithelium
37
The 2 classes of benign epithelial tumours
1. Papilloma (non-glandular)
| 2. Adenoma (glandular)
38
What is a carcinoma
A malignant epithelial tumour
39
What suffix do all benign mesenchymal tumours have
"oma" e.g. leiomyoma (smooth muscle)
40
What is a sarcoma
A malignant mesenchymal tumour e.g. rhabdomyosarcoma (skeletal muscle tumour)
41
2 classes of germ cell tumours (arise in gonads)
Seminomatous e.g. seminoma
| Non-seminomatous e.g. teratoma
42
What is a blastoma (
Embryonal tumour e.g. nephroblastoma/Wilm's tumour
| Histological resemblance to embryonic cells of that organ
43
Malignant tumours with benign names
Melanoma
Mesothelioma
Myeloma
Lymphoma
44
What is carcinosarcoma
Malignant tumour of the ovaries
45
What is a hamartoma
Non-neoplastic overgrowth of normal tissue (tumour like lesion)
Indigenous to the site of occurrence
eg. Lung hamartoma contains cartilage and bronchial epithelium.
46
What is a choristoma AKA Heterotropic rests
Nodules of organ parenchyma in another organ
| E.g. normal (non-neoplastic) pancreas nodule in stomach
47
Routes of metastasis
1. Blood e.g. sarcomas
2. Lymphatics e.g. carcinomas
3. Transcoelomic- Across peritoneal, pleural, pericardial cavities or in CSF e.g. ovarian
4. Implantation- Spillage of tumour during biopsy/surgery
48
What is a hydatidiform mole
Androgenetic
Mostly homozygous 46,XX
Proliferation of abnormal trophoblast tissue
Can develop into malignant trophoblastic tumour
No (remaining) embryo
49
What are benign ovarian teratomas
```
Derived from oocytes which have completed first or both meiotic divisions
Diploid
Wide spectrum of tissues
Predominantly epithelial
No skeletal muscle
No membranes/placenta
(parthogenesis)
```
50
Difference between parthenogenetic embryos and androgenetic embryos
Parthenogenetic embryos die due to failure of development of extra embryonic structures e.g. Trophoblast, Yolk sac
Androgenetic embryos die at 6 somite stage
Well developed extra-embryonic membranes
Poor embryo development
51
What is genomic imprinting
A mechanism that ensures the functional non-equivalence of the maternal and paternal genomes
Not encoded in the DNA nucleotide sequence i.e. epigenetic e.g. methylation
Depends on modifications to the genome laid down during gametogenesis
Spermatogenesis vs. oogenesis
Affects the expression of a small subset of 100-200 genes
Evolutionarily conserved
52
Cytogenetic abnormalities in Angelman Syndrom and Praderman Willi Syndrome
Deletion of chromosome 15
Always de novo- Recurrence risks very low
PWS- Lack of a paternal 15q11-13 contribution
AS- lack of maternal contribution
53
What is the function of DNA methylation
```
Post-synthetic DNA modification- Epigenetic
Does not normally alter DNA sequence
DNA methyltransferases
Reversible
Has to be “maintained” after replication
Occurs at CG dinucleotides
Many promoter regions spared
CG “islands”
Gene regulation
```
54
What is Beckwith-Wiedemann syndrome
```
Fetal overgrowth
High birthweight (>5 kg)
+/- normal adult size
Organomegaly
Exomphalos
Hypoglycaemia
Asymmetry
Tumour risk
Sporadic occurrence
(Epi)genetic abnormalities 11p15 hypermethylation
~1 in 10,000
Large tongue
Ear pits/ creases
Exomphalos
Hemihypertrophy
Neonatal hypoglycaemia
Increased risk of Wilms tumour (nephroblastoma)
```
55
What is russell-silver syndrome
```
Growth retardation
Fetal (IUGR)
Persistent postnatal growth failure
Triangular face
Brain size more preserved
Asymmetry
Sporadic occurrence
It involves hypomethylation of H19 and IGF2. In 10% of the cases the syndrome is associated with maternal uniparental disomy (UPD) on chromosome 7. This is an imprinting error where the person receives two copies of chromosome 7 from the mother (maternally inherited) rather than one from each parent.
```
56
What is di george syndrome
```
22q11.2 deletion
Very variable
~1 in 5,000
Congenital heart defect 75%
Hypocalcaemia
Seizures
Imvariable
~1 in 5,000
Learning difficulties ~70%
Cleft palate ~15%
Velopharyngeal insufficiency 32%
```
57
What is achondroplasia
```
form of dwarfism
~1 in 20,000
Autosomal dominant- often new mutation
Risk increases with paternal age
Rhizomelic limb shortening
Short stature
Foramen magnum compression/ hydrocephalus
Prone to spine disclocation
```
58
What is kabuki syndrome
```
~1 in 30,000
Learning difficulties
Congenital heart disease (50%)
Poor growth
Hearing impairment + sticky out ears
Cleft palate
Premature breast development
Persistent fetal finger pads (96%)
```
59
What is Peutz-jeghers syndrome/ hereditary intestinal polyposis syndrome
60
What is treacher-collins syndrome
```
~1 in 50,000
Autosomal dominant
Very variable
Cleft palate
Hearing impairment
characterized by craniofacial deformities, such as absent cheekbones
```
61
What is waardenburg syndrome
```
~1 in 250,000
Sensorineural hearing impairment
Iris heterochromia
Premature greying
White forelock
Areas of skin hypopigmentation
Congenital malformations (Hirschprungs/ VSD)
```
62
What is williams (beuren) syndrome
```
7q11 deletion
~1 in 20,000
Learning difficulties
‘Cocktail party’ speech
Congenital heart disease
Supravalvular aortic stenosis
Peripheral pulmonary artery stenosis
Hypercalcaemia
characterized by: a distinctive, "elfin" facial appearance, along with a low nasal bridge; an unusually cheerful demeanor and ease with stranger
```
63
What is pallister-killian syndrome
Mosaic tetrasomy for 12p
Developmental delay
Various congenital malformations
5.1 per 1,000,000 live births
64
What is cardio-facial-cutaneous / CFC syndrome
Developmental delay
Poor feeding/ failure to thrive
Relative macrocephaly
mutations in proteins that function in the MAP kinase pathway.
Mutations that cause CFC are found in the KRAS, BRAF, MEK1 and MEK2 genes.
65
What is smith-lemli-opitz syndrome
Sterol pathway enzyme isnt working so cant make 7-dehydrocholestrol and low levels of 8-dehydrocholesterol
7-dehydrocholesterol reductase deficiency
66
What is huntingtons disease
Progressive neurodegenerative disorder with motor, cognitive, and psychiatric disturbances - movements – memory – mood
Movement disorder – chorea, dystonia, bradykinesia, swallowing/ choking, dysarthria
Mood – depression, euphoria, apathy, anxiety, aggression, psychotic symptoms
Cognition – loss of executive functioning, rigidity of thought, memory loss, dementia
Mean age of onset is 35 to 44 years (range 2 - 80 years)
Median survival time is 15 to 18 years after onset
67
What is the genetic mutation responsible for hunting tons
Autosomal dominant disorder
Complete penetrance
HTT gene at 4q16.3
Normal HTT gene contains, within exon 1, a run of CAG trinucleotide repeats
The HD mutation = an expansion of CAG repeats ≥ 40 repeats
(a few people develop HD with CAG rpt of 36-39)
increased number of glutamine amino acids = polyglutamine (polyQ) expansion which alters protein structure and biochemical properties.
PolyQ cellular protein aggregates form – unknown if they cause disease
Basal ganglia especially caudate nucleus primarily affected
68
What is anticipation
Anticipation = the onset of a disorder occurs at an earlier age as it is passed from one generation to the next. Often this is associated with an increase in severity of symptoms
A phenomenon associated with triplet repeat disorders
Triplet repeat expansions are unstable and may increase (occasionally contract) when passed to the next generation
The phenomenon of anticipation is often linked to the gender of the parent:
e.g. more likely in paternal inheritance in hunting tons
69
Examples of Xlinked dominant genetic conditions
```
Rett syndrome (lethal in males, phenotype only in females)
Fragile X syndrome – females:- asymptomatic to fully symptomatic ( due to X-inactivation pattern)
```
70
What is satellite DNA
```
Large blocks at centromeres and heterochromatic chromosomal regions
Simple tandemly repeated sequences
Many types e.g. alphoid DNA
Centromere repeat
Chromosome-specific
Size of blocks may be polymorphic
```
71
What chromosomes are translocated into the philadelphica chromosomes and what conditions is this indicative of
9 and 22
creates BCR-ABL fusion gene
found in CML, ALL and sometimes AML
72
What is alphoid dna
A type of satellite DNA found at centromeres
171-bp repeat unit
Repeat unit sequence shows chromosome-specific sequence variation
Probes for individual chromosome identification
Alphoid DNA is required for assembly of the centromere
73
The genetics of alzheimers
tangles of b-amyloid protein in nerve fibres of hippocampus
familial clustering
early onset form is now known to be genetically heterogeneous:
different genes may be involved in different families, but give similar end-stage symptoms
presenilin 1 (PSEN1) and presenilin 2 (PSEN2) both encode novel transmembrane aspartyl-proteases with g-secretase activity responsible for proteolytic cleavage of amyloid beta A4 precursor protein (APP) and NOTCH receptor proteins
missense mutations in APP
74
The link between ApoE haplotypes and alzheimers
E4 haplotype confers increase in susceptibility
*E2 haplotype confers a protective effect
E4/E4 homozygotes are affected much earlier than heterozygotes
75
Leading cause of irreversible central visual dysfunction
Age related macular degeneration
Characterized by the early deposition of drusen, a hallmark risk factor for AMD
Major risk; smoking
Intermediate risk; light exposure.
76
Most familial cancer syndromes show what type of inheritance
Autosomal dominant
77
Which familial cancer syndromes show autosomal recessive inheritance
MYH associated polyposis, Fanconi anaemia, Ataxia telangiectasia
78
What is the Amsterdam criteria used for
HNPCC Classification:
One member diagnosed with colorectal cancer before age 50 years
Two affected generations
Three affected relatives, one of them a first-degree relative of the other two
FAP should be excluded
Tumours should be verified by pathologic examination
79
What is non-disjunction and when is it most likely to occur
Failure of chromosome or chromatid separation
80-90% happen at meiosis 1 (chromosomes) = worse outcome
10% happen at meiosis 2 (chromatids)
80
consequences of parental origin of triploidy
Double paternal = large placenta
= some growth delay
Double maternal = tiny placenta
= significant growth delay
= head-saving macrocephaly
Conclusions: Maternal genome for foetus
Paternal genome for placenta
81
What is a molar pregnancy
Double paternal genome
“Conceptus without an embryo”
Massive cystic placenta
82
Examples of balanced chromosomal rearrangements
Translocation:
Reciprocal
Robertsonian
Inversion:
Pericentric
Paracentric
Insertion
83
What is a robertsonian translocations
```
whole arm fusion
acrocentric chromosomes (13, 14, 15, 21, 22)
1/1000
no phenotype risk
but there is a reproductive risk
```
84
What are chromosome inversions
2 breaks, rotation, then rejoining
1/1000
5-10% phenotype risk
reproductive risk
Pericentric= breaks on both sides of the centromere
paracentric= breaks only on one side of the centromere
85
What drugs does Thiopurine methyltransferase inactivate and what can be the consequences of a TPMT mutation
Azathioprine (immunosuppressant used in organ transplantation and autoimmune disease)
6-mercaptopurine & 6-thioguanine (chemotherapies)
TPMT gene polymorphisms reduce TPMT protein activity
Severe toxicity if both copies of the gene have the variant
86
What does N-Acetyltransferase do and the consequences of a mutation in its gene
Group of liver enzymes inactivating drugs by acetylation
“Fast” and “slow” acetylators – due to SNP variations in genes e.g. NAT2
Different distributions in different ethnic populations
e.g. isoniazid used for TB – Slow acetylators at increased risk of side effects including neuritis and liver toxicity
Other drugs – sulfasalazine (Crohn's dis), hydralazine (hypertension)
87
Rare BCHE gene variant homozygotes have reduced butyrylcholinesterase activity- what are the consequences
Succinycholine- Related to the poison curare
Muscle relaxant used in anaesthesia (to stop breathing) BCHE gene variant homozygotes have reduced butyrylcholinesterase activity
Effects may last for an hour or more and risk of death if artificial ventilation is not continued
88
Which genes explain ~50% of genetic variability of warfarin activity
CYP2C9 (one of the cytochrome p450 family) and vitamin K oxidoreductase complex-1 (VKORC1)
