EMS Flashcards
TSG in retinoblastoma
RB1 - retinoblastoma
TSG in Li Fraumeni
TP53- sarcomas, breast tumour
TSG in familial adenomatous polyposis
APC- colorectal tumours
Caretaker gene mutation in familial breast cancer
BRCA1 BRCA 2- breast and ovarian tumours
Caretaker gene mutation in HNPCC
hMLH1, hMSH2 (mismatch repair genes) - colon, endometrial cancer
What are proto-oncogenes
Promote cell proliferation, survival, angiogenesis and negative regulation of apoptosis
What is an oncogene
Activated mutated versions/increased expression of proto-oncogenes (caused by carcinogens), which causes their products to have increased/uncontrolled activity
How many mutational hits does an oncogene need to be activated
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
Mechanisms of oncogene activation
- 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
What is RAS oncogene
Cytoplasmic messenger. Activated by point mutation making it permanently active, allowing cell proliferation independent of GF
What is HER2 oncogene
Growth factor receptor. Activated by gene amplification allowing cell proliferation independent of GF
What is PI3K oncogene
Bladder cancer. cytoplasmic messenger. Activated by a point mutation making it permanently activated, allowing cell proliferation independent of GF
Tumour Suppressor Genes
negative regulators of cell growth/survival, positive regulator of apoptosis.
- Caretakers- maintain genetic stability
- Gatekeepers- antioncogenes
Inactivating TSGs
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
Inherited TSG mutations in familial cancer
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
How many genetic alterations needed to transform a normal cell into a neoplastic cell
Minimum of 3 genetic alterations :
- Telomerase expression- cell immortality
- Inactivation of TSG- removal of growth inhibition
- Activation of oncogene- autocrine growth stimulation
Inactivating Rb growth factor
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
What is TP53
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)
How do tumours invade the basement membrane
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
5 Features of poor differentiation
- 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
What are the 3 main types of carcinogens
- 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
2 methods of metabolically activating carcinogens
- 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)
Repair process affected in inherited Xeroderma Pigmentosa
NER (nucleotide excision repair) - leading to skin cancer
Repair process affected in inherited Ataxia Telangiectasia
ATM gene defect affecting Recombinational repair (HR, EJ) - leading to acute lymphocytic leukaemia or lymphoma in children and solid tumours in adults.
Repair process affected in inherited HNPCC
Mismatch repair (MLH, MSH) - leading to colorectal, ovarian, endometrial cancers
Main carcinogens in tobacco smoke (approx 19)
- PAHs e.g. benzopyrene which is converted in vitro to BPDE
- Acrolein- potent direct-acting mutagen
- Nitrosamines- alkylating agents of bases of DNA changing coding properties
- Radioactive lead and polonium
- Heavy metals - cadmium, chromium, nickel
Carcinogenic effects of alcohol
- converted into acetaldehyde (mutagen not that potent)- can cause DNA damage
- Increases levels of oestrogen and testosterone
- increases uptake of carcinogenic chemicals into cells within the upper GI e.g. benzopyrene
- reduces levels of folate, needed for accurate DNA replication
- can kill surface epithelium leading to unscheduled proliferation
Dietary genotoxins (mainly linked to GI cancers)
- Nitrosamines- Reaction of nitrites with amino acids
- Polycyclic aromatic hydrocarbons (PAH)- Combustion of organic material e.g. burnt toast, BBQ meat
- Heterocyclic amines- Proteins heated to high temperatures
Viral carcinogens
- HPV (cervix) - inhibits the activity of proteins encoded by tumour suppressor genes
- HBV/HCV (liver)
- Epstein-Barr virus (Burkitt’s lymphoma, nasopharyngeal)
Cancer caused by Helicobacter Pylori
Gastric cancer- H Pylori inhibits the activity of proteins encoded by tumour suppressor genes
Cancer caused by Schistosoma haematobium (parasite)
Bladder Cancer
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
How is obesity linked to cancer
- fat tissues in overweight people produce oestrogen and insulin
- protective factors may be missing from unhealthy diets
- Eating more meat etc
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
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
What is a papilloma
Benign tumour of Surface (non-glandular / non-secretory) epithelium
The 2 classes of benign epithelial tumours
- Papilloma (non-glandular)
2. Adenoma (glandular)
What is a carcinoma
A malignant epithelial tumour
What suffix do all benign mesenchymal tumours have
“oma” e.g. leiomyoma (smooth muscle)
What is a sarcoma
A malignant mesenchymal tumour e.g. rhabdomyosarcoma (skeletal muscle tumour)
2 classes of germ cell tumours (arise in gonads)
Seminomatous e.g. seminoma
Non-seminomatous e.g. teratoma
What is a blastoma (
Embryonal tumour e.g. nephroblastoma/Wilm’s tumour
Histological resemblance to embryonic cells of that organ
Malignant tumours with benign names
Melanoma
Mesothelioma
Myeloma
Lymphoma
What is carcinosarcoma
Malignant tumour of the ovaries
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.
What is a choristoma AKA Heterotropic rests
Nodules of organ parenchyma in another organ
E.g. normal (non-neoplastic) pancreas nodule in stomach
Routes of metastasis
- Blood e.g. sarcomas
- Lymphatics e.g. carcinomas
- Transcoelomic- Across peritoneal, pleural, pericardial cavities or in CSF e.g. ovarian
- Implantation- Spillage of tumour during biopsy/surgery
What is a hydatidiform mole
Androgenetic
Mostly homozygous 46,XX
Proliferation of abnormal trophoblast tissue
Can develop into malignant trophoblastic tumour
No (remaining) embryo
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)
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
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
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
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
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)
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.
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%
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
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%)
What is Peutz-jeghers syndrome/ hereditary intestinal polyposis syndrome
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
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)
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
What is pallister-killian syndrome
Mosaic tetrasomy for 12p
Developmental delay
Various congenital malformations
5.1 per 1,000,000 live births
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.
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
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
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
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
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)
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
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
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
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
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
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.
Most familial cancer syndromes show what type of inheritance
Autosomal dominant
Which familial cancer syndromes show autosomal recessive inheritance
MYH associated polyposis, Fanconi anaemia, Ataxia telangiectasia
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
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)
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
What is a molar pregnancy
Double paternal genome
“Conceptus without an embryo”
Massive cystic placenta
Examples of balanced chromosomal rearrangements
Translocation:
Reciprocal
Robertsonian
Inversion:
Pericentric
Paracentric
Insertion
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
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
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
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)
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
Which genes explain ~50% of genetic variability of warfarin activity
CYP2C9 (one of the cytochrome p450 family) and vitamin K oxidoreductase complex-1 (VKORC1)
