week 9 Flashcards
what is mutation of BRCA1 indcator of?
breast cancer
what is the normal function of BRCA1 and BRCA2?
are DNA repair proteins
what chromosome is BRCA1 found on?
chromosome 2
the BRCA1 and 2 mutations are only responsible for what percentage of familial cancers?
responsible for 16% of familial cancers
the mutation in BRCA1/2 account for what percentage of breast cancer? Is it different for people under the age of 35?
Account for 5-10% of all breast cancers
Responsible for 16% of breast cancer for females under the age of 35yrs
what is the average risk of a women getting breast cancer?
12% risk of developing breast cancer
what is the risk of a women getting breast cancer if they have the BRCA1/2 mutation?
BRCA1 or BRCA2 increases risk of breast cancer to 85%
what ther type of cancer has a increase in risk if there is mutation is BRCA1/2? By how much?
Increases risk of developing ovarian cancer from
what are the advantages to testing for BRCA mutations?
Women may feel relieved knowing for certain whether or not they are at a higher risk for breast cancer.
Women with breast cancer may have better responses to certain treatments that are specifically designed for BRCA positive patients (eg. cisplatin and PARP inhibitors).
Women may take preventive measures to help reduce their risk of breast cancer if they test positive for BRCA mutations (diet, exercising, tamoxifen).
Other family members may decide if they wish to be tested for BRCA mutations based on the results of a woman’s test.
what is the disadvantage of testing for the BRCA mutations?
Women may become worried, panicked, or stressed if they discover they have a higher than average risk for breast cancer.
Women who test positive for BRCA mutations are faced with the difficulty of telling family members (some of whom may also have the mutation).
Women who test negative for BRCA mutations may falsely believe they will never get breast cancer.
Women who test positive for BRCA mutations may have to deal with complications with health or life insurance
what is the reduction of risk of ovarian cancer if you reduce your ovaries after having a family?
reduces the risk by 85%
how effective is a Preventative mastectomy from developing breast cancer?
reduces the risk by 90%
what is Retinitis pigmentosa ?
a chronic hereditary eye disease characterized by black pigmentation and gradual degeneration of the retina.
what is Treacher Collins Syndrome?
Affects migration of neural crest cells –> in this syndrome the neural crest cell don’t fully make it
Narrowed chin and compressed airway –> need tracheotomy –>need to breathe through a tube
why is it important to get prenatal screaning for Treacher Collins Syndrome?
So pediatric surgeons know and can act straight away after the birth of the baby
what are the different prenatal diagnosis and when are they done?
Amniocentesis (~17 weeks)
Chorionic villus sampling (~11 weeks)
what is preimplantation diagnosis?
If you know the mother has the condition and the mother does not want to carry on the condition
Take the egg –> implant with sperm –> grow embryos
Take a cell from the embryo - see if the cells contains that condition if it does throw it away - if does not contain it then you implant that embryo
what monogenic disorders are preimplantation diagnosis used for?
CF Beta thalassemia Sickle cell disae Fragil X Spinal muscular atrophy
what is Non-disclosure testing?
It is a test for HD
Without knowledge of disease status of the parent
To make sure the embryo does not have HD
what type of twins show there is some inheritance of obesity?
Dizygotic Twins
what is the inherited deficiency that causes obseity?
Leptin deficiency
How does leptin deficiency cause obesity?
Decrease food intake
Increase thermogenesis
Increase physical activity
how does leptin in a normal body work?
Mutation that codes for leptin
leptin produced by fat cells to targets the brain
tells it to reduce food intake
increase metabolism and increase exercise
this reduce fat intake and then this reduces the leptin increase and so regulation occurs
what is the treatment for leptin deficiency?
leptin replacemennt therapy
what is gene therapy?
Gene therapy is the use of genetic material- DNA or RNA- as a medicine.
what is classic gene therapy and what is the aim?
introduction of functional genes, in the form of DNA, to replace mutated genes.
Aim is to to repair mutated genes, silence overactive genes and to also provide our immune cells with the tools they need to recognise and kill cancer cells and infections
what is Leber’s congenital amaurosis (LCA?
Rare inherited eye disorder
Blindness at birth or in infancy
Accounts for 10-18% of congenital blindness
18 genes implicated
Recessive inheritance pattern
why is it effective to do gene therapy on eye?
Eye is immune privileged –> less likely for the immune body to attack
Eye is accessible for subretinal injection
what gene was identified to be a cause of LCA?
RPE65 mutations
how can you undo the RPE65 mutation?
Sub-retinal injection between RPE and photoreceptors with adeno-associated virus containing human RPE65 and human RPE65 promotor
what are the Important considerations to take before doing a Sub-retinal injection for treatment of RPE65?
Retina must be structurally normal
Single gene with loss of function
Missense mutations only (in case of immune response)
Amblyopia may inhibit results so best to inject children
what is amblyopia?
lazy eye
what are Cytochrome P450 oxidases
Multigene family of enzymes found predominantly in the liver
what do Cytochrome P450 oxidases do?
Responsible for the metabolic elimination of most drugs currently used
Also important for converting pro-drugs to their active forms (eg codeine
what is the relation between Tamoxifen and CYP2D6 ?
rate limiting step converting tamoxifen to its active metabolite endoxifen
Poor metabolizers due to CYP2D6 polymorphisms are associated with worse survival less effective
what is Tamoxifen ?
a synthetic drug used to treat breast cancer and infertility in women. It acts as an oestrogen antagonist
what occurs in Parthenogenesis?
fertilization without any input from sperm as the second cell body does not leave the egg
what occurs in Androgenesis?
oocyte is empty and then fertilized by one or two sperms
what is hydatidiform moles?
Androgenetic
Mostly homozygous 46,XX
Proliferation of abnormal trophoblast tissue
Can develop into malignant trophoblastic tumour
No (remaining) embryo
what is produced in Parthenogenesis?
Benign ovarian teratomas
Derived from oocytes which have completed first or both meiotic divisions
Diploid
Wide spectrum of tissues
what type of tissues are present in parthenogenesis?
Predominantly epithelial –> hair, teeth, neurons
No skeletal muscle
No membranes/placenta
why does Parthenogenetic embryos die?
due to failure of development of extraembryonic structures –> Trophoblast + Yolk sac
why do androgenetic embryos die?
Well developed extra-embryonic membranes
Poor embryo development
What is Genomic imprinting?
Certain gene is expressed in a parent-of-origin-specific manner.
what are the symptoms of Angelman syndrome?
Facial dysmorphism:
Prognathism, wide mouth, drooling
Smiling/laughing appearance
Mental handicap:
Microcephaly
Absent speech
Seizure disorder
Ataxic, jerky movements
what are the symptoms of Prader-Willi syndrome?
Infantile hypotonia
Feeding problems
Gross motor delay
Mental handicap
Male hypogenitalism/cryptorchidism
Small hands and feet
Hyperphagia
Obesity
Stereotypic behaviour
what is cryptorchidism?
absence of one or both testes from the scrotum
what is Hypogenitialism?
Partial or complete failure of maturation of the genitalia
what are the causes of Angelman and Prader-Willi syndromes?
Deletion of chromosome 15
Always de novo
Recurrence risks very low
if both ngelman and Prader-Willi syndromes have deletion of chromosome 15 what is the difference?
Angelman –> mums chromosome has the deletion
PWS fathers chromosome has the deletion
what are the Molecular mechanisms in Prader-Willi syndrome?
Lack of a paternal 15q11-13 contribution
Can be either due to the inheritance of the farther chromosome with the deletion –> 70%
or it can be due to both mothers chromsomes being inherited –> 25%
what occurs in DNA methylation?
Post-synthetic DNA modification
Epigenetic
Does not normally alter DNA sequenc
DNA methyltransferases
Reversible
Has to be “maintained” after replication
Occurs at CG dinucleotides
Many promoter regions spared
CG “islands” –>Gene regulation
What are all the epigentic changes that can affect gene activity?
DNMT DNA methyltransferase
HMT histone methyltransferase
HDAC histone deacetylase
UBE ubiquitin protein ligase
PK protein kinases
what occurs in Beckwith-Wiedemann syndrome?
Fetal overgrowth
High birthweight (>5 kg) \+/- normal adult size
Organomegaly
Exomphalos
Hypoglycaemia
Asymmetry
Tumour risk
Sporadic occurrence
(Epi)genetic abnormalities
11p15
if there was only expression from paternal what would happen in development of baby?
for the mother –> High mortality
Poor long-term reproductive potential
For farther –> High fetal fitness, Evolutionary advantage for father
- if polygamous
If there was only expression from maternal what would happen in development of baby?
For mother –> Better maternal survival rate and reproductive fitness
For farther –> Increased fetal mortality - decreased paternal reproductive fitness
What occurs in Russell-Silver syndrome?
Growth retardation:
Fetal (IUGR)
Persistent postnatal growth failure
Triangular face
Brain size more preserved
Asymmetry
Sporadic occurrence
what is the importance of Insulin-like growth factor 2 in fetal development?
it is a major fetal growth promoter
what happens when IGF2 is surpressed? When does it happen?
Hypomethylation –> turned off in mother
Leads to Russell-Silver syndrome
what happens when IGF2 is overexpressed? When does it happen?
Hypermethylation –> happens in the father chromosome
Leads to Beckwith-Wiedemann syndrome
what is X inactivation?
is the inactivation of one of the X chromosomes
what is the affect of X inactivation between somatic and germ cells?
Somatic cells remember silenced status
Reversed in germ cells
what is the difference between X inactivation and gene imprinting?
Whole X chromosome is silenced –> entire chromosome that contains thousands of gens
Random choice of parental chromosome
Different in different cells
Somatic cell clones “remember”
Occurs early in embryogenesis
Blastocyst
who are affected by X linked mutations?
males are affected
but Females are carriers
What can be seen with a female carrying a X linked mutation?
Hypohidrotic ectodermal dysplasia
Starch/iodine test
Patches of skin with or without sweat glands
when does X inactivation occur?
occurs at a time when there are a small number of precursor cells
what is the consequence of X inactivation?
functional mosaicism –> Have chromsomes that are active and healthy while other chromsoomes have the mutation
Mixture of both cells
What factors affect altered outcome to treatment?
Changes in the protein in the human body
What factors cause changes in the protein in the human body?
Gene amplification Promoter polymorphisms Translocations Deletions, insertions Single Nucleotide Polymorphisms (SNPs
What happens in a Single nucleotide polymorphisms?
A common type of genetic variation
Changes at a single nucleotide –> base pair level
May change protein structure/activity e.g. missense changes –> cause kinks so therefore the drug could no longe be soluble
What Genetic variation are present that can effect the action of the drug?
Absorption
Activation
Altered target
Catabolism
Excretion –> To slow or to fast excretion of the drug and therefore have to adapt the dosage.
How can genetics help to ensure the correct drug and dose it given?
Identify genetic variations that lead to altered outcomes
Change dose of drug where appropriate
Use a different drug that works better and/or has reduced toxicity
Guide new targeted drug development
Stratified/personalised medicine
Reduce financial costs of inappropriate treatment
What is Azathioprine used for?
immunosuppressant used in organ transplantation and autoimmune disease.
Malignancy, crons disease, standard treatment for rheumatoid arthertiis
What are the by products of Azathioprine? What is the problem of these by products?
6-mercaptopurine & 6-thioguanine
They can cause damage to the DNA
What is the role of Thiopurine methyltransferase and what is the possible consequence if there is a polymorphism in Thiopurine methyltransferase?
TMPT inactive 6-mercaptopurine to 6-methyl MP and therefore prevents the drug from damaging the DNA.
If there is a polymorphism in TMPT it can cause reduce TPMT protein activity
When will severe toxicity be caued by polymorphism in Thiopurine methyltransferase?
Severe toxicity if both copies of the gene have the variant
What is Succinylcholine?
Related to the poison curare
Muscle relaxant used in anaesthesia (to stop breathing)
How long does Succinycholine last for?
It usually last for a few minutes
What mutation can cause danger in giving Succinylcholine?
Rare 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
What process accounts for 30% of aminoglycoside ototoxicity?
There is a mutation that changes mitochondrial 12s rRNA
to resemble E-coli 16S rRNA.
This has toxic effect on the hair of the inner ear.
If this protein persists then Aminoglycosides more likely to bind to patients rRNA → increased risk of hearing loss at younger age
Maternal inheritance
What is the use of Warfarin ?
Widely used oral anticoagulant to reduce embolism/thrombosis
What is the consequence if the dose of warfarine is to low or to high?
To low –> patient is sitll at risk
To high –> patient is at risk of Haemorrhage
What is the role of VKOR and how can this effect the dosage of warfarine?
VKOR is invovled in the metabolism of vitamiin K and is acted on by Warfarin.
Polymorphism of VKOR can reduce its activity which will cause a change in warfarin dosage
What two proteins are genotyped to see if the warfarin will be effective for the patient? Explain why
Genotyping of CYP2C9 and vitamin K oxidoreductase complex-1 .
These genes explain ~50% of genetic variability of warfarin activity
What are potential targets for cancer treatment?
Potential targets are genetic variations that cancer cells contain but are not present in germline DNA
What is the aim of the new cancer treatment?
Increase overall response rates & survival
Reduce treatment failure and toxicities
What is the drug Trastuzumab used for?
Used to treat breast cancer that have over expression HER2 (human epidermal growth factor receptor 2). Occur in 20% of cases
What is trastuzumab?
Monoclonal antibody to the HER2 receptor
What is the effect of chemotherpy on Melanoma?
It is notoriously resistant to chemotherapy treatment. Only 5% response rate to the treatment
What somatic mutation is seen in melanoma?
~50% of melanomas have a somatic mutation in the BRAF gene
Which is a change in valine to glutamate acid
V600E variant
What treatment is being used to treat melanoma that tackles the somatic mutation on the BRAF gene?
New targeted therapy Vemurafenib.
Only effective though if the mutation is present
What is the future for genetic testing and drugs?
Use of SNP chips and next generation sequencing which can potentially identify genetic variations for multiple genes/polymorphisms in an individual, or even the whole genome!
