In which fields does genomics particularly want to be involved in?
Rare diseases
Cancer
What percentage of rare diseases are genetic?
80%
What is the difference between the use of lab based and point of care tests?
Less urgent cases like cancer diagnosis = lab based
Testing for warfarin sensitivity in a stroke patient = point of care testing
What is the 100 000 genome project?
Aims at genotyping 70 000 rare disease patients and their families
To look for genes associated with these patients
Potential benefits of 100 000 genome project
Improve current treatments
Discover new treatments
Diagnose future patients
Help understand the underlying mechanisms of disease
What are the ethical concerns of genomic sequencing?
Clone a person from DNA
Finding out about being adopted
What project is taking place in the North East Regional Genetics Unit?
100 genetic point mutation tests are being done looking at parts of the genome
How is looking at specific sequences better than the whole genomic sequence?
Looking at the whole genomic sequence is
- expensive
- not accessible to everyone
- complex to interpret
Why is X-linked genetic testing important?
A lot of diseases occur on the X chromosome
Conditions occuring on the X chromosome
Haemophilia
Duchenne Muscular Dystrophy
How are X linked conditions currently being diagnosed?
Single gene testing
What is warfarin?
Anticoagulant that thins the blood
Treatment for stroke
What is the characteristic of warfarin sensitive patients?
Patients that have low tolerance to the drug
This means they are less able to break down warfarin, and so the dose used must be lower than usual
Which patients are prescribed warfarin?
Heart valve disease
Irregular heart beat
History of heart attack/stroke
Prior blood clot in the deep veins of the arms and legs
Which genes are involved with warfarin sensitivity?
Polymorphisms of :
CYP2C9
VKORC1
What percentage of variation to warfarin metabolism do CYP2C9 and VKORC1 polymorphisms represent?
30%
How can polymorphisms in warfarin metabolism be detected?
Lab based test
Point of care test
Why is there a need for POCT in detecting warfarin sensitivity?
Highly urgent nature of patients who take warfarin
Example of a POCT used to test for warfarin sensitivity
QuantumDX
What is the turnaround time for QuantumDX?
20 minutes
What are other potential applications for POCT?
UTI
MRSA
Viral outbreaks
What does NIPT stand for?
Non invasive prenatal diagnostic testing
What is the aim of NIPT?
Detect fetal abnormalities through the detection of fetal DNA in the mother’s blood
Rationale behind NIPT
When foetal cells apoptose, the DNA is released into the mother’s bloodstream
A small vial of blood can be obtained for the mothers arm, and the DNA can be sequenced through next generation sequencing
How long are foetal DNA fragments?
150 bases long
What procedure does NIPT aim to replace?
Amniocentesis - very risky
Examples of conditions that can be tested for using NIPT
Trisomies
Sex aneuploidy
Rare/inherited alterations
What, regarding NIPT, must be ensured?
No ability to determine the phenotypic qualities of the embryo like eye colour and height
This brings out the possibility of designer babies
What has been a fear with the rise of more advanced embryonic genomic testing?
That termination rates would increase amongst parents
This has not been the case however
What other application can NIPT be used for?
Cancer
Since these cells also release fragments of their DNA into the circulation when they apoptose
What is the area where genomics has had the biggest benefits?
Cancer
Applications of genomics in cancer
Diagnosis - earlier gives better treatment outcomes
Stratification - cost reduced since less patients are on unnecessary treatments
Personalised therapy - tailoring therapy to individual patients
Examples of genomic technologies used in cancer
Mammaprint
ConfirmMDx
OncomineDx test
Describe how a mammaprint is carried out
Analyses the activity of certain genes in early-stage breast cancer and stratifies patients depending on their likelihood of recurrence 10 years after diagnosis
Group with increased risk of recurrence = more treatment
Group with decreased risk of recurrence = mastectomy and nothing more
Which cancer is ConfirmMDx used for?
Prostate cancer
Which patient cohort is ConfirmMDx targeted for?
False-negative and false-positive biopsies
Describe how a ConfirmMDx test is carried out
This is a epigenetic test which looks at the methylation status of genes known to be linked to cancer
What genes are looked at in ConfirmMDx?
GSTP1
APC
RASSF1
How are prostate cancer results confirmed currently?
Patients undergo a painful biopsy procedure to rule out risk
Involves sticking up to 96 needles into the prostate and extracting tissue to be biopsied
Why are false negative test results from biopsies so common?
The possibility of extracting tissue with cancer using a thin needle is relatively small
What is an OncomineDx test?
Personalised therapy genomic test involving stratisfying patients to therapy groups depending on their genomic changes
Why is it important to appropriately administer the correct medication to the correct patient group?
A lot of therapies are high risk and can do more harm than good
What was the first FDA-approved test used for stratifying patient groups to correct therapies?
OncomineDx test for non-small cell lung cancer
Selects which patients with lung cancer are eligible for treatment with specific FDA-approved drugs
What is the current method for monitoring a patients’ response to therapy?
CT scan
What are the disadvantages of using CT scans to monitor the patients’ response to a therapy ?
Small risk through increased X-ray exposure
Expensive
Takes time report
How can genomic technologies be used to replace CT scans in monitoring the response of a patient to a treatment?
Cell free DNA can be used to measure the size of the tumour
The bigger the tumour, the more likely it is to shed DNA into the vascular system
cfDNA sequencing can be used to look for tumour evolution, relapse and personalised treatment plans
How are cfDNA sequencing techniques better at looking at the progression of a tumour that single markers?
Not all cells may express the single marker, but the part of the cancer that secreted the specific gene might have been killed off, and the rest of the non-p53 secreting cancer may still be growing
Measuring only this marker therefore gives false results
What are the cells that originate from the original event called?
Clonal cells
What are the cells that originate from secondary events leading to intatumoural heterogeneity called?
Subclonal cells
What drives the heterogeneous response of a tumour to therapy?
Intratumour heterogeneity
Why is it important to understand the difference between clonal and subclonal mutations?
Because this determines the use of targeted therapies
Targeted therapies are less successful against subclonal mutations compared to clonal mutations
Examples of hormone receptors targeted for cancer therapy
BCR-ABL
EGFR
Oestrogen receptors
What drug targets the BCR-ABL muation?
Imatinib
Tyrosine kinase inhibitors
What drug targets the EGFR mutation?
Gefitinib
Tyrosine kinase inhibitors
What drug targets the oestrogen receptor?
Tamoxifen
What is the only way that targeted therapies can be effective?
If all the tumour cells express the mutation you are targeting
In which cancer is the BCR-ABL mutation found?
Chronic myeloid leukemia
What cancer is BRCA asscociated with?
Breast cancer
Where is BRCA normally expressed?
Breast and other tissue
What type of gene is BCRA?
Tumour suppressor gene
Involved in repairing damaged DNA
What is the inheritance of BRCA?
Inherited
What is the probability of developing breast cancer if you have abnormal BRCA genes?
80% risk by the age of 90
What is the probability of developing ovarian cancer if you have abnormal BRCA genes?
55%
Which company patented BRCA testing?
Myriad
In 1994
What has happened following Myriad’s patent on BRCA testing?
In 2013, the US supreme court ruled that a naturally occurring DNA segment is not able to be patented
What was the problem with Myriad’s patent on BRCA testing?
It was almost impossible to get a second opinion of the test result as no other lab could independently test for BRCA mutations
What act protects against insurance discrimination?
GINA
Genetic information nondiscrimination act
Describe the case of Pet Reilly
23andMe showed she had high risk of developing Alzheimers
So she changed her insurance policy and paid more to be guratanteed long term care
What is gene therapy?
The introduction of normal genes in place of missing or defective ones in order to correct the germline or genetic disorders
What is an adenovirus?
Inserts a new gene into a cell
If integrated, the new gene will make a functional protein to treat a disease
In which diseases is gene therapy particularly useful?
In single-gene diseases
When was the first time gene therapy provided first somatic treatment?
1993
Diseases cured through gene therapy
ADA-SCID
CLL
Retinal dystrophy
Melanoma
What, apart from gene therapy, is another targeted therapy being developed?
CAR-T cells
The future of cancer treatment
Potential disease to be treated by gene therapy
DMD
First gene therapy trials have been approved
How have chickens been used to make vaccines?
Chickens modified to make IFN a 2a
Can be extracted from eggs and used for therapy