Use of Genomics in Clinical Practice

Question 1

What role exists for using genomics in clinical practice?

Answer 1

• Genomic technologies are becoming increasingly important in clinical practice.
• Historically genetic tests have been performed in a low throughput, low resolution format e.g. Sanger sequencing of single genes and chromosome analysis for gross structural abnormalities
• Technological advances have meant that higher-throughut, high resolution tests (NGS, arrays, WES/WGS) are readily avaiable and bring numerous advances
• Improved ability to identify mutations that respond to specific drugs means that genomic technologies are critical for delivering stratified/personalized medicine of the future

Question 2

What specific patient benefits are delivered by genomics?

Answer 2

1. Provide / confirm a diagnosis
2. Enables better prediction of prognosis. Even for very rare disease can study other patients at different ages.
3. Clarification of inheritance pattern and risk to other family members / future offspring
4. Enables family planning via PND/PGD
5. Predicitve testing in adult-onset disorder & ecommendations for screening
6. Identification of most effective drug therapy. e.g. gene therapy in RD, chemotherapy in cancer
7. Clinical trial participation

Question 3

What genomic technologies are commonly utilised when managing Rare Disease patients?

Answer 3

1. G-banding: SVs in specific referrals
2. Array CGH: CNVs
3. NGS Panels / Exomes: SNVs / indels

Question 4

How might genomic technologies for treating Rare Disease patients change in the future?

Answer 4

• WGS: can largely homologate CNV, SNV, SV, STR detection into a single assay
• Expense and technical challenges has been main limitation
• Large scale sequencing projects (100kg) aim to overcome these issues in order to geliver WGS into routine clinical practice
• cfDNA analysis has potential to revolutionise PND and is largely based on genomic technology
• Increasing use in PGS and PGD

Question 5

What is the principle of stratified medicine?

Answer 5

• Targeting of treatment according to characteristics shared by a group of patients.
• Identifies key molecular changes common to different patients, who can be grouped based on these shared genetic faults, allowing some to receive a targeted therapy matched to their group.

Question 6

What are the benefits of stratified medicine?

Answer 6

• More effective treatment
• Less side effects
• Avoidance of treatment for those who won’t benefit
• Patients more likely to adhere to treatment regimen
• More cost effective

Question 7

How is genomic medicine currently utilised in stratified medicine?

Answer 7

• Genomics is used extensively to characterise mutations in cancers which may respond to targeted therapies:
• Malignant melanoma:
  
  • BRAF V600E mutation +ve patients (40-60%) eligible for treatment with the BRAF inhibitors Vemurafenib, Dabrefenib, or MEK inhibitor Trametinib
  • c-KIT mutation Exon 11 +ve patients (20-30%) eligible for treatment with the tyrosine kinase inhibitor Imatinib
• NSCLC:
  
  • EGFR mutations in exons 18-21 (15% of patients) respond to Gefitinib, Erlotinib – block EGFR ATP binding site.
  • EML4-ALK fusion gene +ve patients (5%) respond to treatment with the ALK inhibitor Crizotinib

Question 8

How is genomic technology being utilised to aid the development of new drugs and treatments for stratified medicine?

Answer 8

• NGS/WGS has revealed the complex genomic landscape of cancer, identifying many different tumour driver mutations
• Whilst there are no specific drugs for many of these newly identified mutations patients are being tested for targeting to clinical trials that will eventually help develop accurate therapies.
• eg the CRUK Stratified Medicine partnership with the National Lung MATRIX trial for developing targeted therapies for NSCLC. Uses a 28 gene panel.

Question 9

How might genomic technologies used in stratified medicine change in the future?

Answer 9

• WGS is having a massive impact on stratified medicine
• Sequencing of Tumour DNA vs normal tissue DNA can provide a genome wide screen for actionable driver mutation
• WGS data can be used to produce a tumour ‘profile’ which can correlate with specific subtypes, prognosis and relapse risks
• ctDNA overcomes many of the disadvantages of obtaining biopsy samples and is likely to have a massive impact.

Question 10

Give an example of genomic medicine enabling personalised medicine in rare disease patients.

Answer 10

Genomic diagnosis is shaping precision management of neonatal diabetes.

>25 different genes cause neonatal diabetes, new genomic technology has found 5 new genetic subtypes which inform therapy options

1. KCNJ11 p.V59M: Permanent diabetes and development delay. Sulphonylurea therapy.
2. EIF2AK3 p.E371*: Wolcott Rallinson Syndrome. Liver transplant.
3. FOXP3 c.227deIT: IPEX syndrome. Bone marrow transplant.
4. GATA6 c.1448-1455del: Syndromic pancreatic agenesis. Insulin and exocrine supplements.
5. STAT3 p.T716M: Multi-organ autoimmune disease. STAT3 inhibitor.

Question 11

Give an example of genomic medicine enabling personalised medicine in acquired cancer patients.

Answer 11

• Melanoma is a common and often fatal skin cancer where the cancer cells have frequent genetic mutations.
• 40 to 60% of cutaneous melanomas carry BRAF V600E.
• The biological therapy drug vermurafenib blocks active BRAF so is an effective treatment in the patient group.

Question 12

Give an example of genomic medicine enabling personalised medicine with regard to drug response.

Answer 12

• Azathioprine is used to treat many diseases in rheumatology and dermatology.
• The drug is converted to its active metabolites by several enzymes, the most critical of which is thiopurine methyltransferase (TPMT).
• Low levels of TPMT activity results in the overproduction of azathioprine metabolites that are toxic to bone marrow, leading to bone marrow suppression.
• Individuals carrying mutations in TPMT may therefore be at higher risk of adverse side effects from azathioprine treatment
• Dose is then modulated

Question 13

What is the impact of genomics on counselling?

Answer 13

• Large impact and increasing role
• Results can be more difficult to interpret as many gene less well known and lots of results of uncertain significance
• Patients need to be fully informed about the risks of additional findings and decide what information they do or do not want to rceive
• Dicussions on how / when they would like to receive these secondary findings

Question 14

What other areas of clinical practice are being changed by genomic medicine?

Answer 14

• Microbiology and virology and their role in infectious diseases diagnostics and public health surveillance.
• Sequencing of pathogen genomes can be used to discriminate between species while informing about features such as virulence, resistance and phylogeny.
• Pathogen sequence information can therefore be used for rapid diagnosis and treatment and transfusion safety, as well as monitoring data for outbreak protection and guideline for drug uses