1. (Personalised / stratified medicine)
Precision Medicine
(Personalised / stratified medicine)
Andrew P Read
Emeritus Professor of Human Genetics, University of Manchester
Centre for Genomic Medicine, St Mary’s Hospital, Manchester
Galton Institute teachers’ day, Nowgen, 28th June 2017

3. Agenda The new technology Predicting individual risk Pharmacogenetics
Personalised treatment
Stratified medicine in cancer

4. Precision medicine is driven by technology
David Cameron’s 100,000 Genomes Project to ‘transform how diseases are diagnosed and treated’ £300 million
Barack Obama’s Precision Medicine initiative, $215 million.

5. Clinical applications
Diagnosis
Prediction
Treatment
Traditional medicine: treat according to phenotype
Precision medicine: treat according to genotype
Head in clouds Head in sand
Cartoon by Maya Evans

6. SNP chips genotype ca. 1 million single nucleotide polymorphisms in a DNA sample
Affymetrix SNP Illumina OmniExpress-24

9. Predicting individual risk of common complex disease
6 long-term prospective studies on Type 2 diabetes:
Before SNPs
After SNPs
Clinical indicators
AUC from clinical indicators
Susceptibility loci genotyped
AUC using combined clinical and genetic data
Reference
BMI, plasma glucose level
0.68
PPARG, CAPN10
Lyssenko et al. (2005)
Age, sex, BMI
0.82
GCK, IL6 , TCF7L2
Vaxillaire et al. (2008)
0.78
18 established loci
0.80
Lango et al. (2008)
0.66
Van Hoek et al. (2008)
Age, sex, family history, medical history, physical examination, blood sample
0.90
0.901
Meigs et al. (2008)
Age, sex, BMI, family history, liver enzyme levels, smoking, measures of insulin secretion and action
0.74
16 established loci
0.75
Lyssenko et al. (2008)

10. Br J Cancer 110: 827; 2014

11. Pharmacogenetics
Pharmacokinetics – genetic variation in what you do to a drug
Pharmacodynamics – genetic variation in what a drug does to you

12. Debrisoquine and Nortryptilene Effects of variable activity of CYP2D6
In 1975 Bob Smith, a laboratory director at St Mary’s Hospital Medical School in London, ingested 32 mg of debrisoquine, as did some of his co-workers. “Within two hours severe orthostatic hypotension [low blood pressure] set in with blood pressure dropping to 70/50 mm Hg. Hypotensive symptoms persisted for up to two days after the dose…”. His colleagues, who had taken a similar dose, had no significant effects.
Effects of variable activity of CYP2D6

13. Phase 1 and Phase 2 metabolism

14. P450 cytochromes
A family of around 60 enzymes that insert a single oxygen atom derived from molecular oxygen into a very wide range of organic compounds.
Wide and often overlapping specificities
The Roche Amplichip® genotypes a patient’s DNA sample for 30 P450 variants involved in drug metabolism.
Activity often varies widely between different individuals because of point mutations and variable copy number of genes

15. Basis of variable Phase 2 responses
Fast & slow acetylation of Isoniazid
Glutathione S-transferases

16. Adverse drug reactions
Responsible for about 100,000 deaths a year in the USA
Responsible for 6.5% of admissions to two large general hospitals in the UK
2% of those patients died
projected annual cost to the NHS was up to £466 million
Pirmohamed M et al. (2004) Adverse drug reactions as cause of admission to hospital: prospective analysis of patients. Br.Med. J. 329: 15–19.
Two types:
Type A ADRs (the great majority) are an exaggerated response to a standard dose of a drug, because of variants that make an individual particularly sensitive to that drug.
Type B ADRs are unrelated to the normal action of the drug and are the consequence of some quite unexpected interaction. Type B reactions are rare, can be very serious and are hard to predict or understand.

17. Adverse drug reactions
Adverse reaction
Reaction type
Azathioprine
Life-threatening bone marrow suppression from normal dose in people with low activity thiopurine methyltransferase A
Fluorouracil
Potentially fatal toxicity in people with deficiency of dihydropyrimidine dehydrogenase
Irinotecan
Severe neutropenia and diarrhea in people homozygous for a low-activity variant of the UGT1A1 gene
Succinylcholine
Prolonged apnea in people with butyrylcholinesterase deficiency
Warfarin
Excessive bleeding in people with low-activity CYP2C9 or VKORC1
Abacavir
Serious and sometimes fatal hypersensitivity reactions in patients with HLA-B*5701 genotype B
Carbamazepine
Life-threatening Stevens–Johnson syndrome in East Asians with HLA-B*1502 and Europeans with HLA-A*3101 genotypes

18. Warfarin
A powerful anticoagulant, used for patients at risk of embolism or thrombosis
The therapeutic window is narrow, but the effective dose varies up to twentyfold.
After insulin, warfarin is the most common prescription drug responsible for emergency hospital admissions. The estimated average cost of a bleeding episode is $16,000.

19. Low-tech treatment of genetic disease
NCG3 Table 14.2

20. Inborn errors of phenylalanine / tyrosine metabolism
Succinyl acetone
Lethal toxicity
Use nitisinone to inhibit tyrosine aminotransferase

21. Hi-tech treatment of genetic disease
NCG3 Fig 14.9

22. Stratified medicine in cancer

23. Multi-level analysis of tumour samples
The Cancer Genome Atlas Research Network (2013) Nat Genet 45,

24. Dysregulated pathways in tumour cells
Blue: inactivating mutations
Yellow: activating mutations
(A) 87% of glioblastoma multiformae tumours have mutations that compromise the pathways through which p53 affects senescence and apoptosis. B) 88% of tumours have changes affecting the pathways by which receptor tyrosine kinases (EGFR, ERBB2, PDGFRA, and MET) act to control cell proliferation and survival.

25. Overviews of cancer 6 Hallmarks of cancer. Hanahan & Weinberg
Cell 100: 57; 2000; 144: 646; 2011
Signalling pathways affected in cancer
Vogelstein Science 339: 1664; 2014

26. Targeting the BCR-ABL oncogene
A ‘magic bullet’ against chronic myelogenous leukaemia

27. Brand name (generic name)
Drug targets in cancer
Tissue / cancer
Brand name (generic name)
Protein target
Mode of action
Breast
Many brands (Tamoxifen)
Estrogen receptor in ER-positive breast cancers
Blocks ER, preventing growth signals
Leukocytes / leukaemia
Glivec® (Imatinib)
BCR-ABL1 fusion protein
Inhibits abnormal signalling by fusion protein tyrosine kinase
Skin / melanoma
Zelboraf® (Verumafenib)
BRAF V600E mutant protein
Specifically inhibits V600E mutant BRAF, triggers apoptosis
Non-small cell lung cancer
Xalkori®
(Crizotinib)
EML4-ALK fusion protein
Ovarian (advanced)
Lynparza® (Olaparib)
PARP1 enzyme
Blocks repair of DNA breaks in BRCA1-mutant cancers
Lung / various
Iressa® (Gefitinib)
EGFR mutants
Binds cytoplasmic part of EGFR, blocks signalling
Tarceva® (Erlotinib)
Various advanced cancers
Tagrisso® (Osimertinib)
EGFR T790M mutant
Binds cytoplasmic part of T790M mutant EGFR, blocks signalling
Small molecules
Monoclonal antibodies

28. Synthetic lethality: PARP inhibitors

29. Companion diagnostics
See the Pharmgkb database for information on drug interactions and pharmacogenetic effects:
FDA lists around 200 drugs where the label includes pharmacogenomic data – but most are advisory, not mandatory.  
Treatment determined
by phenotype
Treatment determined by
genotype