Biomarkers Flashcards
Define a biomarker:
A characteristic that is objectively measured and evaluated as an indicator of normal biological processes, pathogenic processes or pharmacologic responses to a therapeutic intervention.
Give examples of biomarkers:
A biomarker may be a gene, protein, imaging result or a clinical measure.
Can be used individually or in combination as part of a biomarker signature.
What are the 4 Broad uses of biomarkers in personalised healthcare?
Diagnostic biomarkers – used for early detection, disease classification.
Predictive biomarkers - predict patients likely to develop a disease, to respond to a specific pharmacotherapy, or likely to have an adverse effect.
Metabolism biomarkers - dose defining / monitoring.
Outcome biomarkers - forecast progression or recurrence.
Remember - a biomarker can have more than one use.
How are biomarkers used as diagnostic tools?
Diagnostic biomarkers can be used to enable early detection of a condition.
Can be used for late onset conditions to identify disorder before symptoms appear.
How do biomarkers do carrier testing?
Used as a predictive or prenatal testing tool within a family to identify those heterozygous for a recessive allele that, when homozygous, causes a genetic disorder or altered phenotype.
How are biomarkers used for diagnosis of diseases?
Disease classification - used as a diagnostic tool to confirm or rule out a cause of illness.
Used to guide treatment.
How are biomarkers use to inform on metabolic response?
Use of a biomarker to define / monitor pharmacotherapy dose to achieve efficacy and reduce ADRs.
Warfarin - CYP2C9 genotyping & INR measurement.
Irinotecan - uridine diphosphate glucuronosyltransferase 1A1(UGT1A1) activity.
Thiopurines - thiopurine S-methyltransferase activity.
Examples of biomarkers use to personalise drug treatment:
Tamoxifen - Oestrogen receptor presence in breast cancer biopsy.
Traztuzumab - HER-2 overexpression in breast cancer biopsy.
Gefitinib - EGFR mutation in non small cell lung cancer.
Gleevac - Philadelphia chromosome in positive chronic myeloid leukaemia.
Abacavir - HLA-B*5701 allele associated with a severe hypersensitivity reaction.
Simvastatin - Solute Carrier Organic Transporter variation associated with statin induced myopathy.
What is a biomarker signature?
A Biomarker Signature is a set of two or more biomarkers that, when applied to an empirical model or rule, predicts an outcome.
E.g. Biomarker signature of 2 biomarkers:
Biomarker 1 - a genetic variation (wildtype or allele 1).
Biomarker 2 – level of expression of a mRNA (high or low).
Candidate gene approach:
Gene / variation selection - A priori, rational selection of genes increases biological plausibility of finding.
Small number of genes variations examined.
Low genotype technology.
Large number of subjects.
Limited analytical support.
Low cost.
Backed by biology, more targeted and sensitive approach but novel genes cannot be identified.
Explain drug induced hypersensitivity:
Can affect the skin as a rash or display as hypersensitivity syndrome with skin blistering and systemic effects (e.g. liver toxicity; renal failure) and can lead to anaphylactic shock and death.
Inappropriate immune reaction where the drug acts as the antigen leading to activation of the adaptive immune response.
Associated with the MHC locus on chromosome 6.
What is abacavir?
Abacavir - HIV reverse transcriptase inhibitor used in the treatment of HIV.
Candidate gene analysis of MHC alleles for association with this life threatening ADR.
Sequencing of the HLA loci - identification of alleles associated with hypersensitivity to Abacavir in a retrospective study.
Genome wide association studies:
Gene / variation selection - Unprejudiced, analysis of whole genome allows identification of genes previously unlinked to the response
Large number of genes variations examined.
High throughput technology.
Modest number of subjects.
Sophisticated analytical support.
High cost.
What are microarrays?
A microarray is a panel of single stranded samples that collectively represent the DNA to be analysed.
DNA fragments (oligonucleotide probes) are spotted onto a solid support to form a microarray.
Each spot on the microarray has multiple copies of a single DNA sequence.
The sample is labelled, hybridised against the array and labelled spots are detected.
Used for comparative analysis of expression between 2 samples – gene expression profiling.
How does profiling microarrays work?
Gene expression profiling in patients with Crohn disease (35) and ulcerative colitis (32).
Extracted mRNA from CD4+ and CD8+ cells isolated from each patient.
Hydridised against a microarray presenting 28,000 genes identified from the human genome project and the sequence databases (NCBI and ENSEMBL).
13,250 genes expressed, upregulation of the expression levels of some genes correlated with relapsing disease.
2 Biomarker signatures identified IBD-1 and IBD-2
