W9 Cancer Genomics (SH-guest) Flashcards
Definitions:
Genomics?
Genetics?
Pharmacogenetics?
Pharmacogenomics (PGx)?
Personalised medicine?
- Genomics is the study of an organisms genome (its DNA) and how that information is applied
- Genetics is a study of genes and how they are inherited.
- Pharmacogenetics how variation in one single gene influences the response to a single drug
- Pharmacogenomics (PGx) – study of how an individual’s genetic information determines how an individual manages and responds to medicines.
- Personalised medicine- individualising drug therapy in light of genomic, diagnostic and clinical information
Variant?
Allele?
Any difference between the sequence of two individuals’ genomes, or a reference genome. Variants can be harmless or disease-causing (pathogenic).
Alternate forms of a gene at the same
position on a chromosome (locus)
Genotype?
Phenotype?
Genotype
The DNA sequence of an organism or
individual, which determines (along with environmental influences) the specific characteristics (phenotype) of that organism or person. (blood group)
Phenotype
An organism’s observable physical and
biochemical characteristics directly
influenced by the genotype and/or
environment. (eye colour, height)
Cancer genomics in practice
3 principles?
- Screening
-e.g. Lynch Syndrome, BRCA - Diagnosis
-e.g. Somatic testing – lung cancer - Treatment
-e.g. targeted treatments based on somatic variation and Pharmacogenomics
Types of variants
- Constitutional (germline): Occur in gametes (sperm and eggs) and can be passed on to offspring
- Somatic: Arise in an individual and are not heritable. These type of variants are the most common cause of cancer.
Types of sequencing?
- Targeted sequencing
- Panel sequencing
- Whole exome sequencing (WES)
- Whole genome sequencing (WGS)
Types of Genetic Variation?
- D e l e t i o n s
- Copy Number Variations (CNVs)
- Chromosomal Rearrangement: Gene fusions and translocations
- Single Nucleotide Polymorphims
- Frameshifts
- Premature stop codons
- Alternate Splicing
- P r o m o t e r s a n d E n h a n c e r s
NSCLC
What is associated with this?
- Smoking is most strongly associated with SCLC
- Adenocarinoma is a type of NSCLC and is the most common
histology in never smokers and associated more commonly
with driver mutations such as EGFR mutations - EGFR mutations – most common in women and east Asian populations
Why is testing important in lung cancer?
- Studies have shown that patients with actionable variants who receive appropriate targeted therapy have improved outcomes
- Important to consider molecular testing to select the correct treatment either immunotherapy or targeted treatments
- E.g. if you have an EGFR mutation, you will not benefit from immunotherapy
When are patients tested?
At diagnosis
* To determine if EGFR variant or PD-L1 overexpression detected
* Metastatic disease (need comprehensive panel test)
At disease progression
* To check for treatment resistance
* E.g. targetable EGFR resistance mechanisms – T790M
* For other biomarkers, mostly informational for clinical trials
* Patient by patient basis
What is Tissue testing?
Gold standard practice – taken from a surgical biopsy of tissue
* May be unable to repeat biopsy due to difficult tumour location, procedural availability, and patient preference
* Lung cancer biopsies are more heterogeneous/less cellular compared to other solid cancers
* Bone biopsies less reliable decalcification can degrade DNA
* Turnaround time 2-3 weeks and can be longer
What is a Liquid biopsy?
- Circulating tumour DNA (ctDNA)
- Molecules released into circulation actively or passively which originate from tumour cells due to apoptosis or necrosis
- ctDNA can be measured most commonly in the plasma but can also be measured in other bodily fluids such as urine, saliva, pleural or CSF
When should you use a liquid biopsy?
- Cancer diagnosis/plasma first approach: for inadequate or no tissue biopsy possible or available – advice if negative to re-biopsy for tumour tissue
- Cancer diagnosis/sequential approach: tumour tissue adequate for genotyping – follow with liquid biopsy only when results from tissue incomplete
- Cancer diagnosis/ complementary approach: increased rate of biomarker detection
Treatment selection/resistance to TKIs
* Monitoring disease burden/treatment
monitoring
* Prognosis – risk of relapse
Molecular tumour board
- MDT meeting to understand and utilise molecular reports
- e.g. oncologists, geneticist, clinical scientists, pharmacists, pathologists, bioinformaticians, clinical nurse specialists
- Aim is to interpret molecular tumour reports and make treatment decisions based on genomic results and other clinically relevant details
- More complex treatment decisions – e.g. unlicensed medicine use, decision on further genetic testing or clinical trial implications.
What is Pharmacogenomics?
An example of Personalised medicine
* One aspect of genomics
* Genetic test – single/panel/WGS
* Test result used to guide treatment decisions with consideration for other relevant factors
Pharmacology + Genomics= Safe, effective medicines tailored to
variations in a person’s genes
Pharmacokinetics versus Pharmacodynamics?
pharmacokinetics is the movement of drugs through the body, (ADME) whereas pharmacodynamics is the body’s biological response to drugs (drug action and mechanism)
Types of metabolisers?
● Poor metaboliser
● Intermediatenmetaboliser
● Extensive (normal) metaboliser
● Ultra rapid metaboliser
So what causes these inter-individual genetic variations?
- Single Nucleotide Polymorphisms (SNPs) – most common type of genetic variation among people
- SNPs are DNA sequence variation that occurs when a single nucleotide in the genome sequence is altered
- Occurs in at least 1% of the population and make up about 90% of human genetic variation
Star Allele nomenclature
Many important pharmacogenomics PGx genes encode metabolizing enzymes such as cytochrome P450 (CYP) enzymes and thiopurine methyltransferase
* Star alleles – nomenclature for variant sequences of these PGx
genes that encode metabolizing enzymes e.g. CYP2D6*2.
* Sometimes, a star allele is defined by a single genetic variant, such as a single‐nucleotide polymorphism (SNP),
- In other cases the star allele is a name for a combination of variants
(or SNPs) across the gene, i.e., a haplotype. In these cases, the phenotype depends on the haplotypes present on both chromosomes, referred to as the diplotype - There is a need to standardise the star allele (haplotype) definitions
across labs - Assigning haplotypes and diplotypes enables publishing of prescribing recommendations, such as those from Clinical Pharmacogenetics Implementation Consortium (CPIC) or Dutch Pharmacogenetics Working Group (DPWG) guidelines
Types of drugs
● Prodrugs
○ Codeine
○ Clopidogrel
○ Tamoxifen
● Active drugs
○ Warfarin
○ Omeprazole
○ Phenytoin
Examples of gene-drug pairs
- Codeine is activated by CYP2D6
- Azathioprine is inactivated by TPMT
- Warfarin is inactivated by CYP2C9
- Clopidogrel is activated by CYP2C19
What determines our response to medication?
- Diet (e.g. grapefruit juice)
- Drug-drug interactions
- Comorbid diseases
- Sex
- Age
- Genetic Variation in receptors and transporters
- Genetic Variation in Metabolism
Pharmacogenomics in Practice: DPYD Testing
Aim: DPYD pharmacogenomic test offered to all patients prior to starting fluoropyrimidine chemotherapy (5-fluorouracil, capecitabine)
The Pharmacogenomic
approach vs standard approach
Standard approach: Patient Rx a medicine for their health problem, a ‘one size fits all’ approach
Patients genes affect how the respond to the meds and whether they have SE
Rx is changed or adjusted to suit the person (Inc/Dec dose or Stop meds)
Pharmacogenomic approach: Patient has a pharmacogeniomiv blood test carried out once in their lifetime
Result:
…. Patient is given the right medicine at the right dose for them
