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
