Pharmacogenetics in various cancers Flashcards
What is the role of genetic components in diseases?
Almost all diseases have a genetic component in determining risk, with the extent varying among diseases.
The understanding of genetic risk comes from familial studies and population-based GWAS.
What are the main enzymes involved in the activation of cyclophosphamide?
CYP3A4, CYP2C9, CYP2C19, CYP2B6.
Polymorphisms in these genes can affect the activation process.
What is the significance of the CYP2C19*2 allele in cancer patients?
It decreases the elimination of cyclophosphamide and is associated with a lower risk of developing ovarian failure in homozygous individuals.
However, it is linked to a higher probability of poor renal response.
How do risk alleles for cancer vary?
They vary in penetrance and population frequency, being either monogenic or polygenic.
Monogenic diseases are caused by a single gene, while polygenic diseases involve multiple genes.
Define monogenic diseases.
Diseases caused by a single gene resulting in a very high probability of disease.
An example is the BCRA1 mutation and breast cancer.
Define polygenic diseases.
Diseases involving several genes, where each gene confers a small increase in risk.
Most human pathologies, including cancer and cardiovascular diseases, are polygenic.
What is the role of family studies in identifying monogenic diseases?
They use linkage of microsatellite markers to identify disease genes.
Exome sequencing is also utilized.
What is the methodology used for polygenic disease identification?
Case-control association studies, candidate gene association studies, and GWAS.
Family studies are more useful for rare high penetrance diseases.
What is the purpose of case-control studies?
To determine the risk of disease development by comparing frequencies of genetic traits in cases versus matched controls.
Odds ratios are calculated to assess risk.
How is the odds ratio calculated?
Odds ratio = A x D / B x C.
A and B represent the diseased group, while C and D represent the non-diseased group.
What is GWAS?
Genome-wide association studies that genotype SNPs across the human genome in cases versus controls to identify novel disease-related genes.
Strong linkage disequilibrium allows for accurate prediction of neighboring SNPs.
What are common sources of carcinogens?
- Tobacco smoke
- Food (e.g., barbecued food, aflatoxin)
- Occupational exposure
- Cellular processes (e.g., molecular oxygen)
- Radon gas
Many components in tobacco smoke are known or potential carcinogens.
What genes are commonly associated with breast cancer risk?
> 70 genes including:
* FGR2 receptor for fibroblast growth factor
* TNRC9, transcription factor
* MAPK31, involved in cell signaling.
Effect sizes are small, typically with odds ratios of 1.1 to 1.3.
What findings were reported in GWAS for lung cancer?
18 loci show genome-wide significance, including:
* 5p15 (TERT)
* 6p21 (HLA)
* 15q25 (nicotine acetylcholine receptor gene cluster)
* 19q13 (CYP2A6).
These loci are linked to lung cancer susceptibility.
What is the role of CYP2A6 in lung cancer?
It activates nitrosamines and metabolizes nicotine, affecting smoking behavior and lung cancer risk.
Confirmed as a significant risk factor for lung cancer.
Why is the HLA complex important in cancer?
It encodes immune system proteins and presents foreign peptides to immune cells.
1 in 7 cancers are caused by infections; in Africa, it’s 1 in 3.
How do genetic and exposure factors interact in cancer susceptibility?
The relative importance is disease-specific; familial cancers tend to be genetically dominated, while other cancers may be more influenced by environmental exposures.
Environmental factors can interact with susceptible genotypes.
List endogenous methylating agents that increase cancer risk.
- Procarbazine
- Dacarbazine
- Temozolomide
- Streptozotocin.
They cause DNA mispairs and require functional DNA mismatch repair for cell death.
What is the significance of the Rs1800734 G>A position-93 (MLH1)?
It is a risk factor for MSI colorectal cancer and linked to bowel cancer and AML risk due to methylating agents.
It highlights the interaction between genetic predisposition and environmental factors.
What is the role of CYP2D6 in tamoxifen treatment?
It metabolizes tamoxifen into its active metabolites, 4-hydroxytamoxifen and endotoxifen.
Endotoxifen has much greater affinity for the estrogen receptor than tamoxifen.
How do polymorphisms in CYP2D6 affect breast cancer treatment?
CYP2D6*4 lowers survival rates and worsens relapse-free time.
Antidepressants can decrease CYP2D6 activity, affecting tamoxifen efficacy.
What is the effect of codeine metabolism variability?
Polymorphic metabolism affects clinical effects and can lead to opioid toxicity, especially in ultra-rapid metabolizers.
Codeine is metabolized to morphine, and children with sleep apnea are at high risk of adverse reactions.
What is the role of TMPT in 6-MP therapy?
TMPT inactivates 6-MP, influencing thiopurine therapy outcomes.
Low TMPT activity correlates with severe toxicity from thiopurine therapy.
What is the significance of UGT1A1 in irinotecan treatment?
It is involved in glucuronidation of SN-38, the active metabolite of irinotecan, impacting toxicity risk.
Variants in UGT1A1 are associated with increased risk of severe side effects.
What adverse effects were observed in a patient treated with 5-FU?
Elevated concentrations leading to a prolonged stuporous state after chemotherapy.
This highlights the importance of monitoring drug metabolism.
What correlates inversely with the number of UGT1A1*28 alleles?
Risk of severe diarrhoea and/or neutropenia in patients receiving irinotecan
Subsequent clinical studies detected this association (Micheal et al, 2006)
What significant event occurred in 1985 involving a 27-year-old woman with breast cancer?
Lapsed into a prolonged stuporous state after 2 cycles of 5-FU containing chemotherapy
Found to have elevated concentrations of thymidine and uracil in her body fluids
What did investigators propose as the cause of severe 5-FU toxicity in the patient?
A heritable defect in dihydropyrimidine dehydrogenase
This was based on biochemical abnormalities in family members and known pathways of pyrimidine salvage
What was found in multiple family members of the patient who experienced severe 5-FU toxicity?
Reduced DPD activity
This was linked to prolonged exposure to 5-FU after rechallenging with a small dose
Where does DPD activity primarily occur?
In the liver
This is where most 5-FU metabolism occurs
What led to the identification of a 165 bp deletion in the DYPD gene?
Cloning cDNA of the gene encoding DYPD
This deletion spans a complete exon of DYPD in family members with low DPD catalytic activity (Micheal et al, 2006)
