Pharmacogenetics and response to cancer chemotherapy Flashcards
What are constitutional polymorphisms?
Present since fertilization and in every cell
Less tolerance for variation; contributes to disease development and response to chemotherapy.
Name three examples of constitutional polymorphisms.
- Trisomy 13 - Patau syndrome
- Trisomy 18 - Edward syndrome
- Trisomy 21 - Down syndrome
What are somatic mutations?
Acquired as we age and present in individual cells
More tolerance for variation; contributes to disease development and response to chemotherapy.
How do older cancer drugs generally function?
- Target highly proliferating cells
- Target DNA synthesis
- Not tailored to specific mutations
What do newer cancer drugs aim to target?
- Cancer cell-specific features
- Genomic translocations (e.g., BRC-ABL)
- Overexpressing oncogenes (e.g., EGFR-TKIs, B-RAF)
- Phenotypic characteristics (surface protein expression)
What does Dihydropyrimidine Dehydrogenase (DPYD) metabolize?
5-fluorouracil
Used for 40 years to treat colorectal, stomach, breast, and pancreatic cancer.
What are the side effects of 5-fluorouracil?
- Diarrhoea
- Cardiac toxicity (15-30% of patients)
- Myelosuppression
What genetic variants reduce DPYD activity?
- 2846 A>T, Asp949Val
- 1236 G>A, HAPB3
What is the consequence of null activity in DPYD variants?
DYPD*2A has a splicing defect resulting in 50% activity (heterozygotes) and no activity (homozygotes)
1679 T>G*13 is another null allele.
What is the recommendation for individuals with absent DPD activity?
No fluorouracil dose has proven safe.
What is Irinotecan metabolized by?
UGT1A1
Used to treat colorectal and lung cancer.
What are the side effects of Irinotecan?
- Diarrhoea
- Neutropenia (15-30% of patients)
What causes Gilbert syndrome?
Reduced or absent UGT activity by UGT1A1*28
Linked to hyperbilirubinemia and jaundice.
What is the prevalence of poor metabolizers in the general population?
8-78% depending on ethnic background.
What is Cytarabine used for?
Backbone therapy for acute myeloid leukaemia
What is the role of Thiopurine methyltransferase (TPMT)?
Metabolizes 6-mercaptopurine, azathioprine, and 6-thioguanine
Used for treating various cancers and as immunosuppressants.
What are the TMPT polymorphisms?
- TMPT*1 (wild-type)
- TMPT*2 (G>C at 238 bp)
- TMPT*3A (480G>A & 719A>G)
- TMPT*3B (460bp G>A)
- TMPT*3C (719bp A>G)
- TMPT*4 (626-1G>A)
What is the relationship between TPMT activity and thioguanine nucleotides?
Activity is inversely related to TGNs concentration in patient cells.
What is the significance of cancer chemotherapy based on tumour cell genotype or phenotype?
Allows for targeted therapies that should have little or no effect on non-tumour cells.
What mutation is associated with CML?
BCR-ABL fusion oncoprotein
Encodes a constitutive ABL kinase activity.
What is the gatekeeper residue in the ABL kinase domain?
Thr315 (T315)
What does the mutation Thr315Ile do?
Prevents hydrogen binding between imatinib and the 315 residue.
What is Herceptin used for?
Monoclonal antibody to HER2 amplified cancer
What is the most common mutation in B-RAF?
BRAF(V600E)
What is the future of pharmacogenetics in cancer therapy focused on?
- Individual variability
- Genetic profiling
- Gene expression profiling
- Protein expression profiling
What is the clinical significance of TPMT genotype/phenotype?
Dose adjustment based on genotype/phenotype is warranted.
