W8.3_Pharmacogenomics

Question 1

Contrast the percentage difference in coding and non-coding regions. Define genetics, genomics, pharmacogenetics, and pharmacogenomics.

Answer 1

• Coding regions (Exon): 2% vs Non-coding regions (Intron): 98%
• Genetics: study of genes and their inheritance
• Genomics: study of coding and non-coding regions
• Pharmacogenetics: impact of single gene on interactions between medicines and the body
• Pharmacogenomics (PGx): study of how genome influence patients respond to medicines

Question 2

Explain the genomic variations in humans and how it might impact our health. What are the factors that may impact the variations in drug response?

Answer 2

• Only 0.1% of genome but ≈3 million differences
• Essential, contributes to biological/visual differences
• Cause rare health conditions, alter risk of developing common health problems, change response to medicines, or no effect at all
• Variations in drug response: ∵ health conditions, genomic variation, demographic, environment, drug-food interactions, drug-drug interactions, poor adherence, kidney and liver function

Question 3

Describe the different ways that genomics can be altered with some examples.

Answer 3

• Deletion: delete all/part of a gene
• Big deletions: common cause of clinical problems (ex. WAGR -> Wilm’s tumour)
• Partial deletions: may be fatal to genes (deleted exon critical to protein function? Create frameshift?)
• Copy number variants: multiple copies of same gene (ex. 2D6 gene -> morphine overdose after codeine intake)
• Chromosomal rearrangement: gene fusion/translocation (balanced/unbalanced) (ex. BCR-ABL & CML genes -> leukaemia)
• Single nucleotide polymorphism (SNP): single code change -> direct cause of rare condition/ change predisposition to common diseases/frameshift/premature stop codon/no effect
• Frameshift: change the way codons are read -> different amino acid sequence
• Premature stop codon: convert codon for amino acid to stop codon (ex. APC gene -> colorectal cancer)
• Others: alternate splicing (ABCD -> ABD + ACD), variants in non-coding DNA (promoters and enhancers)

Question 4

What are germline variants and what do they impact?

Answer 4

• Germline/Inherited variants: born with, passed onto future generations
• In drug metabolising enzymes/transporters (ex. P450)
• Target proteins
• In major histocompatibility complex -> change ADRs
• Related to rare diseases (ex. CFTR in cystic fibrosis)
• Predicting risk of some cancers (ex. BRCA in breast cancer)

Question 5

What are somatic variants and what do they impact?

Answer 5

• Somatic/Acquired variants: gained over lifetime, vary number of cells containing it, X passed onto future generations
• Relevant in cancer diagnosis/classification/treatment selection
• Predict risk of some cancers
• Detect rare diseases (ex. paroxysmal nocturnal haemoglobinuria)

Question 6

Explain the DYPD gene and how it impacts cancer treatments.

Answer 6

• DPYD gene encodes DPD: patients with complete/partial deficiency have increased risk of severe/fatal toxicity to fluoropyrimidines (common anti-cancer drugs)
• ∴ DPYD hotspot testing: test for 4 targeted variants