L10: Cancer Pharmacogenomics and Personalized Medicine Flashcards
1
Q
What is cancer genomics?
A
Study of human cancer genome that contribute to the development of a cancer cell to progression from a localized cancer to one that grows uncontrollably and metastasizes
2
Q
What is mutation?
A
- Change in normal base pair sequence
- Commonly used to define DNA sequence changes that alter protein function
- Can occur to non coding (mostly silent but if it is regulatory gene, can affect downstream signalling) or coding regions (silent vs addition/deletion, change in amino acid sequence)
3
Q
What are somatic and germline mutations?
A
- Somatic: Occurring in nongermline tissues, not heritable
- Germline: Occurring in germline cells (egg/sperm), are heritable, can cause cancer family syndrome affecting all offsprings)
4
Q
What does tumour are clonal mean?
A
- Originating from single parent cell where first mutant cell can be of germline or somatic origin
- Most cancers arise from several genetic mutation accumulating in the cells of the body over a person’s lifespan
- Mutations can give survival adv/no survival adv (survival adv can accumulate and result in tumour/malignancy)
5
Q
**What are denovo mutations?
A
- A genetic alteration that is present for the first time in one family member as a result of a variant (or mutation) in a germ cell (egg or sperm) of one of the parents, or a variant that arises in the fertilized egg itself during early embryogenesis -> affect offsprings
- Common in: Familial adenomatous polyposis (FAP, mutation on the APC gene leading to aberrant activation of Wnt signalling pathway -> many downstream signalling for cancer, 30%), Multiple endocrine neoplasia 2B (thyroid, 50%), hereditary retinoblastoma (Rb protein that regulates cell cycle, 50%)
- **MCQ qn: which of the following is not a common de novo mutation
6
Q
What are the different point mutations?
A
- Missense (substitution, may or may not alter the protein structure and function)
- Frameshift insertion -> in PTEN -> resistant to doxetaxel for endometrial cancer -> hence do not prescribe this drug for patient -> better treatment and prognosis
- Frameshift deletion
- Splicesite mutations (splice at the wrong bp, either transcribe a bit of intron or splicing out one exon) -> correlate positively with tumourigenesis and drug resistance
- Regulatory mutation (Eg. Several copies of HER2 gene -> HER2 gene amplification -> many HER2 receptors on the cell -> would prescribe HER2 treatment)
- Large deletion or insertions of genome (Using SKY chromosome painting to look at the chromosomes; normal chromosomes would be the same colour but chromosomes in breast cancer appear multicoloured because they exchanged genetic material) -> would zoom in on the multicoloured and focus on targeting
- ^Eg. Translocation of Bcr-Abl gene -> driving CML -> Gleevac to target Bcr-Abl gene
7
Q
What are the precursors to cancer? Does one genetic mutation cause cancer?
A
- Heterozygous condition: Normal gene still balances the mutated gene
- BUT loss of heterozygous condition can occur in 6 ways: chromosome loss, deletion, unbalanced translocation, loss of normal and reduplication of originally mutated, mitotic recombination, point mutation
- Cancer is a complex disease, involving accumulation of somatic mutations (for a 80yr life span, require 10mil bil body cells to copy themselves correctly)
8
Q
What causes the difference in cancer outcomes for different patients?
A
- Same lifestyle but 1 gets cancer, and 1 does not
- Or same cancer but different response to cancer treatment
- Single nucleotide polymorphism (frequently occurring genetic variants) -> happens to 0.1% of the genome
9
Q
What are these single nucleotide polymorphism?
A
- Variations in DNA between individuals
- Can be insertions/deletions
- Variations can cause no changes, harmless changes (tall/short), latent changes (2 smokers, one sick one not)
10
Q
Why are SNPs important?
A
- Scattered throughout the genome and found in both coding and noncoding regions
- Can cause silent, harmless, harmful or latent effects
- Can study these variations -> Can cause altered proteins
11
Q
General examples of SNPs mutations
A
- Silent: DNA SNP C to G -> RNA CUG to CUC -> change from leucine to leucine -> No change in shape
- Subtle/harmless changes in protein: DNA SNP A to C -> RNA GAU to GAG -> Aspartic acid to glutamic acid -> Slight change in shape (slightly different in folding)
- Harmful changes in protein: DNA SNP T to A -> GAU to GUU -> Aspartic acid to valine -> Major alteration to protein shape
- Latent changes: turned on under specific conditions
12
Q
Other factors affecting cancer onset/progression
A
- Internal factors: Mutated susceptibility genes, weak immune system, mutated detox enzymes, mutated repair genes, change in hormone levels
- External factors: Alcohol, diet, physical activity
13
Q
How do we personalize medicine?
A
Genome-wide profiling
- Comparative genomic hybridization
- Spectral karyotyping
- Polymorphism analysis
- Gene expression profiling
14
Q
Why is it important to collect/perform genome wide profiling?
A
- Need a wide range of data from the population (general population profiling)
- See if the patients with a particular SNP is eventually down with cancer -> cancer risk/causing marker
- However, it cannot predict cancer 100% as cancer is driven by both intrinsic (genetic) and extrinsic factors (lifestyle, environment) -> just higher risk of getting cancer
15
Q
How is comparative genomic hybridization done?
A
- Can detect large-scale changes in chromosomes [Look at slides]
1) Label probes for all tumour DNA (green)
2) Label probes for all normal DNA (red)
3) Hybridize to normal metaphase chromosomes for 48-72h - Results: Yellow (equal binding of labeled normal and tumour probes), Green (more binding of labeled tumour probes, gain of tumour DNA), Red (more binding of normal probes, loss of tumour DNA)
