Pharmacogentics And Cancer Susceptibility Flashcards
Define monogenic
Caused by a single gene which results in disease w very high probability
Define polygenic
Serval or numerous genes involved which are inherited by the same individual
Each individual gene confers a small increase in risk
Describe how monogenic and polygenic vary in penetrance and population therapy
Mono: low frequency but high penetrance for disease
Poly: high frequency but low penetrance for disease
Describe the polygenic disease model
Penetrance with each individual gene despite each gene having a low penetrance allele
Describe AML as a monogenic disease
High penetrance variants are rare
Some genes are mutated soamtically
Recurrence is strong evidence of functionality
Describe the approach to identify monogenic disease
Family studies using linkage of microsatellite markers
Exome sequencing
Describe the approaches to identify polygenic disease
Case control association studies
Candidate gene association or e genome wide association study using unrelated individuals
When are case-control studies used
Determine the risk of disease development by comparing frequency of genetic trait in cases and appropriately matched controls
What is the odds ratio
Ratio of odds of exposure to non exposure among disease compared to non diseases
How to calculate odds ratio
OR = A x D / B x D
Assess significance of OR
Calculate 95% confidence using X2 analysis
What is genome wide association studies
Genotype for 500,00 to 1,000,000 SNPs scattered throughout human genome in a group of cases vs group of controls
What is imputation
Strong linkage disequilibrium in human genome allows accurate prediction of neighbouring SNPs that haven’t been directly genotype
What are the limitations of using case-control studies
Increases risk of obtaining false-positives associations Cases may be different genetically due to ethnicity
Data needs to be carefully cleaned
Good information needed on disease phenotype and environmental risk factors
How can case-control studies ensure that the association is genuine
Need to replicate a significant finding in several groups
Name some cancers due to a single gene defect
BRCA1/2 in breast cancers
MLH1 mismatch repair gene in colon cancer
TP53 associated w susceptibility to particularly cancers
What genetic components that are common in almost all cancers with polygenic effects
Xenobiotic biotransformation genoptype
DNA repair genes
What are common sources of carcinogens
Tobacco smoke
Food
Occupational exposure
Cellular processes
Describe how GWAS data has helped in identifying breast cancer risk genes
> 70 genes now identified including FGFR2, TNRC9 and MAP3K1
Difference in distribution between cases and controls shown
Does not exclude role for pharmacogenetic polymorphisms
How many loci show genome wide signifance in lung cancer
18
How many loci carrying common variants have been identified using GWAS in CLL
> 45 that’s count for 25% of the heritable risk of CLL
What is the link between CYP2A6 and lung cancers susceptibility
Confirmed risk factor for lung cancer
Allele: *4
One or more variant CYP2A6 alleles protects against lung cancer
Describe HLA
Located in 6p21.3 and many of the genes encode immune system proteins
Antigens on specialised immune cells present peptides from foreign substances to effector cells
How many human cancers are caused by infection
1 in 7
HPV = cervical cancer
Hep B and Hep C = liver cancer
What defines the outcome (risk)
Interactions between genes and exposure
How do somatic mutations occur
CH3 group is added onto the O
Mismatch: instead of G + C it’s actually G + T
Describe how a mismatch due to a methyl group is fixed
Excises the T has been inserted
Attempts to replace with a C but methyl group is still present so T is readded
End up with strand breakage = cell death
What happens if a cancer cell loses its ability for strand mismatch repair
Lose the ability to die, stay as mutation and drive colon cancer risk
Describe the MLH1 mutation
G>A position -93
Affects levels of MLH1 txn and protein levels
= not fully competent for mismatch repair
Approx 15% mutation and slightly increased risk of colon cancer
What is the link between methylating agents and leukaemia
Risk factor for this who were treated w chemotherapeutic methylating agents in first cancer
Often Hodgkin’s lymphoma
