Pharmacogentics And Cancer Susceptibility

Question 1

Define monogenic

Answer 1

Caused by a single gene which results in disease w very high probability

Question 2

Define polygenic

Answer 2

Serval or numerous genes involved which are inherited by the same individual
Each individual gene confers a small increase in risk

Question 3

Describe how monogenic and polygenic vary in penetrance and population therapy

Answer 3

Mono: low frequency but high penetrance for disease
Poly: high frequency but low penetrance for disease

Question 4

Describe the polygenic disease model

Answer 4

Penetrance with each individual gene despite each gene having a low penetrance allele

Question 5

Describe AML as a monogenic disease

Answer 5

High penetrance variants are rare
Some genes are mutated soamtically
Recurrence is strong evidence of functionality

Question 6

Describe the approach to identify monogenic disease

Answer 6

Family studies using linkage of microsatellite markers
Exome sequencing

Question 7

Describe the approaches to identify polygenic disease

Answer 7

Case control association studies
Candidate gene association or e genome wide association study using unrelated individuals

Question 8

When are case-control studies used

Answer 8

Determine the risk of disease development by comparing frequency of genetic trait in cases and appropriately matched controls

Question 9

What is the odds ratio

Answer 9

Ratio of odds of exposure to non exposure among disease compared to non diseases

Question 10

How to calculate odds ratio

Answer 10

OR = A x D / B x D

Assess significance of OR
Calculate 95% confidence using X2 analysis

Question 11

What is genome wide association studies

Answer 11

Genotype for 500,00 to 1,000,000 SNPs scattered throughout human genome in a group of cases vs group of controls

Question 12

What is imputation

Answer 12

Strong linkage disequilibrium in human genome allows accurate prediction of neighbouring SNPs that haven’t been directly genotype

Question 13

What are the limitations of using case-control studies

Answer 13

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

Question 14

How can case-control studies ensure that the association is genuine

Answer 14

Need to replicate a significant finding in several groups

Question 15

Name some cancers due to a single gene defect

Answer 15

BRCA1/2 in breast cancers
MLH1 mismatch repair gene in colon cancer
TP53 associated w susceptibility to particularly cancers

Question 16

What genetic components that are common in almost all cancers with polygenic effects

Answer 16

Xenobiotic biotransformation genoptype
DNA repair genes

Question 17

What are common sources of carcinogens

Answer 17

Tobacco smoke
Food
Occupational exposure
Cellular processes

Question 18

Describe how GWAS data has helped in identifying breast cancer risk genes

Answer 18

> 70 genes now identified including FGFR2, TNRC9 and MAP3K1
Difference in distribution between cases and controls shown
Does not exclude role for pharmacogenetic polymorphisms

Question 19

How many loci show genome wide signifance in lung cancer

Answer 19

18

Question 20

How many loci carrying common variants have been identified using GWAS in CLL

Answer 20

> 45 that’s count for 25% of the heritable risk of CLL

Question 21

What is the link between CYP2A6 and lung cancers susceptibility

Answer 21

Confirmed risk factor for lung cancer
Allele: *4
One or more variant CYP2A6 alleles protects against lung cancer

Question 22

Describe HLA

Answer 22

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

Question 23

How many human cancers are caused by infection

Answer 23

1 in 7

HPV = cervical cancer
Hep B and Hep C = liver cancer

Question 24

What defines the outcome (risk)

Answer 24

Interactions between genes and exposure

Question 25

How do somatic mutations occur

Answer 25

CH3 group is added onto the O
Mismatch: instead of G + C it’s actually G + T

Question 26

Describe how a mismatch due to a methyl group is fixed

Answer 26

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

Question 27

What happens if a cancer cell loses its ability for strand mismatch repair

Answer 27

Lose the ability to die, stay as mutation and drive colon cancer risk

Question 28

Describe the MLH1 mutation

Answer 28

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

Question 29

What is the link between methylating agents and leukaemia

Answer 29

Risk factor for this who were treated w chemotherapeutic methylating agents in first cancer
Often Hodgkin’s lymphoma