Cancer Susceptibility

Question 1

what are the two types of genetic risks associated with cancer

Answer 1

monogenic
polygenic

Question 2

what is a monogenic genetic risk in cancer

Answer 2

caused by a single gene which results in disease with very high probability
e.g. BRCA1 mutation and breast cancer

Question 3

what is a polygenic genetic risk in cancer

Answer 3

several or numerous genes involved which are inherited by the same individual
each individual gene confers a small increase in risk
e.g. most human pathologies are polygenic diseases. E.g. cancer, cardiovascular disease

Question 4

Acute myeloid leukaemia can be a _ disease

Answer 4

monogenic
○ High penetrance variants are rare
○ Some risk genes are also mutated somatically (CEPBA,RUNX1 etc)
○ Some are responsible for human syndromes, with AML as a component (e.g FANCA, TP53)
○ Recurrence is strong evidence of functionality (i.e disease-causing)

Question 5

how to identify monogenic disease

Answer 5

• family studies using linkage of microsatellite markers
• exome sequencing

Question 6

how to identify polygenic diseases

Answer 6

• Case-control association studies
  (Candidate gene association or genome-wide association, study using unrelated individuals)
• Family studies possible but more useful for studies on rare high penetrance disease

Question 7

how do case control studies

Answer 7

Determine risk of disease development by comparing frequency of genetic trait in cases and appropriately match controls
- Calculate Odds Ratio = Ratio of odds of exposure (or risk allele carriers) to non-exposure (non-carriers) among diseased (A/C) compared to non-diseased (B/D) =
Odds Ratio = A x D / B x C.

Question 8

how are odds ratios used in CC studies

Answer 8

• Assess significance of OR and calculate 95% confidence interval using X2 analysis.
• Significant if p < 0.05 and confidence interval does not cross 1.
  □ Use formula 95% CI = OR(1±1.96/c)
  □ 1.96 is 5% point of the normal distribution with 95% of all observations expected to be between -1.96 and +1.96 standard deviations away from the mean

Question 9

what are the limitation of CC studies including GWAS

Answer 9

○ Screening for multiple alleles increases risk of obtaining chance false-positive associations
○ Danger than cases may be different genetically to controls (due to ethnicity)
○ Data needs to be carefully cleaned for low quality samples and SNPs (genotyping errors)
○ Need to replicate a significant finding in several different groups to be sure that association is genuine
○ Good information needed on disease phenotype and environmental risk factors for the disease (e.g. smoking, diet)

Question 10

Common sources of carcinogens

Answer 10

○ Tobacco smoke = Many of the approx. 4000 components present are known/ potential carcinogens
○ Food = Barbecued food, aflatoxin
○ Occupational exposure =Many industrial processes, Petrochemicals
○ Cellular processes = molecular oxygen, endogenous methylating agents formed in the gut

Question 11

Outline GWAS study on breast cancer

Answer 11

□ Differences in distribution between cases and controls shown by GWAS
□ >70 genes now identified including
= FGFR2, receptor for fibroblast growth factor
= TNRC9, transcription factor
= MAP3K1, involved in cell signalling via protein kinases
□ Effect size for each risk factor small with typical odds ratio of 1.1 to 1.3
□ Does not exclude role for pharmacogenetic polymorphism

Question 12

Outline GWAS study on lungs cancer

Answer 12

□ Nicotinic acetylcholine receptor gene clusetr has high p value in manhattan plot
□ Recent GWAS
= 18 different loci show genome-wide significance
= A role for “addiction genes” and other pathways (telomere maintenance, immune function)
□ CYP2A6
= CYP2A6 is a major contributor to nitrosamine activation to its active form (4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK))
= Also metabolizes nicotine and complex relationship reported between smoking behaviour and CYP2A6 genotype (affects addiction and ability to stop smoking).
= Now a confirmed risk factor for lung cancer

Question 13

how many different loci are associated with a risk of developing Chronic lymphocytic leukaemia

Answer 13

> 45 loci carrying common variants accounting for 25% of the heritable risk of CLL

Question 14

what locus carries risk alleles for numerous human cancers such as AML,CLL, Colon and cervical

Answer 14

HLA
- The HLA complex is located within the 6p21.3 region of the short arm of chromosome 6 and contains >240 genes of diverse functions. Many of the genes encode immune system proteins.
- HLA antigens on specialized immune cells present peptides from foreign substances (e.g. viruses and bacteria) to effector cells of the immune system.

Question 15

1 in _ human cancer is caused by infection

Answer 15

7
Human papilomavirus = cervical
Hep B/C = liver cancer
epstein Barr virus = multiple
ect