GiM lecture 4 and 5 Flashcards
Does Multifactoral disease have a genetic component
Twin Studies
- monozygotic twins had higher concordance than Dizygotic twins
What are problems with Twin Studies
Assumes MZ twin have same environment
DZ twins can share more that half of their genes
What causes phenotypes
many genes at different Loci
genes are additive
gaussian distribution curve
influenced by environment too
what disordes show multifactoral inheritance
Congenital Malformations - cleft lip, hip dislocation, heart defects, neural tube defects,
Acquired diseases
asthma, autism, cancer, epilepsy, crohns, MS, parkinson,
What is a genome wide association study
relate variation in human DNA with disease or trait
estimates population attributable risk
controls match cases and be representative of population
What are Single Nucleotide Polymorphisms
common mutations
What is linkage disequilibrium
most disease bearing chromosomes come from an ancestral chromosome
What are the genetics of alzhrimers
sequence variants at polymorphic locus have affect on age of onset
- APOE gene - app-lipoprotein - also linked heart disease
3 types of APOE
APOE*E2/3/4
How does APOE gene affect alzheimers
APOEE4 - increase susceptibility
APOEE2 - protective effect
E4/E4 homozygotes - very early onset
What is age related macular degeneration
irreversible central visual dysfunction - degeneration of macula
early deposition of drusen = hall mark risk for AMD
What are the genetic effectors of AMD
What are the environmental factors that increase AMD risk
CFH (1q) ARMS2(10q)
Smoking x70 increase
Define Penetrance
% with gene who get condition
- modified by genetic variation
- modified by environmental factors
What Gatekeepers
Monitor and control cell division, death preventing accumulation of mutations
What are caretakers
improve genomic stability (repair mutations)
What are landscapers
control surrounding stromal environment
A sporadic Defect causes what> and what chance of colorectal cancer?
adenomatous polyp
5% risk
A Gate keeper Defect causes what> and what chance of colorectal cancer?
Multiple adenomatous polyps
>95% risk
FAP
A Caretaker Defect causes what> and what chance of colorectal cancer?
andenomatous polyp
70% risk
HNPCC
a landscaper defect causes what and what chance of colorectal cancer
Hamartomatous polyps
10-20% cancer
What are tumor suppressor genes
protect cells from becoming cancerous
loss = inc risk cancer
APC, BRACA1/2, TP53, Rb
What are oncogenes
Regluate cell growth and differentiation
gain of function = cancer risk inc
growth and signal transduction factors, RET gene
what rule do most cancers obey
Knudson’s two hit hypothesis
Recessive at celluar level
Autosomal dominant inheritance
examples of cancers that follow an autosomal recessive inheritance pattern
MYH associated polyposis, Fanconi anaemia,
Ataxia telangiectasia
name mutation types
splice site mutations
Deletions, duplications
translocation
Signs of Sporadic Cancer
Onset older age
one cancer in individual
unaffected family members
cancer type rarely genetic - lung, cervix etc
Signs of familial cancer
onset younger age
multiple primaries in individual
family members affected
same type/genetically related cancers
Explain Retinoblastoma
childhood ocular cancer
1/15,000-30,000
classic knudson 2hit
retinoblastoma Rb1 gene
Bilateral cases = usually germline fault
15% “sporadic” actually germ line = new mutation rate is high
increases risk of other cancers
FAP Familial Adenomatour Polyposis
1% of all bowel cancers
high risk of bowel cancer if untreated
HUNDREDS of bowel polyps
CHRPE, desmoid tumors, osteomas,
fault in APC tumor supresson genes
autosomal dominant inheritance
colonoscopies and cholectomy
HNPCC Hereditart Non polposis colorectal cancer
2-3% of bowel cancers
polyps common
60-80% risk of bowel cancer
risk of other cancers - endometrial, ovarian, stomach
Error in Mismatch repair genes
MLH1 50%, MSH2 (40%) MSH6 10%
Autosomal dominant inheritance
Amsterdam Criteria
- 1 member diagnosed colorectal cancer b4 50yo
- 2 affected generations
- 3 affected relatives
- FAP excluded
- tumours verified by pathology
BRCA1/2 genes
involved in DNA repair
autosomal dominant inheritance
80% risk breast cancer
BRCA1 40% BRCA2 - 20%
Li Fraumeni syndrome
P53 mutations (RARE) autosomal dominant 50% risk cancer by 40yo 100% lifetime avoid radiotherapy - inc cancer risk poor prognosis