GiM lecture 4 and 5

Question 1

Does Multifactoral disease have a genetic component

Answer 1

Twin Studies

- monozygotic twins had higher concordance than Dizygotic twins

Question 2

What are problems with Twin Studies

Answer 2

Assumes MZ twin have same environment

DZ twins can share more that half of their genes

Question 3

What causes phenotypes

Answer 3

many genes at different Loci
genes are additive
gaussian distribution curve
influenced by environment too

Question 4

what disordes show multifactoral inheritance

Answer 4

Congenital Malformations - cleft lip, hip dislocation, heart defects, neural tube defects,

Acquired diseases
asthma, autism, cancer, epilepsy, crohns, MS, parkinson,

Question 5

What is a genome wide association study

Answer 5

relate variation in human DNA with disease or trait

estimates population attributable risk

controls match cases and be representative of population

Question 6

What are Single Nucleotide Polymorphisms

Answer 6

common mutations

Question 7

What is linkage disequilibrium

Answer 7

most disease bearing chromosomes come from an ancestral chromosome

Question 8

What are the genetics of alzhrimers

Answer 8

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

Question 9

How does APOE gene affect alzheimers

Answer 9

APOEE4 - increase susceptibility
APOEE2 - protective effect

E4/E4 homozygotes - very early onset

Question 10

What is age related macular degeneration

Answer 10

irreversible central visual dysfunction - degeneration of macula

early deposition of drusen = hall mark risk for AMD

Question 11

What are the genetic effectors of AMD

What are the environmental factors that increase AMD risk

Answer 11

CFH (1q) ARMS2(10q)

Smoking x70 increase

Question 12

Define Penetrance

Answer 12

% with gene who get condition

• modified by genetic variation
• modified by environmental factors

Question 13

What Gatekeepers

Answer 13

Monitor and control cell division, death preventing accumulation of mutations

Question 14

What are caretakers

Answer 14

improve genomic stability (repair mutations)

Question 15

What are landscapers

Answer 15

control surrounding stromal environment

Question 16

A sporadic Defect causes what> and what chance of colorectal cancer?

Answer 16

adenomatous polyp

5% risk

Question 17

A Gate keeper Defect causes what> and what chance of colorectal cancer?

Answer 17

Multiple adenomatous polyps
>95% risk
FAP

Question 18

A Caretaker Defect causes what> and what chance of colorectal cancer?

Answer 18

andenomatous polyp
70% risk
HNPCC

Question 19

a landscaper defect causes what and what chance of colorectal cancer

Answer 19

Hamartomatous polyps

10-20% cancer

Question 20

What are tumor suppressor genes

Answer 20

protect cells from becoming cancerous
loss = inc risk cancer
APC, BRACA1/2, TP53, Rb

Question 21

What are oncogenes

Answer 21

Regluate cell growth and differentiation
gain of function = cancer risk inc
growth and signal transduction factors, RET gene

Question 22

what rule do most cancers obey

Answer 22

Knudson’s two hit hypothesis
Recessive at celluar level
Autosomal dominant inheritance

Question 23

examples of cancers that follow an autosomal recessive inheritance pattern

Answer 23

MYH associated polyposis, Fanconi anaemia,

Ataxia telangiectasia

Question 24

name mutation types

Answer 24

splice site mutations
Deletions, duplications
translocation

Question 25

Signs of Sporadic Cancer

Answer 25

Onset older age one cancer in individual unaffected family members cancer type rarely genetic - lung, cervix etc

Question 26

Signs of familial cancer

Answer 26

onset younger age multiple primaries in individual family members affected same type/genetically related cancers

Question 27

Explain Retinoblastoma

Answer 27

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

Question 28

FAP Familial Adenomatour Polyposis

Answer 28

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

Question 29

HNPCC Hereditart Non polposis colorectal cancer

Answer 29

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

Question 30

BRCA1/2 genes

Answer 30

involved in DNA repair autosomal dominant inheritance 80% risk breast cancer BRCA1 40% BRCA2 - 20%

Question 31

Li Fraumeni syndrome

Answer 31

``` P53 mutations (RARE) autosomal dominant 50% risk cancer by 40yo 100% lifetime avoid radiotherapy - inc cancer risk poor prognosis ```