Genetics Of Cancer Flashcards
What are the features of genetic predisposition?
Family history
Early onset cancer
Multiple cancers - bilateral organs
Other abnormalities - DNA repair deficiency
What percentage of cancers are sporadic?
95% from somatic mutations
How are predisposing genes cloned?
Conventional positional cloning - linkage analysis
- chromosomal abnormalities
- allele loss studies
- whole genome sequencing
What types of predisposing genes have indirect involvement in cancer?
DNA repair genes
Those involved in carcinogen metabolism
What type of predisposing genes have a direct involvement in cancer?
Tumour suppressor genes
Proto-oncogenes
What are the features of ataxia telangiectasia?
Rare autosomal recessive
Ataxia
Telangiectasia- dilated capillaries at body surfaces
Immune deficiency
Sensitivity to ionising radiation
Predisposition to leukaemia and lymphoma
Heterozygotes have increased cancer risk - don’t manifest AT symptoms
What is the gene affected in AT?
ATM
Senses changes in chromatin structure when DNA damaged
Phosphorylates p53 after damage
AT cells cannot arrest cell cycle in response to DNA damage
What are the features of Xeroderma pigmentosa?
Rare, autosomal recessive Dwarfism Mental retardation Blindness and deafness Severe UV sensitivity - develop cancer of every sun exposed part of body
What genes are affected in XP?
Involved in DNA excision repair
Mutations in any of 7 genes
Two thymines combine to form a big lesion
What are the features of Bloom syndrome?
Rare autosomal recessive
Leukaemia and lymphoma
DNA helicase deficiency
Chronic lung disease and diabetes
What are the features of Fanconi anaemia?
Rare autosomal recessive Anaemia Mental retardation Skeletal abnormalities Leukaemia 12 genes involved in regulation of DNA repair by homologous recombination
What is homologous recombination?
Repairs DNA damage
Uses opposite strand as template to check for damage
When it goes wrong - cancer
What is BRCA likely to cause if mutated?
Inherited breast cancer
One mutant copy needed
Susceptibility to childhood cancer depending on how mutation is inherited
Can also cause Fanconi anaemia due to a mutation
What is mismatch repair?
A DNA repair system whereby one member of a mismatched pair of bases is converted to the normally matched base.
What are the features of hereditary non-polyposis colon cancer?
Autosomal dominant
Early onset colon cancer
Few adenomas
Mutations in mismatch repair genes
What is carcinogen metabolism?
Body metabolises compounds to get rid of them - some carcinogens activated by this
Cytochrome P450-dependent enzymes involved
Can measure activity of CYP2C9 by ability to hydroxyl ate debrisoquine
Rapid metabolisers may have increased cancer risk
What is retinoblastoma?
Childhood eye tumour 1:20000 incidence Autosomal dominant but gene is recessive Hereditary Knudsons 2 hit theory
What is knudson’s two hit theory?
Hereditary tumours - first hit germ line (carry mutation in every cell in body), second hit somatic
Sporadic tumours - first hit somatic, second hit somatic
What is the supporting evidence for Knudson’s two hit theory?
First hit usually small point mutation or deletion - second hit is large scale with loss of an allele (loss of heterozygosity) usually by nondisjunction and duplication
Somatic cell hybrids with normal and cancer cell -> nontumorigenic heterokaryon -> loss of specific chromosomes that suppress cancer cells -> tumorigenic revertant
Oncogenes vs TSGs
Oncogenes - gain of function
- dominant mutations (point, amplification, chr translocations)
- mutations rarely inherited
TSGs - loss of function
- recessive mutations (point, deletions, epigenetic silencing)
- many inherited mutations
What is RB1?
Retinoblastoma TSG Mutated in all retinoblastomas and some other cancers Large gene Encodes nuclear phosphoprotein Involved in regulating cell cycle
How can viruses cause retinoblastoma?
E1A (adenovirus), E7 (papilloma virus) and SV40 tag bind to unphosphorylated version of RB1 keeping it in cell cycle
No need for transcription factors
What are the features of Wilm’s tumour?
Childhood kidney tumour
WAGR (Wilm’s tumour, aniridia, genitourinary abnormalities, mental retardation)
11p13 deletion
WT1 gene - TSG encodes DNA/RNA binding zinc finger proteins which have role in regulating transcription
Follow 2 hit theory
What is p53?
Discovered as protein that bound to SV40 T antigen
17p deletion and mutations found in human cancers
Regulates transcription
Increases with DNA damage to arrest G1
High levels in tumours
Functions as tetramer
