L10 - DNA repair genes Flashcards
(20 cards)
how many cancer genes werer identified in 2018
700
give 1 reason why we study cancer
family planning
prohylactic prevention —> angelina jolie removal of breast due to family histoyr with BRACA gene mutation
= high risk of breast cancer
describe 2 methods for cancer genes
Linkagae analysis:
studies inheritance of genetic markers in families with a history of cancer to locate chromosomal regions linked to disease
= which loci/markers are inherited together = narrows down region
Whole genome sequencing:
compare sample vs reference genmome to identify differences in DNA sequence
= identify mutations
what are the 2 classes of predisposing genes
Direct - Prtimary cause of cancer:
- TSGs
- Oncogenes
Indirect - control of DNA damage:
- DNA repair genes
- genes involved in carcinogen metabolism
what is Ataxia telangiectasia
Rare Autosomal recessive disease
ATM mutation - p55 kinase
features of Ataxia telengiectasia
‘Ataxia’ = loss of co-ordination
defeinciecy in immune system –> highly snesitive to UV light
how many people does Ataxia telengiectasia affect
1 in 40,000 births
describe the genetics of Ataxia telengiectasia
mutation in ATM gene
protein phosphoylates p53 when DNA damage is sensed
= AT cells cannot cause cell cycle arrest –> build up of mutations
what is Xeroderma pigmentosa
rare autosomal recessive disease
involves genes in DNA excision repair
features of Xeroderma pigmentosa
dwarfism
intelluctual disability
severe UV sensitivity –> pyrmidine dimers are not removed
= early onset of skin cancers
genetic cause of Xeroderma pigmentosa
mutations in DNA excision repair genes
= damaged DNA such as prymidine dimers are not removed
describe how defects in the BRCA pathway cause Faconi anemia
- BRCA1/2 binds to Rad51 at double strand breaks
- enables strand invasion for homologous recombination
= defects PREVENT repair of ds breaks
= high risk cancer and genomic instability
what is Faconi anemia
rare genetic disorder that increases succeptibility to cancers
= defects in BRCA DNA repair pathway
what is the lifetime risk of getting Breast cancer with BRCA mutations
70%
how do microsateoite regions cause mutations/common site of DNA replication error
microsatelites are short tandem repeated sequences of 1-6 nucleotides
DNA polymerase can ‘slip’ causing INDELS
what is Hereditary non-polyosis colon cancer/lynch syndrome
Autosomal dominant inherited cancer caused by germline mutations in mismatch repair (MMR) genes
= Mutation in MMR genes → defective repair → accumulation of errors in microsatellites
consequence of muated mismacth repair genes in HNPCC/lynch syndrome
TGFβ-Receptor contains
poly-A microsatellite = prone to replication errors
MMR deficiency → frameshift mutations in TGFβR → truncated and nonfunctional receptor
= TGF-β inhibits epithelial cell proliferation and stimulates apoptosis:
Mutant TGF-βR → unregulated cell growth → tumour growth
(also involved in immune tolerance by Tregs)
describe the idea of carcinogen metabolism
Carcinogens are not directly harmful but require activation to become DNA-damaging agents
= Cytochrome P450 (CYP) enzymes convert procarcinogens → ultimate carcinogens
name the typoe of enzymes that metabolically activate carcinogens
Cytochrome P450 - CYP
= different speeds of metabolisation depending on indivdual
describe ‘initiation’ and ‘promotion’ in Chemical Carcinogenesis
Initiation:
cell aquires potential cancer driver mutation
Promotion:
changes in environment/particular carcinogen introduced provide cells with driver mutation a slective advantage
–> clonal expansion –> outgrowth of ‘normal’ cells and conversion to invasive malignant carcinoma = metastasis
