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
How does p53 work with mdm2?
Mdm2 degrades p53
Normal cells p53 is low
Mutant p53 - decrease mdm2 so p53 degradation decreases
What is the function of RET?
Encodes receptor tyrosine kinase
Binds GDNF
Mutations cause it to be constitutively active
What diseases are caused my germline missense mutations in RET?
MEN2A (multiple endocrine necrosis 2A)
MEN2B
FMTC (familial medullary thyroid carcinoma)
Autosomal dominant syndromes that map to same region of chr10q
What are the symptoms of MEN2A?
Thyroid cancer
Parathyroid cancer
Pheochromocytoma - benign tumour of adrenal medulla which increases Bp by releasing high spikes of adrenaline.
What are the symptoms of MEN2B?
Like 2A but no parathyroid hyperplasia
Ganglioneuromas
What are the symptoms of FMTC?
Thyroid cancer
What is MET?
Encodes receptor tyrosine kinase
Binds hepatocyte growth factor
Chr7q
What disease is caused by germline missense mutations in MET?
Hereditary papillary renal carcinoma
Mutations homologous to RET mutations
Somatic mutations in kidney cancer
What is KIT?
Encodes tyrosine kinase receptor for stem cell factor
Important in development
Somatic and germline mutations in gastrointestinal stromal tumours
What is ALK?
Encodes tyrosine kinase receptor
Unknown ligand
Somatic and germline mutations in neuroblastoma - childhood cancer
What is CDK4?
Proto-oncogene Phosphorylates RB1 Involved in S phase entry p16 (TSG) inhibits Mutations cause familial melanoma
Why is the RAS pathway important?
Activates cell signalling pathways
If mutated causes cancer(k-ras), facial and heart defects, developmental abnormalities
What indications are needed to screen for an inherited predisposition to cancer?
Family history
Early onset tumours / multiple tumours
Abnormalities
What tests are used to screen for cancer?
Karyotype- rare to get cytogenetic abnormalities
Sequence gene - known mutation
Normally point mutations that can’t be seen by microscope
What are the benefits of screening for cancer?
Early screening
Genetic counselling
Prenatal diagnosis
How is gene expression used to diagnose tumours?
Expression profiling using microarrays - screen whole genome for gene expression to see patterns of tumours
Expression profiling using 2nd generation sequencing - shoes small RNA sequences, looks at all transcripts
How are chromosome translocations used to diagnose tumours?
Many cancers have specific translocations
Used fusion protein to fuse together path of two genes to make a novel protein - chronic myelogenous leukaemia 9:22 translocation
How are immunoglobulin and T cell receptor rearrangements used to diagnose tumours?
Monoclonal rearrangements indicate leukaemia or lymphoma
Leukaemia is a clone of B/T cells - pick up using FISH
How is whole genome sequencing used to diagnose tumours?
2nd generation sequencing to detect all mutations and chromosome rearrangements
Widely used
Shows which genes are most highly mutated in certain cancers
Why is knowing the prognosis of cancer important?
How tough does treatment have to be?
Gene amplification - multiple copies shows as homologous staining regions….used as way of deciding treatment
Residual disease - immunoglobulin and T cell receptor clonal rearrangements can detect residual leukaemia cells in bone marrow - lower detection limit to determine if disease has actually gone.
Expression profiling using microarrays and RNA-seq
Why are microarrays used?
Shows which genes are more highly expressed
How is a microarray done?
Make cDNA
Label
Hybridise to microarray
How is a RNA-seq done?
Library of cDNA
short sequence repeats
Align
Allows tumours to be divided into subgroups for prognosis deepening
What is used to look for gene amplification?
Southern blotting
How is gene therapy used to treat cancer?
TSG replacement
Antisense RNA to oncogenes
RNA interference - gene missing that interacts with p53
Possible but not used
How can our knowledge of p53 be used to treat cancer?
Use anti-p53 virus that selectively kills cells with mutant p53
How can drugs be used to treat cancer?
Gleevec inhibits bcr-Abl kinase in CML
Gefitnib inhibits EGFR in lung cancer
Only work if patient has corresponding molecular defect
