cancer detection and diagnosis
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Cancer Detection and Diagnosis
Early Cancer May Not Have Any symptoms
Pap Test
Mammograms
Mammograms
Mammograms Mammograms Mammograms Blood tests
Prostate-specific antigen (PSA)Carcinoembryonic antigen (CEA)Fecal Occult Blood Test (FOBT)
TISSUEBIOPSY
Tumour grading
Microscopic examination - - likely behavior- responsiveness to treatment.
"grade"
a low number grade (grade I or II) refers to cancers with fewer cell abnormalities than those with higher numbers (grade III, IV).
Tumour Staging
1. How large is the tumour, and how far has it invaded into surrounding tissues?
2. Have cancer cells spread to regional lymph nodes?
3. Has the cancer spread (metastasized) to other regions of the body?
RetinoblastomaRare childhood cancer of the eye that develops in children,
typically under five years old.
Incidence• 2 % of childhood malignancies
Influencing factors
30-40% hereditary
60-70% sporadic
Treatment
Surgery, radiation, chemotherapy
Retinoblastoma protein (pRb) • Normally inhibits cell proliferation • localised in the nucleus• tumour suppressor protein of ~110kD• pRb has > 10 phosphorylation sites (affects protein-
protein interaction)• Rb gene is 300kb long & mutations in this gene leads to
loss of function. • Most mutations involve gross chromosomal changes in
the 3kb coding region and 1/3 are point mutations. • Loss of heterozygosity at chromosome 13q14.2.
Initially identified as a tumour
specific nuclear antigen with a
Mol wt of 53kDa
Comparison with normal cells
showed the presence of
mutations in cancer cells
When wild-type gene
transfected into tumours, it
stopped their growth
i.e. a tumour suppressor gene
p53 – guardian of the genome
p53 – guardian of the genome 50% of all cancers show mutations in p53 90% mutations in Squamous Cell Carcinoma (SCC) 80% point mutations and 20% truncations Mutations cause loss of function Leads to continued cell division despite having DNA damage Leads to increased mutation rate
Wild typemutant
DNA binding
P53 – domain structure
1 393
Transactivationdomain
300200100
Tetramerformation
Autoinhibition
DNA binding
P53 – Transcriptional activation
Transactivationdomain
Tetramerformation
Autoinhibition
stimulates transcription indirectly by binding to other nuclear proteins
e.g.Mdm2, GADD45, Cyclin G, BAX, IGF –BP3
P53 – transcriptional activation
Mdm2
transcription degradation
Mdm2
ARFP
Cell proliferationDNA damage
DNA binding
P53 – DNA binding
Transactivationdomain
Tetramerformation
Autoinhibition
Sequence specific DNA binding:
Certain genes have a p53 response element that specifically binds to the p53 tetramer e.g. BAX, p21
P53 – mutational hotspots
The C-terminal regulatory domain has 2 functionsNegative regulation: Phosphorylation destabilises the folding
of the DNA binding domainPositive regulation: Acetylation of the C-terminus of DNA-
bound p53 stabilises p300 binding, which is required for p53 driven transcription
DNA binding
P53 – tetramer formation
1 393
Transactivationdomain
300200100
Tetramerformation
Autoinhibition
DNA binding
P53 – Autoinhibitory domain Transactivation
domainTetramerformation
Autoinhibition
Causes transcriptional repression
e.g. JUN, FOS, PCNA, MYC, BCL2 genes
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