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?

Cancer is a multi-

step process

Proto-Oncogenes and Normal Cell Growth

Tumour Suppressor Genes

Tumour Suppressor Genes

P53

Rb

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.

Rb regulation

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

p53 – guardian of the genome

Cell proliferation

Stimulates DNA repair

Apoptosis

Cellularstress

p53

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

P53 – DNA binding

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

Cancer is a multi-

step process