Under construction-more colour OHTs to come...
  
  Dr. R.Barnard



     RECOMMENDED READING:

1. Ponder, B. (1997) Genetic testing for cancer risk. Science 278, 1050-1054.

2. Sidransky, D. (1997) Nucleic acid-based methods for the detection of cancer. Science 278, 1054-1058.

3. Fearon, E.R. (1997) Human cancer syndromes. Clues to the origin and nature of cancer. Science 278, 1043-1048.

4. Lu, R. et al. (1997) A mammalian DNA repair enzyme that excises oxidatively  damaged  guanines maps to a lesion frequently lost in lung cancer. Current Biology 7, 397-407




  
KEY LECTURE POINTS:

Cancer is a common disease and its incidence is increasing.

Possible reasons for latter observation.


CANCER IS A CONSEQUENCE OF ACCUMULATED DNA DAMAGE (MUTATION) 

     CATEGORIES OF DNA MUTATIONS

1) Acquired or somatic mutations
-environmental agents or spontaneous mutation.
2) Inherited or germline mutations
eg. BRCA-1,BRCA-2, APC. 

CANCER CAUSING MUTATIONS INVOLVE  DAMAGE TO THREE CLASSES OF GENES ENCODING:

1) proteins in signal transduction pathways.
 ras, TGFb.  
2) proteins controlling cell cycle arrest and progression. 
p53, APC, telomerase, ATM
3) proteins required for DNA repair 
MSH-2, HOGG-1 

4) others  - undiscovered





















CURRENT or OLDER  DIAGNOSIS METHODS:

1. detection of rectal bleeding.
false +>70%; only tumours greater than 2 cm

2. per rectum  digital examination.
limited by length of finger.

3. sigmoidoscopy-invasive, expensive, often used as a follow up to other signs or elevations in biochemical markers.

4. biochemical markers of cancer:
CEA, APRP, serum hexose, serum copper.
 
THE BEST METHOD OF EARLY CANCER DETECTION WILL BE THE SIMULTANEOUS USE OF MULTIPLE  GENETIC MARKERS

 Current approaches to DNA based diagnosis of colon cancer:

-detection of mutations in DNA of cells sloughed off colonic epithelium into faeces.

-the premise is that the mutations present in the faeces provide a reliable indicator of mutations that are present at an early stage of growth.

MUTATION ENRICHMENT METHODS,


-allele specific PCR

-PNA clamping/PCR




-restriction enrichment/PCR

-magnetic beads/PCR

POST-ENRICHMENT CONFIRMATION OF SEQUENCE:


-FIRST NUCLEOTIDE CHANGE

-MISMATCH RESOLVASE CLEAVAGE/GEL

-DIRECT SEQUENCING/GEL

-SSCP/GEL

-HYBRIDIZATION METHODS-(SNAAC)
-(ASO)