Download 4. Molecular Pathology – general principles - UQMBBS-2013

Survey
yes no Was this document useful for you?
   Thank you for your participation!

* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project

Document related concepts
no text concepts found
Transcript
Molecular Pathology – Cell cycle
Dr. Leonard Da Silva
Senior Lecturer
Molecular & Cellular Pathology
Molecular Pathology
• study and diagnosis of disease 
molecules  organs, tissues or fluids
• anatomic pathology, clinical pathology,
molecular biology, biochemistry,
proteomics and genetics
Tissue sources
Time Line
• 1902 Boveri – abnormal chromosomal
segregation
• 1960’s Philadelphia Chromosome
• 1970’s – oncogenes – 2 hit hypothesis
• 1980’s cloning of RB
• 1990’s BRCA1/2
• 2000 Human genome
Grade, Stage & Prognosis
Cancer As A Disease Of Genetic
Material
 Heritable predisposition - Retinoblastoma

Chromosomal Abnormalities - Burkitt’s
 Rare genetic disorders have inability to repair DNA e.g.
Xeroderma pigmentosa

Many chemical carcinogens are also mutagens

Transfer of DNA from tumour cells to normal cells leads
to transformation
Cancer Producing Genes
Any mutated gene that contributes to neoplastic transformation
• Oncogenes
• Tumour suppressor genes
• Stability/DNA repair genes
Dominant Oncogenes
Identified as transforming genes in viruses
Altered forms of normal cellular genes - Proto-oncogenes
Products of oncogenes involved in:
- Cell cycle
- Cell division
- Differentiation
This maintenance is lost in cancer cells
Dominant Oncogenes
Control of normal cellular Growth & Differentiation
mediated by:
 Growth Factors
 Growth Factor Receptors
 Cytokines
Intracellular pathways activated
Activation / Repression of various genes
Examples of Dominant Oncogenes
abl
CML
translocation
bcl2
Follicular Lymphoma
translocation
erbB-2
Breast/ovarian carcinoma
amplification
c-myc
Burkitt’s lymphoma
translocation
ras
Thyroid /Colon carcinoma point mutation
ret
Thyroid carcinoma
Rearrangement
Tumour Suppressor Genes
 Loss of function
 Familial Syndromes
- Retinoblastoma
- Familial Adenomatous Polyposis
ab
cd
ac
ad
bc
bd
Retinoblastoma
Examples of Tumour Suppressor Genes
APC
Colon Cancer
BRCA1
Breast & Ovarian Cancer
BRCA2
Breast Cancer
NF1
Neurofibromatosis (malignant neurofibromas)
TP53
Brain, Breast, Colon, Liver, Lung carcinomas
RB
Retinoblastoma, Sarcomas, Bladder
WT1
Wilm’s tumour
Dominant
Oncogenes
Tumour Suppressor
Genes
Enhanced
Reduced
Activating
Gain in function
Dominant
Inactivating
Loss of function
Recessive
DNA REPAIR
• Homologous recombination (HRR)
• Non-homologous end joining (NEHJ)
• Nucleotide excision (NER)
• Base excision (BER)
• Mismatch Repair (MMR)
Mechanism of Mutations
 Point Mutations
 Amplification
 Translocation / Rearrangements
 Deletions
 Altered Expression
Point Mutation
Change in single base-pair
e.g. G:C to A:T
SHE HAD ONE MAD CAT AND ONE SAD RAT
SHE HAD ONE BAD CAT AND ONE SAD RAT
Translocation
IgH
C-myc
8
14
8
14
Amplification
N-Myc Gene in Neuroblastoma
CerbB2 gene in Breast Cancer
HER2 amplified
HER2 non-amplified
Acquired from Vysis Educational Slide Set
Deletions
Tumour suppressor genes
e.g. retinoblastoma
Which cell does cancer arise in?
MULTISTEP MODEL OF CARCINOGENESIS
Principles of mammographic screening
Cell cycle
• The cell cycle is an ordered set of events
The cell cycle
Key regulators
• Cdk (cyclin dependent kinase, adds
phosphate to a protein), along with cyclins,
are major control switches
Master regulators
Checkpoints
P53 and cell cycle
• p53 is a protein that functions to block the cell cycle if
the DNA is damaged. If the damage is severe this
protein can cause apoptosis (cell death).
• p53 levels are increased in damaged cells. This allows
time to repair DNA by blocking the cell cycle.
• A p53 mutation is the most frequent mutation leading to
cancer  Li Fraumeni syndrome, where a genetic a
defect in p53 leads to a high frequency of cancer in
affected individuals.
HPV pathogenesis
HPV pathogenesis
cell cycle <=> patient care