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

Control of normal cellular Growth & Differentiationmediated by:

Intracellular pathways activated

Activation / Repression of various genes

Growth Factors Growth Factor Receptors Cytokines

Dominant Oncogenes

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

a b c d

a d

a c

b c

b d

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

ActivatingGain in function

Dominant

InactivatingLoss 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-paire.g. G:C to A:T

SHE HAD ONE MAD CAT AND ONE SAD RAT

SHE HAD ONE BAD CAT AND ONE SAD RAT

8 14 8 14

C-myc

IgH

Translocation

Amplification

N-Myc Gene in NeuroblastomaCerbB2 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