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/ 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 & Differentiation mediated by: Intracellular pathways activated Activation / Repression of various genes  Growth Factors  Growth Factor Receptors  Cytokines Dominant Oncogenes

Examples of Dominant Oncogenes abl CML translocation bcl2Follicular Lymphoma translocation erbB-2 Breast/ovarian carcinoma amplification c-mycBurkitt’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 bc d a d a c b c b d Retinoblastoma

Examples of Tumour Suppressor Genes APCColon Cancer BRCA1 Breast & Ovarian Cancer BRCA2 Breast Cancer NF1Neurofibromatosis (malignant neurofibromas) TP53Brain, Breast, Colon, Liver, Lung carcinomas RB Retinoblastoma, Sarcomas, Bladder WT1Wilm’s tumour

Dominant Oncogenes Tumour Suppressor Genes EnhancedReduced 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

8148 C-myc IgH Translocation

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

cell cycle patient care