Tumour precursors, Carcinogenesis and genetic changes Flashcards
What are the most common cancers for males and females?
Female; breast, lung, bowel
Male; prostate, lung, bowel
How long does cancer take to develop?
Different cancers have different mutation rates, with defective DNA repair, UV and smoking associated with the highest levels of mutation
Cancer does not develop suddenly (multiple steps). Changes in the epithelium that precede invasion and metastasis
What is the evidence of precursors?
Changes in architecture of epithelium
Cytological morphology of the cells that precede invasion and metastasis
What are the precancerous stages of cervical cancer described as?
(and the vulva, anus, skin & bronchus) intra-epithelial neoplasms or intra epithelial lesions (also called severe dysplasia or carcinoma in situ for high grades).
What are the precancerous stages called/ what are they?
Abnormal neoplastic cells not invaded (benign)
Epithelial side of basement membrane- intra-epithelial
- Cervical Intra-epithelial Neoplasia (CIN – UK & Europe)
- Squamous Intra-epithelial Lesions (SIL – in USA) Spectrum: low grade to high grade
What are the cytological features of neoplasia?
(Intra-epithelial neoplasms have a proliferating epithelium)
- abnormal nuclei (pleomorphism & hyperchromasia)
- abnormal mitosis
- loss of nuclear polarity- now vertically orientated
- loss of differentiation.
What tests are done for cervical cancer screening?
Pap smear, Liquid Based Cytology
What is Ductal Carcinoma In Situ (DCIS)?
Excess numbers of neoplastic epithelial cells larger than normal with a range of nuclear cytological abnormalities build up within enlarged ducts or groups of small ducts, causing them to dilate (breast)
What is an adenoma (intestine)?
Intra-epithelial phase preceding adenocarcinoma of colon/ rectum- 90%, also known as polyps
dysplastic glandular epithelium and this is graded into low grade or high grade dysplasia
Invasive cancers develop from adenoma; “adenoma-carcinoma” sequence
How do neoplasms occur?
result of the escape of tumour cells from the normal homeostatic mechanisms that control the maintenance of organ and tissue architecture and function
-corruption or breakdown of them results from loss or errors in key controls and the downstream effects from this
How do mutations lead to neoplasms?
- The “errors” are direct damage to DNA – mutations
- The targets for mutations are genes controlling proliferation and genomic stability
- The transition from a normal growth controlled cell through to a malignant cancer cell requires several mutations
What are Carcinogens/oncogens?
agents which induce cancer in man or animals
What is Carcinogenesis/Oncogenesis?
the process of cancer induction
What are the classes of carcinogens?
Chemical - synthetic or naturally occurring molecules
Physical- UV or ionising radiation
Biological- Viruses, bacteria, parasites
How do we study cancer progression?
- Animal models of carcinogenesis
- In vitro carcinogenesis - transformation
- Replicative Senescence, Immortalisation & Telomeres
- Inherited cancers in humans
- Molecular genetic analysis of cancers and their precursor lesions
What concepts of carcinogenic activity was defined by animal models in the early 1900’s?
(a) Dose response- linear relationship between the amount of carcinogen in single dose and number of tumours which develop
(b) Latent period- time lag between administration of carcinogen and appearance of macroscopic tumours.
Length is dose-dependent – high reduce, low extend
(c) Threshold dose- below which no tumours form Secondary non-carcinogenic growth-promoting stimulus (e.g. wounding, chemicals such as Phorbol Esters)- subthreshold dose of carcinogen, then tumours develop.
(d) Initiation and Promotion
What is initiation?
the alteration of a normal cell to a potentially cancerous cell
Carcinogens cause this and it is irreversible
Carcinogens are mutagens.
What is promotion?
a process which permits the clonal amplification of the initiated cell.
Promoters are NOT carcinogens, they induce proliferation (“fix the mutation”- make mutation permanent). A benign neoplasm (e.g. papilloma) forms.
What is progression?
acquisition of further mutations within the neoplastic clone drive progression to a malignant neoplasm.
Describe in-vitro carcinogenesis/ the transformation assay
Monolayer of growth controlled cells treated with carcinogen, cellular transformation pile up in focuses, treated with serum, can grow in suspension, acquired features of neoplasm- behaviour and phenotype
What is replicative senescence of primary diploid cells?
Cells can only undergo a defined number of cell divisions in tissue culture - the Hayflick number
Cell cycle arrest- held in G0- die by apoptosis
How do cells become immortal?
Escape senescence at low frequency
Rare and spontaneous in long-lived animals
The viral oncogenes of DNA tumour viruses eg SV40 T, adenovirus E1A and E1B, HPV 16 E6 and E7, can immortalize primary human cells (chemical carcinogens rarely do so)
What are telomeres?
Repetitive sequences (TTAGGG) at ends of chromosomes, Form loops to protect chromosome ends (not appear as DNA d/s breaks – causing end-end fusions) 3 prime overhang invades into double strand
What are the problems with semiconservative replication?
Never fully replicates entire chromosome, gene shortening, last okazaki fragment not synthesised
How to telomeres replicate?
Clock mechanism- Expression of telomerase enzyme, binds to repetitive sequence allows enzyme to fully replicate, uses Telomerase RNA and primer
Describe the Telomere hypothesis of replicative senescence
Telomerase OFF- somatic cells, telomere length reduced
Telomerase ON- germ and stem cells, length maintained
Describe the progression of telomeres in cancer
Telomere length decreases until too short (crisis)- induction of telomerase 90% active in cancers- immortalisation
How does telomerase affect the hierarchy of cells?
•Stem cells express telomerase
•Transit-amplifying progenitor cells have a programmed
decline in replicative capacity (no telomerase)
•replicative senescence is one of the strict controls
that minimise the chances of cells escaping mechanisms that restrict proliferation
Can cancer be inherited?
In rare instances tumour mutations can be inherited in the germ line giving rise to an inherited predisposition to a particular cancer
What is retinoblastoma?
cancer of retinoblasts with a peak incidence at 3-4 years of age both sporadic (no family history) and inherited
What is the Knudson 2 step mutational process?
Inherited: (1) pre-zygotic mutation, (2) post-zygotic mutation (bilateral)
Sporadic: (1) & (2) both steps post-zygotic (acquired)- unilateral- in same cell
mutations affect the 2 alleles of the gene RB1, loss of heterozygosity
Examples of syndromes in which the heterozygotes express the tumour phenotype
Retinoblastoma- RB1- Cell cycle checkpoint control
Familial adenomatous polyposis coli - APC- Signal transduction
Li Fraumeni- p53 or TP53- Cell cycle control/DNA damage
Hereditary non polyposis colon cancer/ Lynch- MLH1,MSH2- DNA Mismatch repair
Familial breast and ovarian cancer- BRCA-1, BRCA-2, DNA repair – d/s break
Basal cell naevus - Ptch - Signal transduction
Examples of syndromes in which the homozygotes express the tumour phenotype
Ataxia telangiectasia- AT- Checkpoint control/ DNA repair
Blooms- BI- DNA Helicase
Fanconi’s anaemia- FA- DNA repair (crosslink repair)
Xeroderma pigmentosum- XP- DNA repair (Excision)
What do studies of inherited cancer tell us?
Cancer is a genetic disease – the initiating event
is a somatic mutation in a single cell
More than one mutation is necessary for progression
Maintaining error free DNA is crucial
Controls restricting cellular lifespan must be overcome
for tumour progression
Cancer is a multi stage process
What genes are targeted for mutation in cancer?
• Genes that control: Cell proliferation, Cell death, Signalling to other cells from other cells to the matrix from the matrix
• Genes that maintain tissue organisation and architecture: Cell movement, Cell adhesion
• Genes that maintain genetic stability / genomic integrity
Tumour Suppressor Genes, Oncogenes
