Tumour Pathology 5 Flashcards
What influences disorders of cell growth?
- Tumour suppressor genes
- Inherited factors in carcinogenesis
- Oncogenes
- Viral carcinogenesis
- Precursors of cancer
- Multistep process of tumour development
What influences carcinogenesis?
- Geographic and environmental factors
- Age
- Hereditary
What are proto-oncogenes?
-Normal genes that promote normal cell growth and mitosis
What are tumour suppressor genes?
Normal growth inhibiting genes
What do tumour suppressor genes include?
- Genes negatively regulating mitosis-Rb
- Genes regulating apoptosis
- Genes regulating DNA repair
What usually happen to tumour suppressor genes before a normal cell transforms into a cancer cell?
A series of several mutations
What is a key event in tumour formation?
Uncontrolled cell proliferation via cell cycle dysregulation via loss of tumour suppressor gene function
What is the retinoblastoma gene?
An anti-oncogene
What do Rb gene mutations favour?
Cell proliferation
What mimics the effect of pRb loss?
Mutations in other genes controlling pRb phosphorylation
- Mutational activation of cyclin D or CDK4
- Mutational inactivation of CDKIs also drive proliferation
What releases the cell cycle brake?
Absent or inactive pRb
What has to happen to tumour suppressor genes for cancer to arise?
There must be loss/inactivation of both normal allelic copies
Describe the 2 hit hypothesis in the inherited and sporadic forms of anti-oncogenes such as Rb.
Inherited form -One defective inherited copy of pRb -Somatic point mutation of other copy Sporadic form -Both hits occur in a single cell
What chromosome contains the defective inherited copy of pRb?
13q14
How can carcinogenesis be hereditary?
- Inherited cancer syndromes
- Familial cancers
- Autosomal recessive syndromes of defective DNA repair
Describe inheritance of cancer syndromes?
- Strong family history of uncommon site-specific cancers
- Autosomal dominant inheritance of a single mutant gene
Give examples of inherited cancer syndromes?
- Familial retinoblastoma
- Familial adenomatous polyposis of colon
- Multiple endocrine neoplasia
- Neurofibromatosis
- Von Hippel-Lindau syndrome
Describe familial cancers.
- Family clustering of cancers but individual predisposition unclear
- Multifactorial inheritance
- Early age of onset
- Multiple/bilateral tumours
Give examples of familial cancers.
- Some breast cancers
- Some ovarian cancers
- Non-FAP colon cancers
What are oncogenes?
Cancer causing genes derived from proto-oncogenes
How are oncogenes activated?
Alteration of proto-oncogene structure
-Point mutation
-Chromosome rearrangements and translocations
Dysregulation of proto-oncogene expression
-Gene amplification
-Overexpression
What do oncogenes generate?
Active oncoprotein products
Give examples of active oncoprotein products.
- Growth factors
- Growth factor receptors
- Proteins involved in signal transduction
- Nuclear regulatory proteins
- Cell cycle regulators
What are 2 exampled of cancer which can arise as a result of overexpression of oncogenes?
- Burkitt lymphoma: C-myc moves close to IgH gene
- Mantle cell lymphoma: cyclin D1 gene to IgH
Give an example of a cancer that results due to recombination to form chimeric proteins.
Chronic myeloid leukaemia
What DNA viruses are known to cause cancer in humans?
- HPV (cervical cancer)
- Hepatitis B (liver cancer)
- EBV (Burkitt lymphoma)
What are the different mechanisms or viral carcinogenesis?
- Virus genome inserts near a host proto-oncogene
- Viral promoter or other transcription regulation elements cause proto-oncogene over-expression
- Retroviruses insert an oncogene into host DNA causing cell division
What is a DNA adduct?
A chemical carcinogen or their active metabolite which reacts to form covalently bound products
How does chemical carcinogenesis work?
DNA adduct formation at particular chromosome sites lead to activation of oncogenes and suppression of anti-oncogenes
Why is carcinogenesis considered a multistep process?
- All sporadic cancers harbour multiple genetic aberrations
- Abnormalities accumulate with time
- Activation of several oncogenes and loss of 2 or more anti-oncogenes occurs in most cancers
What are the key regulators in cancer?
- p16
- cyclin D
- CDK4
- Rb
- In the majority of cancers these are mutated
