Tumours 5 Flashcards
what are 6 disorders of cell growth?
- tumour suppressor genes affected (anti-oncogenes)
- inherited factors in carcinogenesis
- oncogens
- viral carcinogenesis (HIV)
- precursors of cancer
- multistep process of tumour development
what 3 factors stimulate carcinogenesis?
- geographic and environmental factors
- age
- genetics/ heredity
On a molecular basis, what are the 2 genes which undergo disruptions of its normal regulatory genes?
- tumours suppression genes (anti-oncogenes)
2. proto-oncogenes
what do tumour suppressors do? what 2 cellular processes do they regulate?
Inhibit abnormal cell growth (genes regulate apoptosis and halt cell division for DNA repair)
what are proto-oncogenes?
Normal genes which promote normal cell growth and mitosis
what are the genes which negatively regulate mitosis?
pRb
before normal cell transforms to a cancer cell, how many mutations are needed?
several mutations (MANY)
what are the 3 key events which occur in tumour formation?
- uncontrolled cell proliferation
- cell cycle dysregulation
- loss of tumour suppressor gene function
what is a retinoblastome gene?
A tumour suppressor (anti-oncogene)
What do mutations in the Rb gene favour?
Cell proliferation (excessive cell division)
Mutations where else mimic the effect of pRb loss?
Mutations in other genes controlling pRb phosphorylation
what are the mutations of the other genes which control pRb phosphorylation?
- mutational activation of cyclin D or CDK4
2. mutational inactivation of CDKIs also drive proliferation
what does pRb on its own act as in the cell cycle?
cell cycle “brake”
what does absent or inactive pRb lead to?
cell cycle brake being released (stimulating cell proliferation)
In what 2 ways can mutations occur in tumour suppressors (anti-oncogenes) such as retinoblastomas?
- somatic (spontaneous)
2. inherited
What is the “two-hit hypothesis” of oncogenesis?
- Inherited form: one defected copy of pRb and somatic point mutation of other copy occurs
- Sporadic form: both hits occur in a SINLGE cell
Loss/inactivation of both normal allelic copies of pRb gives a rise to what?
cancer
what percentage of cancers does heredity account for?
5-10%
What are 3 heredity factors which can be inherited resulting in cancer?
- inherited cancer syndromes
- familial cancers
- autosomal recessive syndromes of defective DNA repair
What does inherited cancer syndrome indicate about family history?
Strong family history of UNCOMMON and SITE SPECIFIC cancers
What type of inheritance needs to occur to inherit a cancer syndrome?
autosomal dominant inheritance of a single mutant gene
what are 5 of the most common inherited cancer syndromes?
- Familial retinoblastoma
- familial adenomatous polyposis of colon (FAP)
- multiple endocrine neoplasia
- neurofibromatosis
- Van-Hippel- Lindau syndorme
What are 3 main characteristics of familial cancers? (family clustering of cancers bud individual predisposition is unclear)
- multifunctional inheritance
- early age of onset
- multiple/bilateral tumours
What are 3 main familial cancers?
- some breast cancers
- some ovarian cancers
- non- FAP colon cancers
what is the function of APC gene?
involved in signal transduction (polarising the cell) and controls cell-cell adhesion/attachment
where does the somatic mutation occur in APC gene? (4)
- gastric
- colon
- pancreas
- melanoma
what is the inherited mutation from an APC mutation?
FAP colon cancer
what is the function of p.53 gene?
Cell cycle/apoptosis after DNA damage, acts as a tumour suppressor and repairs damaged DNA
Where does the somatic mutation occur in p.53 gene?
occurs in most cancers
what is the inherited mutation form a p.53 mutation?
Li-Fraumeni syndrome: multiple carcinomas and sarcomas
what is the role of Rb gene?
controls and regulates cell cycle
where does the somatic mutation occur in Rb gene? (4)
- retinoblastoma
- colon
- lung
- breast carcinomas
what is the inherited mutation from an Rb mutation? (2)
retinoblastoma and osteosarcoma
what is the function of p16(INK4a) gene?
inhibits CDKs
where does the somatic mutation occur in p16(INK4a) gene? (2)
-pancreatic and oesophageal carcinomas
what is the inherited mutation from a p16(INK4a) mutation?
malignant melanoma
what is the function of BRCA-1/2 genes?
DNA repair
what is the inherited mutation from a BRCA-1/2 mutation? (2)
breast and ovarian cancers
what are proto-oncogenes?
normal genes coding for normal proteins that regulate normal growth
what 3 factors do proto-oncogenes work closely with to regulate a normal cell growth?
- growth factors
- growth factor receptors
- signal transduction
what are onco-genes derived from?
proto-oncogenes
what are oncogenes activated by? (2)
- alteration of proto-oncogene structure (point mutation or chromosome rearrangements and translocations)
- dysregulation of proto-oncogene expression (gene amplification or overexpression)
what are oncoprotein products which are made by oncogenes? (5)
- growth factors
- growth factor receptors
- proteins involved in signal transduction
- nuclear regulatory proteins
- cell cycle regulators
What are the 2 chromosomal re-arrangements which involve translocation and overexpression?
- Burkitt lymphoma
2. Mantle cell lymphoma
what can the chromosome rearrangement involving recombination to form chimeric proteins lead to?
Chronic mueloid leukemia
what happens to the viral genome in viral carcinogenesis?
Virus genome insterts near a host proto-oncogene
where do retroviruses insert their oncogene?
Into host DNA causing cell division
what cancer can HPV cause?
cervical cancer
what cancer can Hepatitis B cause?
liver cancer
what cancer can EBV cause?
Burkitt lymphoma
what 2 bases in DNA are critical cellular targets for damage by radiation and various oxidising and alkylating agents?
Purine and pyrimidine
what are formed when chemical carcinogens and their active metabolites react with DNA to form covalently bound products?
DNA adducts
What can adduct formation at particular DNA sites lead to activation of?
Oncogenes (and suppression of tumour suppressors)
what 2 mechanisms occur in most cancers in terms of genes?
- activation of oncogenes
2. loss of 2 or more tumour suppressors (anti-oncogenes)
What are 3 DNA-damaging environmental agents?
- chemicals
- radiant energy
- viruses
What are the 4 key regulators which are mutated in majority of cancers?
- p16
- cyclin D
- CDK4
- Rb
loss or mutation to which gene allows genetically damaged cells to proliferate forming malignant neoplasms?
p.53
what cell cycle phases play the key role in maintaining a normal cell cycle and are often affected in cancer formation?
G1/S (by binding E2F transcription factors)
More E2F, less pRb= mutations occur (no brake on cell cycle)
