Carcinogenesis (UNFINISHED) Flashcards
What are the 6 main categories of human carcinogens?
- chemicals
- infectious agents
- radiation
- minerals
- physiological
- chronic inflammation
What does genotoxic mean?
can chemically modify or damage DNA (initiators)
What does it mean if a carcinogen in ‘complete’?
it can initiate and promote
Give an example of a complete carcinogen?
UV light
What does initiation require?
- chemical modification of DNA
- replication of modified DNA and mis-incorporation of DNA polymerase
What are the 2 main functions of promoters?
- stimulate 2 rounds of DNA replication necessary for mutation fixation
- stimulate clonal expansion of mutated cells
What is the most common TSG inactivation event?
gene promoters can become abnoramlly methylated
What is the consequence of mutations in oncogenes?
gain of function
What is the consequence of mutations of TSGs (tumour suppressor genes)?
loss of function
What common mutations occur in oncogenes?
base pair substitutions, amplification, translocations, inversions
Are oxygen radicals, nitrosomines, UV light and ionising radiation examples of direct acting carcinogens or procarcinogens?
direct acting
Define procarcinogen
require enzymatic (metabolic) activation before they react with DNA
What can inherited defects in the nucleotide-excision repair pathway lead to?
Xeroderma pigmentosum - group of rare autosomal recessive inherited disorders characterised by extreme skin sensitivity to UV light, high frequency of skin cancer and abnormal pigmentations
What is ataxia telangiectasia?
an autosomal recessive disorder due to inherited defects in ATM gene (involved in recombinational repair pathway) and leads to 100-fold increase in rate of cancer
What is the common cause of HNPCC?
,mutations in one of the several mismatch-repair genes
How many carcinogens can be identified in tobacco smoke?
19
What is the active form of propcarcinogen in alcohol?
acetaldehyde
What are all of the strongest risk factors for breast cancer associated with increased exposure to?
oestrogen
How is chronic inflammation linked to cancer?
- DNA damage from release of free radicals by immune cells = INITIATION
- Growth factor induced cell division to repair tissue damage = PROMOTION
What is the role of caretaker genes?
maintain genetic stability by replacing damaged DNA and replication errors
What is the role of gatekeeper genes?
- negative regulation of cell cycle proliferation
- positive regulation of apoptosis
- positive regulation of cell differentiation
Mutations of which gene are associated with retinoblastoma?
RB1 (gatekeeper)
Mutations of which gene are associated with Li-Fraumeni?
p53 (gatekeeper/caretaker)
Mutations of which gene are associated with familial adenomatous polyposis?
APC (gatekeeper)
Mutations of which gene are associated with familial breast cancer?
BRCA1, BRCA2 (caretakers)
Mutations of which genes are associated with HNPCC?
hMLH1, hMSH2 (caretaker)
What is the function of proto-oncogenes?
promote cell proliferation, survival, angiogenesis and negative regulation of apoptosis
For oncogenes, is the mutated or normal gene dominant?
mutated gene is dominant, therefore only 1 copy of the gene needs to be activated to induce gain in function
What are the three main mechanisms of oncogene activation?
transolcation, point mutation and amplification
What ae the 6 main characteristics of cancer cells?
- self sufficiency in growth signals
- insensitivity to antigrowth signals
- tissue invasion and metastasis
- limitless potential for replication
- sustained angiogenesis
- evading apoptosis
Inactivation of which gene is common in tumours resulting in resistance to negative growth regulation?
Rb gene
What gene plays the key role on apoptosis and inherited mutations of this gene causes what familial cancer syndrome?
TP53 - Li Fraumeni
Which adhesion molecuel is commonly abscent from tumours?
E-cadherin
