Lecture 37: Carcinogenesis: causes of cancer Flashcards
What are Heterocyclic aromatic amines (HAAs)?
HAAs are heat-induced mutagenic agent present in some food products. These can cause single stranded DNA breaks, chromosomal aberrations and DNA adducts in guanine-rich regions.
What are Polycyclic aromatic hydrocarbons (PAHs)?
Combustion of organic matter results in the generation of PAHs resulting in the development of breast, skin or lung cancer. Bioactivation of PAHs results in carcinogenesis mediated by cytochrome P450 enzymes
What is ultraviolet (UV)?
This agent is implicated in the causation of skin tumours by targeting pyrimidine bases.
What is ionizing radiation?
Exposure to ionising radiation induces DNA damage. The carcinogenesis effect promotes the production of reactive oxygenation species resulting in oxidative damage, which can result in single stranded breaks. Direct interaction of electrons with DNA resulting in molecular distortion and double stranded breaks.
What is asbestos?
Asbestos is found in industry and household applications. Damage occurs through oxidative stress, fibrosis and interaction with the mitotic apparatus of dividing cells.
What do carcinogens do?
Carcinogens work by interacting with a cell’s DNA and inducing genetic mutations. A carcinogen is a specific chemical or physical agent that has the ability to cause cancer in individuals exposed to that agent.
What is a carciongen?
an external agent associated with causing cancer
Which organisation classified agents into carcinogen related categories from 1-4?
The International Agency for Research on Cancer (IARC)
What does category 1 of the IARC carcinogen list mean?
carcinogenic to humans
What does category 2a of the IARC carcinogen list mean?
probably carcinogenic to humans
What does category 2b of the IARC carcinogen list mean?
possible carcinogenic to humans
What does category 3 of the IARC carcinogen list mean?
carcinogenicity not classifiable
What does category 4 of the IARC carcinogen list mean?
probably not carcinogenic
Give 3 examples of category 1 carcinogens:
1) tobacco
2) UV light
3) processed meats
Give 2 examples of category 2a carcinogens:
1) red meat
2) working night shifts
Give 2 examples of category 2b carcinogens:
1) radio frequency
2) gasoline
Give 3 examples of category 3 agents listed in the IARC carcinogen list:
1) caffeine
2) cholesterol
3) fluorescent light
What is the main general mechanism of carinogenesis?
DNA damage
What are heterocyclic aromatic amines?
heat-induced mutagenic agents present in some food products
Give 3 ways in which heterocyclic aromatic amines cause DNA damage:
1) single stranded DNA breaks
2) chromosomal aberrations
3) DNA adducts
What are DNA adducts?
covalent modifications to DNA due to carcinogens
What process generates polycyclic aromatic hydrocarbons?
the combustion of organic matter
What enzyme mediates polycyclic aromatic hydrocarbon carcinogenesis?
cytochrome p450
What bases does ultraviolet radiation target?
pyrimidine bases (C, T and U)
Give 2 ways in which ionising radiation can damage DNA:
1) it promotes free radical production, resulting in oxidative damage, causing single stranded breaks in DNA
2) direct interaction of electrons with DNA results in molecular distortion and double stranded breaks
Give 3 ways in which asbestos causes DNA damage:
1) oxidative stress
2) fibrosis
3) negative interactions with the mitotic apparatus of dividing cells
Give 6 examples of viral carcinogens:
1) epstien-barr virus
2) hepatitis B and C
3) kaposi sarcoma herpes virus
4) HIV type 1
5) human papillomavirus type 16
6) human T cell lymphotropic virus type 1
What cancers is epstein-barr virus associated with? (2)
1) nasopharyngeal carcinomas
2) lymphomas
What cancer is hepatitis B and C associated with?
Hepatocellular carcinoma
What cancer is kaposi sarcoma herpes virus associated with?
kaposi sarcoma
What cancers is HIV type 1 associated with? (3)
1) kaposi sarcoma
2) carcinoma of the conjunctiva, anus and cervix
3) lymphomas
What cancers is human papilloma virus (HPV) type 16 associated with?
carcinoma of the cervix, vulva, vagina, penis, anus, oral cavity, oropharynx and tonsil
What cancers is human T cell lymphotropic virus type 1 associated with? (2)
1) adult T cell leukaemia
2) lymphoma
Give three examples of carnicogenic protozoa:
1) Clonorchis sinensis
2) Opisthorchis viverrine
3) Schistosoma haematobium
What cancer is Helicobacter pylori associated with?
non-cardia gastric carcinoma
What cancer is Clonorchis sinensis associated with?
cholangiocarcinoma
What is cholangiocarcinoma?
Cancer of biliary tract epithelium
What cancer is Opisthorchis viverrine associated with?
cholangiocarcinoma
What cancer is Schistosoma haematobium associated with?
urinary bladder cancer
Describe the initiation process of carcinogenesis:
the carcinogen reaches a cell activating proto-oncogenes, inactivating onco-suppressor genes and anti-metastatic genes
Describe the promotion process of carcinogenesis:
the initiated cell develops defects in growth control and programmed cell death as well as a resistance to cytotoxicity allowing for selective clonal expansion, forming a pool of preneoplastic cells
Describe the progression process of carcinogenesis:
further genetic changes allow for the preneoplastic cells to become malignant tumours and eventually a cancer invasion
What cell cycle proteins drive progression and act as check points?
cyclins
What enzyme phosphorylates protein substrates by forming complexes with their relevant cyclins?
cyclin dependent kinases
What 2 amino acids do cyclin dependent kinases phosphorylate?
1) serine
2) threonine
In which two stages of the cell cycle can cells be halted and removed?
1) between G1 and S
2) between G2 and M
What is biotransformation in relation to carcinogenesis?
the deactivation or activation of a carcinogen absorbed and distributed by a tissue
Give two examples of geneotoxic carcinogen mechanisms:
1) DNA adductions
2) chromosomal breakages, fusion, deletion, mis-segregation and non-disjunction
Give six examples of non-genotoxic carcinogen mechanisms:
1) inflammation
2) immunosuppression
3) reactive oxygen species
4) reactive nitrogen species
5) receptor activation
6) epigenetic silencing
Give three methods of epigenetic silencing:
1) DNA methylation
2) histone methylation
3) histone acetylation
Give 4 genes associated with breast cancer in women:
1) BRCA1
2) BRCA2
3) ATM
4) BARD1
Give 4 genes associated with colorectal cancer, gastric cancer and endometrial cancer:
1) EPCAM
2) MSH2
3 MSH6
4) MLH1
Give 2 genes associated with melanoma:
1) BAP1
2) BRCA2
Give 6 genes associated with pancreatic and prostate cancer:
1) BRCA1
2) BRCA2
3) ATM
4) MSH2
5) MSH6
6) MLH1
