How and why neoplasms occur Flashcards
How can a carcinogen be an initiator vs promotor? What is a complete carcinogen? Give an example
Initiator by causing a mutation e.g. UV radiation
Promotor by causing uncontrolled monoclonal cell proliferation that predisposes to mutations e.g. infection (regeneration of cells) (polycyclic aromatic hydrocarbons)
A complete carcinogen is both an initiator and a promotor e.g. cigarette smoke
What occurs during cancer progression?
Additional mutations –> in TSG/protooncogenes leading to genetic instability and deregulated cell pathways. Eventually leading to the 6 hallmark signs of cancer
How is an inherited mutagen different to a somatic mutation from a carcinogen?
It speeds up the promotor phase as it is already present in all cells due to being germline –> often present with malignancies younger
What is 2-napthylamine?
An industrial chemical that is an initiator causing a mutation that leads to bladder carcinoma –> seen in factories back in the day
Why is there a long delay from somatic mutation –> cancer
Because after the initiator you need a promotor to lead to increased cell proliferation –> and then progression where you have more mutations that eventually lead to the hallmarks of cancer. These take time.
What is a procarcinogen? How is it made a carcinogen?
Inactive made active by P450 in the liver
Are cancers most commonly due to intrinsic (genetic) factors or extrinsic (behaviours/environment)?
85% extrinsic
How can radiation predispose to cancer (2)?
Either direct damage to DNA
or via free radicals that then cause damage to DNA e.g. single strand/double strand breaks/damages to DNA bases.
Which two ways can infections predispose to cancer?
1) Either by acting on genes causing cell growth
2) Affecting growth indirectly by chronic tissue injury –? regeneration predisposes to cancer
How does regeneration in tissue predispose to cancer?
Either by acting as a promotor for any preexisting mutations or causes new mutations via DNA damage repair errors
How does Human Papilloma Virus predispose to cancer (2)? Is it a direct or indirect carcinogen?
It expresses proteins E6 E7 which act directly to inhibit Rb protein and p53 respectively.
This means the cell cycle is uninhibited even if damaged at the check point
And it means damaged cells will survive as p53 would cause apoptosis –> genetical instability —> cervical cancer
Direct as directly affects Tumour Suppressor Genes and Proto-oncogenes
How are HepB and HepC indirect carcinogens?
Via chronic liver damage –> regeneration leads to increased chance of mutations
Name two other infections that lead to chronic inflammation and carcinomas?
Helico bacter pylori - chronic gastric inflammation –> gastric carcinoma
Fluke worm - chronic bile duct inflammation and bladder —> cholangio/bladder carcinoma
How does AIDs predispose to cancer and which type in particular?
Lowes immune system so allows for potentially carcinogenic infections –> Kaposi’s sarcoma caused by HHV8
What is the two hit hypothesis and how does it relate to retinoblastoma?
That both tumour suppressor gene alleles need to be knocked out in order to suppress their function for favour of neoplastic growth. E.g. retinoblastoma
Can either occur via one germline mutation, one other mutation
Or de novo 2 mutations
Example of neoplasm that can be genetic and de novo
How many proto-oncogenes need to be mutated to favour neoplastic growth? Give an example - is it mutated in one or more cancers?
Only one
RAS - G protein that when mutated causes cell cycle to pass uninhibited past check point. Mutant RAS encodes a protein that is always active. Mutated in 1/3 of all cancers
Name 7 functions/types of photo-oncogenes that are altered in cancer
1) Growth factors PDGF
2) Growth factor receptors HER2
3) Plasma membrane signal transducers RAS
4) Intracellular kinases BRAF
5) Transcription factors MYC
6) Cell cycle regulators CYCLIND1
7) Apoptosis regulators BCL2
Are the functions similar but opposite for TSG? Give an example of one
TP53 yes
Give an example of a germline defective DNA repair mutation leading to cancer (there are 3 here)
XP - Xeroderma Pigementosum - autosomal recessive
Error in NER
Predisposes to skin cancer
HNPCC - Heredity non polyposis colon cancer - autosomal dominant
Error in Mismatch repair
Familial Breast Carcinoma - BRCA1 BRCA2
Error in DSB repair
How do chromosomal segregation errors in cancer cells enhance cancer? What kind of genes protect against this?
Because they lead to increased mutations —> polyclonal expansion and increased genetic instability.
Caretaker genes protect against this
Give an example of adenoma –> carcinoma
Colon cancer
How many mutations approx needed to develop malignant neoplasm?
10 or less
What are the 6 hallmarks of cancer?
1) Self sufficient growth factors
2) Resist antigrowth factors
3) Grow indefinitely
4) Resist apoptosis
5) Invade and metastasise
6) Angiogenesis
How do cancers grow indefinitely?
Most have the gene for telomerase activated –> can regenerate telomeres which allows them to undergo mitosis indefinitely
