Lecture 16 - Neoplasia 3 And 4 Flashcards
What does carcinogenesis mean?
The causes of cancer
What are the 2 types of factors which are risks for the multi factorial nature of neoplasia?
Intrinsic factors
Extrinsic factors
What are 3 Intrinsic factors of carcinogenesis?
Heredity
Age
Sex (particularly hormones)
What are the 2 categories of Extrinsic factors of carcinogenesis?
Environment
Behaviour/lifestyle
What falls in the environment category for extrinsic factors of carcinogenesis?
Chemicals
Radiation
Infection
What is meant by a gene/allele being highly penetrant?
If present will very likely be apparent in the individual
What genes are mutated in breast cancer?
BRCA1
BRCA2
Why does the intrinsic factor of Age increase or make you more likely to develop a neoplasm?
Older you are the more exposer you will have to extrinsic carcinogens
What lifestyle factor makes developpping Endometrial carcinogenesis in post menopausal women more likely?
Obesity
Why does obesity increase risk of Endometrial cancer in post menopausal women?
Adipocytes produce oestrogen (peripheral conversion of androstenedione to oestrogen)
Oestrogen stimulates constant proliferation of endometrial cells
More likely to get endometrial cancer
What are lifestyle factors that can help prevent cancer from developing?
Smoking cessation
Maintains health weight
Balanced diet
Sun safety
Low alcohol consumption
Being Active
How can alcohol cause cancer?
Synergist with tobacco
Liver cirrhosis can lead to hepatocellular carcinoma
What type of cancers does TOBACCO (smoking) increase the risk of developing?
LUNGS
Mouth
Pharynx
Larynx
Oesophagus
Liver
Cervix
What types of cancer does excess alcohol consumption increase the risk of getting?
Pharynx
Larynx
Oesophagus
Liver
Why does smoking increase the risk of getting cervical cancer?
Smoking lowers the immune system
Means cervical cells more vulnerable to HPV (Human Papilloma virus)
What type of cancer is likely to develop with exposure to the chemical 2-napthylamine (in dyes)?
Bladder cancer
What does the risk of cancer depend on?
Total carcinogen dose
How long does it take for a neoplasm to develop following an exposure to a carcinogen?
Long delay
What are the 2 classes of Chemical Carcinogenesis??
Initiators
Promoters
What is special about the chemical carcinogen Tobacco?
Can act as both an Initiator and Promoter
What order do the 2 classes of chemical carcinogens need to be given in for a neoplasm to develop?
Initiator first
Promoter second
What is an Initiator? (Chemical carcinogen)
Chemical carcinogen that produces the initial mutation
What are promoters?
Chemical carcinogens that stimulate the proliferation of the mutated cells allowing for the monoclonal neoplastic population to develop/grow
Where is the chemical carcinogen Benzopyrene normally found?
From Cigarette smoke
Where is the chemical carcinogen 2-naphthylamine normally found?
Cigarette smoke
Dye industry
Where is the chemical carcinogen Aflatoxin B1 normally found?
Fertiliser
What type of cancer is the chemical carcinogen Asbestos likely to cause?
Mesothelioma
What organ does mesothelioma normally affect?
Lungs
What is Mesothelioma?
Cancer which affects the outer lining of organs
Most commonly affects the Pleura of the lungs
Pleura appears thick due to chronic inflammation
What enyzmes convert a Pro-carcinogen to a carcinogen?
Cytochrome P450
Where is cytochrome P450 found?
Liver
What are the 2 classes of chemical carcinogen?
What carcinogen can act as both?
Initiator
Promoter
Tobacco
What types of radiation are ionising/mutagenic?
Alpha particles
Beta particles
Gamma rays
X-rays
UV rays
What are the 2 general ways radiation can be mutagenic?
Directly damage DNA
Indirectly damage DNA
How can radiation Directly damage DNA?
Missense mutations
DNA breaks
How can radiation indirectly damage DNA?
Generating free radicals
E.g: interacting with water forming hydroxyl free radicals
What type of radiation increases risk of skin neoplasms?
UV
How can infections directly lead to neoplasms?
Directly affect genes controlling cell growth
How can infections indirectly lead to development of neoplasms?
Cause Chronic Tissue Damage
This leads to regeneration
This regeneration can either be:
-A promoter for a pre-existing mutation
-Lead to new mutations from DNA replication errors
What is an example of an infection that directly affects genes controlling cell growth?
HPV
How does Hepatits B Viral infection indirectly act as an extrinsic cause of cancer?
Cause constant inflammatory changes in the liver
Leads to liver cirrhosis which can lead to hepatocellular carcinoma
How does a HIV infection increase likelihood of acquiring a neoplasm?
Suppresses immune system
More likely to develop infections that can act as initiators or promoters
What type of cancer is only normally seen with immunosuppressed patients (e.g HIV infection)?
Kaposi’s sarcoma
What is the virus which causes Kaposi’s sarcoma in immunocompromised patients?
Human Herpes Virus 8 (HHV-8)
What virus is associated with Cervical carcinoma?
Human Papilloma Virus (HPV)
What proteins does HPV produce once its invaded cervical cells?
E6
E7
What does the E6 protein produced by HPV affect and why is this important?
p53
When this protein is inhibited the cell will not undergo apoptosis
How does HPV infection cause Cervical Carcinoma?
Makes E6 and E7 in cervical cells
E6 inhibits p53 so cells dont do Apoptosis
Also interferes with Retinoblastoma protein which is important as a cell cycle checkpoint
Virus replicates inside cell marking more virus
So it prevents cells killing themselves and keeps the cells in the cell cycle so they will continually proliferate
What is the cancer Retinoblastoma?
Cancer of the retina cells of the eye
How many alleles need to be mutated in an oncogene for neoplastic proliferation to occur?
Just 1
(Mutant allele is expressed as dominant)
How many alleles need to be mutated in a Tumour suppressor gene for neoplastic proliferation to occur?
Both (2)
(Mutant Tumor suppressor allele expressed as recessive)
What type of gene is the Retinoblastoma gene (RB1)?
Tumour suppressor gene
What is the action of the Retinoblastoma gene (RB1) as a tumour suppressor gene?
Prevents cells from proliferating uncontrollably
Regulates G1 checkpoint mainly
What type of inheritance is the cancer retinoblastoma?
Autosomal dominant
What is normally the difference between an inherited retinoblastoma cancer and a spontaneous/sporadic one?
Inherited = usually both eyes
Spontaneous/sporadic = usually 1 eye
How many hits to the RB1 gene does a healthy person need in order to develop a neoplasm and why?
2
RB1 = tumour suppressor gene so both alleles need to be affected
How many hits to the RB1 gene does a person with a familial mutation to a RB1 allele need in order to develop a neoplasm and why?
1
RB1 = tumour suppressor gene, person was already born with a mutation to RB1, only need 1 more for both to be affected
What is the normal function of tumour suppressor genes?
What happens when they are abnormal/dont work?
Stop cell proliferation
Abnormalities = failure of growth inhibition
What is the function of Proto-Oncogenes?
Drive cell proliferation
What are proto-oncogenes called when they become mutated?
Oncogenes
What do oncogenes do (mutated proto-oncogenes)?
Produce oncoproteins
Oncoproteins promote cell growth without the need of normal growth promoting signals
How many alleles of a proto-oncogene need to be mutated to lead to the damaging affects of the oncogene?
Only 1
Oncogenes dominant over proto-oncogenes
What is the most common oncogene/mutated proto-oncogene called?
RAS gene
What type of cancer has a very high frequency of RAS gene mutation?
Pancreatic adenocarinomas
How does the RAS gene act as a proto-oncogene driving cell proliferation?
Growth factor binds to receptor
Pathway activated combining RAS to GTP = RAS ACTIVATED
RAS leads to Cyclin D1 production
Cyclin D1 phosphorylates Retinoblastoma
Retinoblastoma lets cell through the G1 checkpoint letting it through the cell cycle
When RAS gene mutates how does it act as an oncogene?
Means RAS constantly active (doesn’t need growth factor stimulation)
Cyclin D1 constantly made
Retinoblastoma constantly phosphorylated
Cells always allowed through G1 checkpoint through the cell cycle
How do the functions of proto-oncogenes and tumour suppressor genes differ?
They are opposite
Proto-oncogenes stimulate proliferation
Tumour suppressor genes prevent proliferation
Why is it very worrying if somebody has a RAS mutation and Retinoblastoma defects?
RAS mutation = constantly trying to push cells through cell cycle
Absent Retinoblastoma gene function = Cells constantly being pushed through not prevented from continuing through cell cycle at G1 checkpoint
What can proto-oncogenes encode?
RAS
BRAF
HER2
MYC
What is the function of DNA repair genes?
Prevent accumulation of DNA damage
What are the 3 types of DNA repair?
Nucelotide excision
Mismatch repair
Double strand break
What type of Inheritance is Xeroderma Pigmentosa?
Autosomal recessive disease
What does the mutation in Xeroderma Pigmentosa affect?
DNA nucleotide excision repair
Why are individuals with Xeroderma Pigmentosa very sensitive to UV damage?
DNA nucelotide excision repair affected
Very difficult to repair the Thymine dimers that form
Likely to develop skin cancer at a young age
What type of inheritance is Lynch syndrome also known as Hereditary Non-Polyposis Colon Cancer (HNPCC) syndrome?
Autosomal Dominant
What is mutated in Lynch syndrome/Hereditary Non-Polyposis Colon Cancer (HNPCC) syndrome?
DNA mismatch repair genes
What are the 4 DNA mismatch repair genes likely to be affected in Lynch syndrome/Hereditary Non-Polyposis Colon Cancer (HNPCC) syndrome?
MLH1
MSH2
MSH6
PMS2
What type of cancer are common with DNA mismatch repair protein abnormatlites?
Colorectal cancer
Endometrial cancer
What type of mutation is likely when the MSH2, MSH6 or PMS2 DNA mismatch repair proteins are abnormal?
Likely germ line mutations/inherited
If there is an abnormality in the MLH1 DNA mismatch repair protein, when did this damage likely happen?
Later in life due to environmental exposures
What is the function of the BRCA1/BRCA2 genes?
Reparing double stranded DNA strand breaks
What type of cancer does mutation of BRCA1/BRCA2 normally cause?
Breast cancer
Familial breast carcinoma can arise as a result in mutations in BRCA1/BRCA2 genes, why is important to test someone’s genes if they have breast cancer?
May be at risk of developing many other cancers
What can happen to the chromosomes of malignant cells during mitosis?
Why?
Chromosomes aggregate
Due to accelerated mutation rate called GENETIC INSTABILITY
What are the genes called which maintain genetic stability?
Caretaker genes
What is Li-Fraumeni syndrome?
Fault in TP53 tumour suppressor gene
What are a few cancers your at risk of with Li-Fraumeni syndrome?
Breast cancer
Bone cancer
Acute myeloid leukaemia
Soft tissue sarcoma
Brain tumours
Adrenal gland carcinoma
What is the Adenomcarcinoma sequence of colorectal cancer?
Shows accumulation of mutations leading to a neoplasm must occur in a certain order
Normal epithelium — early dysplasia — intermediate dysplasia — late dysplasia —cancer
What is progression?
When mutated cells that have been exposed to carcinogens accumulate further mutations that help them develop a monoclonal neoplastic population
What are the 6 hallmarks of cancer?
Don’t need growth signals
Don’t respond to stop signals (Tumour suppressor genes)
No limit to the number of times the cell can divide
Can do angiogenesis
Resistant to apoptosis
Can invade and produce metastases
What is the point of an Ames test?
Determines whether a chemical can be an initiator (carcinogen)/mutagenic
What cancer is common in men in Japan?
Stomach cancer
