Lecture 16 - Neoplasia 3 And 4 Flashcards by Callum Donoher

What does carcinogenesis mean?

The causes of cancer

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What are the 2 types of factors which are risks for the multi factorial nature of neoplasia?

Intrinsic factors
Extrinsic factors

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What are 3 Intrinsic factors of carcinogenesis?

Heredity
Age
Sex (particularly hormones)

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What are the 2 categories of Extrinsic factors of carcinogenesis?

Environment
Behaviour/lifestyle

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What falls in the environment category for extrinsic factors of carcinogenesis?

Chemicals
Radiation
Infection

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What is meant by a gene/allele being highly penetrant?

If present will very likely be apparent in the individual

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What genes are mutated in breast cancer?

BRCA1
BRCA2

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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

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What lifestyle factor makes developpping Endometrial carcinogenesis in post menopausal women more likely?

Obesity

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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

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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

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How can alcohol cause cancer?

Synergist with tobacco

Liver cirrhosis can lead to hepatocellular carcinoma

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What type of cancers does TOBACCO (smoking) increase the risk of developing?

LUNGS
Mouth

Pharynx
Larynx
Oesophagus
Liver

Cervix

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What types of cancer does excess alcohol consumption increase the risk of getting?

Pharynx
Larynx
Oesophagus
Liver

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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)

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What type of cancer is likely to develop with exposure to the chemical 2-napthylamine (in dyes)?

Bladder cancer

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What does the risk of cancer depend on?

Total carcinogen dose

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How long does it take for a neoplasm to develop following an exposure to a carcinogen?

Long delay

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What are the 2 classes of Chemical Carcinogenesis??

Initiators
Promoters

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What is special about the chemical carcinogen Tobacco?

Can act as both an Initiator and Promoter

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What order do the 2 classes of chemical carcinogens need to be given in for a neoplasm to develop?

Initiator first
Promoter second

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What is an Initiator? (Chemical carcinogen)

Chemical carcinogen that produces the initial mutation

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What are promoters?

Chemical carcinogens that stimulate the proliferation of the mutated cells allowing for the monoclonal neoplastic population to develop/grow

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Where is the chemical carcinogen Benzopyrene normally found?

From Cigarette smoke

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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?

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