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FunMed Cancer > The Genetics of Cancer > Flashcards

The Genetics of Cancer Flashcards

1
Q

what causes DNA damage which leads to cancer developing

A
  • Inherited this effect germ cells
  • Acquired or sporadic somatic cell
  • External factors – life style
  • External factors – exposure
  • Infections (Virus and bacteria)
  • Parasites
  • Immunosuppression
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2
Q

Name some examples of inherited cancers

A
  • BRACA1/2 – breast and ovarian cancer
  • DNA repair genes –xeroderma pigmentosum (XP)
  • RB1 – retinoblastoma
  • ATM – ataxia telangiectasia mutated-breast cancer
  • APC - (adenomatous polyposis coli) – colorectal cancer
  • P53- brain tumours, sarcomas
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3
Q

Name some examples of acquired or sporadic cancers

A
  • Ras
  • P53
  • ATM- ataxia telangiectasia mutated, lymphoma and leukaemia
  • Epigenetics
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4
Q

name some examples of external factors (lifestyle choices)that can cause cancers

A
  • Smoking-tobacco (polycyclic aromatic hydrocarbons) - lung cancer
  • Alcohol- oral and liver cancer
  • Diet
  • Exercise
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5
Q

what 3 factors cause up to 20% of all cancers

A

alcohol
diet
exercise

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6
Q

name some examples of external factors (exposure) that can cause cancer

A
  • Solar radiation (UV – XP, melanoma, basal cell carcinoma and squamous carcinoma
  • Ionising radiation- radon gas
  • X-rays (e.g. chest = few days of background radiation < 1 in 1 000 000 chance)
  • Industrial - asbestos – lung cancer and mesothelioma
  • Pharmacological – chemotherapeutic agents
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7
Q

name some examples of infections that can cause cancer

A
  • HPV Cervical cancer
  • EBV Burkitt’s lymphoma
  • Hep B  hepatocellular carcinoma
  • H.pylori gastric adenocarcinoma
  • HTLV 1 leukaemia/lymphoma
  • Schistosomiasis squamous cell/transitional cell bladder cancer
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8
Q

How can immunosuppression cause cancer

A
  • Increased cancers in AIDS and transplant recipients
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9
Q

what are the two things that mutations can be

A

quantitative

qualitative

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10
Q

What is a quantitative mutation

A
  • this is a change in the amount of products that is produced
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11
Q

what is a qualitative mutation

A

– altering the gene product to make it constitutively active

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12
Q

what are the 3 mechanisms of gene alterations that activate oncogenes

A
  • point mutations
  • chromosomal rearrangements
  • gene amplification
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13
Q

how do point mutations cause cancer

A

– single base changes in DNA for example Ras oncogenes

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14
Q

how do chromosomal rearrangements cause cancer

A

– translocation
The translocated activated the oncogene by using regulatory elements from a highly transcribed gene to drive the expression of the oncogene for example BCL-2

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15
Q

what is an example of gene amplification causing cancer

A

HER2

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16
Q

describe how the point mutation in H-ras causes oncogenes to become activated

A
  • Single nucleotide exchange GGC to GTC in bladder cancers

- Results in a glycine changing to a valine

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17
Q

what cancers are examples of point mutations in ras genes causing cancer

A 
pancreas
 - 90% of tumours 
thyroid 
- 60% of tumours
colorectal 
- 25% of tumours
bladder 
- 10% of tumours
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18
Q

what is an example of chromosomal translation causing cancer

A

Burkitt lymphoma

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19
Q

describe how the chromosomal translation causes burkitt lymphoma

A
  • C-MYC (transcription factor) translocation places the gene under the control of a highly active transcriptional regulatory from an Ig gene (immunoglobulin gene)
  • Most common – 75%, t(8:14) (q24;q32)
  • Fastest growing tumour
  • The disease characteristically involves the jaw or other facial bone, distal ileum, cecum, ovaries, kidney or breast
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20
Q

what cancers are caused by the up regulation of BCL2

A
  • Leukaemia’s – for example nearly all patients with acute lymphocytic leukaemia
  • Non hodgkin lymphoma e.g. in follicular lymphoma an estimated 90% of patients have a t(14;18) chromosomal translation
  • Solid tumours – e.g. in small cell lung cancer, high bcl-2 expression in greater than 90% of patients reported
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21
Q

what can gene amplification cause

A
  • over expression of porto-oncogenes

- this leads to over expression of oncogenes which leads to tumorigensis

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22
Q

what is an example of gene amplification causing cancer

A
  • HER2 – HER2 positive breast cancer

- EGFR – EGFR positive small cell lung cancer

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23
Q

what is the type of genetic mutation that is found in tumour suppressor genes

A

Loss of function mutations inactive tumour suppressor genes

  • Often point mutations small deletions or truncating mutations
  • Sometimes somatic recombination during which the normal gene copy is replaced with a mutant copy
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24
Q

describe the TP53 mutation (tumour suppressor gene)

A
  • TP53 mutations reported in almost every type of cancer at rates varying between 10% (e.g., in hematopoietic malignancies) and close to 100% (e.g. in high-grade serous carcinoma of the ovary).
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25
Q

Describe the p53 mutation (tumour suppressor gene)

A
  • in human tumours is often found to undergo missense mutations via point mutations in which a single nucleotide is substituted by another,
  • result in loss of p53 ability to bind DNA in a sequence specific manner
  • Loss of suppression function
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26
Q

what is the example of a genetic mutation found in DNA repair genes

A

ATM

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27
Q

describe the genetic mutation in the ATM DNA repair gene

A
  • Ataxia telangeictasia mutated
  • Normally repairs double stranded DNA breaks
  • Mutations result in non function truncated protein and ability to repair breaks leading to more mutations
  • Mutated in mantel cell lymphoma and in inherited diseases
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28
Q

What are the examples of cancers that are caused by ATM DNA repair gene mutation

A
  • Cerebellar cells are particularly affected – ataxia telangiectasia (A-T syndrome) also increases cancer susceptibility, most likely due to impaired DNA damage repair and genomic instability.
  • ATM is one of the most commonly aberrant genes in sporadic cancers (e.g. haematological*) and also found in inherited disease.
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29
Q

What causes testicular cancer

A

Mutations in KITLG, SPRY4 increase risk of testicular cancer

  • Two most common mutations are KIT/KRAS
  • Promotes growth of cells through Ras-MAP kinase pathway
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30
Q

what are the pre existing drivers of DNA damage

A

These are inherited causes of DNA damage
• Breast and ovarian cancer: BREAST CANCER 1/2: BRCA1/2
• Xeroderma pigmentosum: failure to respond adequately UV light, which causes pyrimidine dimers to form in DNA. Nucleotide excision repair is singular pathway for removing these.
• Retinoblastoma; pRB
• Colorectal cancer: APC
• Brain tumours, sarcomas: P53

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31
Q

What are the susceptibility gene

A
  • Small portion of cancers are inherited and are at a higher risk to developing specific cancers
  • Proportion of individuals carrying a pathogenic variant who will manifest the disease is referred to as penetrance
32
Q

What are the classes of genes involved in several classes of gene that may be involved

A
  • tumour suppressor genes
  • oncogenes
  • DNA repair
  • cell cycle control,
  • stimulating the angiogenic pathway
33
Q

what germ line mutation in tumour suppressor genes can develop what cancer

A
  • germ line mutation APC that is autosomal dominant
  • Early teenagers – premalignant bowl polyps
  • Penetrance almost complete by age of 40 colorectal carcinoma 100%
  • 20-30 years earlier than non-inherited colorectal cancer
34
Q

what germ line mutation in DNA repair genes can develop what type of cancer

A

BRAC1 and BRAC 2

  • Germ line mutation
  • Autosomal dominant
  • BRAC1 – 65% breast cancer, 39% ovarian cancer
  • BRAC1 – 45% Breast cancer, 11% Ovarian cancer
  • By 70 years
35
Q

what are the normal genes that stop DNA methylation from happening

A

Normal cells H3K4me3

36
Q

what does H3K4me3 do

A

stops DNA methylation from happening

37
Q

what are the genes that cause methylation in the cell promoter region

A

H3K9me3

38
Q

what does H3K9me3 do

A

causes methylation to happen

39
Q

What is hypermethylation

A

– transcriptional repression, loss of tumour suppressor gene expression
- at the CpG island stops the transcription of the gene, if this is the tumour suppressor gene then cannot carry out repair or go into apoptosis

40
Q

what is hypomethylation

A

– mitotic recombination and genomic instability

- repeated sequences in 3 prime untranslated regions, this causes mitotic recombination and genomic instability

41
Q

what kind of cancers does an increase in DNA methylation cause

A
  • TSG promoter in cervix and breast increased expression with increasing cancer risk
  • DNMT3B associated with colorectal cancer cells
42
Q

what do the CpG islands do

A

CpG islands in 5 prime end upstream of the gene, they are not methylated this means that the gene can be transcribed

43
Q

describe the different types of expression in DNMT3B

A
  • DNMT3B little expression, low amount of brown staining, cytoplasmic in cells underlying the stroma
  • Well differentiated adenocarcinoma – DNMT3B expressed more strongly in nuclei of the carcinoma cells
  • Poorly differentiated aggressive colon carcinoma – DNMT3B – intense expression on nuclei all of carcinoma cells
44
Q

What cancer does DNMT3B cause

A

Colon carcinoma

45
Q

what type of cancer does the TSG promoter cause

A
  • cervix

- breast

46
Q

what is the expression and methylation status in the TSG promoter

A 
Low grade squamous intraepithelial lesion of cervix
-	Promoter methylation is not at surface
Normal breast tissue 
-	No promoter methylation 
High grade lesion of cervix 
-	Promoter methylation in all cells
Normal breast tissue 
-	Lobules so uniform promoter methylation, suggests in these normal lobules have undergone initiating steps in cancer progression
47
Q

what are the two types of mutagenic damage

A
  • endogenous

- exogenous

48
Q

what is endogenous mutagenic damage

A

these are indirect acting carcinogens that require metabolic activation

49
Q

what are examples of endogenous mutagenic activity

A

polycyclic aromatic hydrocarbons and alcohol

50
Q

what is exogenic mutagenic damage

A

direct acting carcinogens

51
Q

Name sume examples of exogenous mutagenic damage

A

oxygen species,
chemical mutagens,
x rays,
UV radiation

52
Q

where do spontaneous mutations occur in DNA

A
  • S, G1 and G2 – Eukaryotes = Rate 10-4 -10-6 per gene per generation
    – Natural error rate for DNA polymerase
    – Many are fixed
53
Q

what is spontaneous DNA damage caused by

A
  • Errors in proofreading
  • Deamination of bases – taking of the NH2 group of cytosine to convert it to uracil, changes the codon
  • Depurination – spontaneous cleavage of the bond linking purine (A or G) to the deoxyribose which removes the base, this is caused by OH- and H+, 1017 chemically altered nucleotides day, most common mutation, changes in the codon
  • Depyrimidination – acts as a lower rate removes T and C pyrimidine bases
  • Oxidation – most common on guanine
54
Q

how many carcinogens are in cigarette smoke

A

more than 70 carcinogens

55
Q

what does smoking cause

A
  • Responsible for double strand breaks
  • DNA is damaged by polycyclic aromatic hydrocarbons
  • Forms DNA adducts when the carcinogen combines with a base
56
Q

What is the example of smoking causing damage

A
  • E.g. BP (found in tobacco smoke) – multiple benzene rings fused together, metabolic activation,
  • cytochrome P450 enzymes make compounds more soluble for excretion but this produces chemical species (ultimate carcinogen) that is highly reactive DNA therefore highly mutagenic
  • BP procarcinogen – has to be metabolised to get to the ultimate carcinogen
57
Q

what does the ultimate carcinogen form when it interacts with DNA

A
  • DNA adducts
58
Q

describe the formation of DNA adducts in lung cancer

A
  • Ultimate carcinogen highly reactive species that interact with DNA to form DNA adducts
  • The genetic lesions often occur in the cells where the initial metabolic activation occurs
  • BPDE – forms adduct with guanosine residues in lung epithelial cancer
59
Q

how do DNA adducts form in oral and oesophageal cancers

A
  • Acetaldehyde interacts with deoxguanosine forming a weak mutagen (DNA adduct- most abundant) which forms a stronger mutagen (DNA adduct)
60
Q

What are the two types of radiation

A

direct and indirect

61
Q

what happens in indirect radiation

A

creation of free radicals where the presence of unpaired electrons damage bases or breaks DNA backbone

62
Q

what happens in direct radiation

A

comes from alpha particles, beta particles or x rays/ these create ions that break the sugar phosphate backbone and causes damage between the base pairs or chemically alter bases

63
Q

what does UV damage do to the DNA

A
  • Formation of pyrimidine dimers – covalent bonds between 2 adjacent pyrimidines on the same strand
64
Q

what are examples of cancers forming due to pyrimidine dimers

A
  • Melanosomes – protect keratinocytes from UVB by acting as sunshade in melanocytes
  • E.g. Basal cell carcinomas many mutation p53 alleles have dipyrimidine substitution
  • Cylcobutane prumidine dimers – very stable
65
Q

what is the cause of xeroderma pigmentosum

A
  • Defect in human nucleotide repair – XPA gene

- Nucleotide excisions repair is the only pathway to remove pyrimidine dimers in humans

66
Q

what are the symptoms of xeroderma pigmentosum

A
  • Very light sensitivity
  • High risk of sunlight induced skin cancer
  • Neurological abnormalities (high rate of oxidative metabolism in neurones)
67
Q

what cancers are caused by xeroderma pigmentosum

A

Non-melanoma (basal cell and squamous cell) skin cancer at UV exposed site
- 10,000x increased risk
- Median age onset 9 years (60 years earlier than general population)
Cutaneous melanoma
- 2000x increased risk
- Median age 22 years (30 years earlier than general population)

68
Q

how many cancers are caused by infectious agents

A
  • 15% cancers worldwide thought linked directly or indirectly to infectious agents predominately in developing world
69
Q

how can some viruses cause cancer

A
  • Some viruses can cause cancer by integrating genes (often oncogenes or TSG inhibitors) into the chromosomal DNA of infected cell
70
Q

what cancer type does HPV causes and how is it transmitted

A
  • cervical cancer

- sexual contact

71
Q

what cancer does EBV cause and how is it transmitted

A
  • Burkitts lymphoma, Hodkins lymphoma
  • Saliva
    Blood/transplants
72
Q

what cancer does leukaemia virus type 1 cause and how is it transmitted

A

Adult T-cell leukaemia/lymphoma (ATLL)

  • mother to child
  • sexual contact
  • blood transfusion
73
Q

what cancer does hepatitis B and C cause and how is it transmitted

A

hepatocellular carcinoma

  • blood transfusion
  • organ transplant
  • contaminated needles
74
Q

what are examples of viruses causing cancer

A

HPV
EBV
leukaemia virus type 1
hepatitis B and C

75
Q

what can helicobacteri pylori cause

A
  • Helicobacter pylori infection predispose individuals towards gastric adenocarcinoma later in life
76
Q

how does helicobacter pylori transmit its disease

A

• indirect inflammatory effects of Helicobacter pylori on the gastric mucosa
• direct epigenetic effects of Helicobacter pylori on individual cells.
Schistosomiasia (parasitic worms - blood flukes) and squamous cell and transitional cell bladder cancer. Formation of N-nitroso compounds

FunMed Cancer (4 decks)

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