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* Year 2 EMS > MOD - carcinogenesis + behaviours of tumours > Flashcards

MOD - carcinogenesis + behaviours of tumours Flashcards

1
Q

what two types of meat can cause colorectal cancer?

A
  • red meat

- processed meat

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2
Q

what carcinogens are workers exposed to in aluminium production, coal gasification, coke production, iron and steel industries?

A

heavy metals

eg cadmium and nickel

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3
Q

mining of hematite and uranium exposes miners to what carcinogen?

A

radon

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4
Q

what sort of cancers have been reported among woodworkers\?

A

cancers of the sinonasal cavities and paranasal sinuses

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5
Q

what industry exposes workers to the carcinogens B-napthylamine and 4-aminobiphenyl?

A

rubber industry

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6
Q

what type of cancer is seen in workers in boot/shoe manufacture and repair?

A

nasal adenocarcinoma

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7
Q

what is EPIC?

A

The European Prospective Investigation into Cancer and Nutrition (EPIC) study is one of the largest cohort studies in the world, with more than half a million (521 000) participants recruited across 10 European countries and followed for almost 15 years. EPIC was designed to investigate the relationships between diet, nutritional status, lifestyle and environmental factors, and the incidence of cancer and other chronic diseases.

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8
Q

what are the 6 categories of human carcinogens?

A

Chemicals e.g. PAHs, nitrosamines

Infectious agents e.g. human papilloma virus, Helicobacter pylori

Radiation e.g. UV light, radon

Minerals e.g. asbestos, heavy metals
Like cadmium and nickel

Physiological e.g. oestrogen, androgens

Chronic inflammation – free radicals and growth factors

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9
Q

what are PAHs

A

Polycyclic aromatic hydrocarbons (PAHs) are a group of more than 100 different chemicals that are released from burning coal, oil, gasoline, trash, tobacco, wood, or other organic substances such as charcoal-broiled meat

they are carcinogens

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10
Q

what type of cancer does exposure to aflatoxin cause? and what is it?

A

liver cancer

a mold found on food products such as corn and peanuts, peanut butter

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11
Q

what 4 types of cancer does alcohol cause?

A

pharynx, larynx, oesophageal, liver

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12
Q

what type of cancer does asbestos cause?

A

mesothelioma

ie of the lung pleura

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13
Q

what type of cancer do x-rays cause?

A

leukaemia (bone marrow)

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14
Q

what kind of cancer does oestrogen cause?

A

breast cancer

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15
Q

what 6 types of cancer does smoking cause?

A

lung, mouth, oesophagus, pancreas, kidney, bladder

and others!!

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16
Q

what kind of cancer does HPV (human papilloma virus) cause?

A

cervix

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17
Q

what is a carcinogen?

A

any agent that significantly increases the risk of developing cancer

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18
Q

what are the 3 types of carcinogen?

A

initiators
- modify or damage dna (genotoxic)

promotors
- induce proliferation and DNA replication (non-genotoxic)

complete carcinogens

  • initiate and promote
  • eg UV light
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19
Q

what 2 steps does initiation of cancer (mutation induction) require?

A
  • chemical modification of DNA

- replication of modified DNA and mis-incorporation by DNA polymerase

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20
Q

what are the two ways in which promoters contribute to carcinogenesis?

A
  • by stimulating the 2 rounds of DNA replication required for mutation fixation
  • by stimulating clonal expansion of mutated cells, which enables the accumulation of further mutations
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21
Q

what are the 3 stages of carcinogenesis?

A
  • initiation
  • promotion
  • progression
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22
Q

why are you a lot more likely to get a basal cell carcinoma than a melanoma?

A

because cancer is directly related to levels of cell division

Basal cells and maelanocytes (produce melanin) are exposed to the same amount of uv light but, because basal cells replicate more in normal physiology, you are 10 fold more likely to get a basal cells carcinoma than a melanoma

This would support a hypothesis that cell division, and by inference DNA replication, is a significant risk factor for the development of cancer

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23
Q

what genetic change is associated with chronic myeloid leukaemia?

A

translocation on chromosome 22 (Philadelphia translocation)

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24
Q

what is aneuploidy?

A

Aneuploidy is the presence of an abnormal number of chromosomes in a cell, for example a human cell having 45 or 47 chromosomes instead of the usual 46.

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25
Q

mutations which result in an over-activation in which genes can cause cancer?

A

activation of proto-oncogenes

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26
Q

mutations which result in an inactivation in which genes can cause cancer?

A

inactivation of tumour suppressor genes (TSGs)

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27
Q

what is a colloquial name for a common type of promoter sequence?

A

CpG islands

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28
Q

what does methylation of promotor sequences result in?

A

loss of gene expression of said gene

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29
Q

what are the two ‘umbrella’ ways that carcinogens can induce cancer?

+ examples?

A

direct acting
- interact directly with DNA
(eg oxygen radicals, UV light, ionising radiation, nitrogen mustard)

procarcinogens
- require enzymatic (metabolic) activation before they react with DNA
(eg polycyclic aromatic hydrocarbons - PAH, found in burnt organic products)

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30
Q

what is benzopyrene? what is it an example of? and what happens to it in the body?

A

a type of PAH

can be generated through combustion of most organic material (eg meat, tobacco, fuel)

example of a procarcinogen
- requires activation to convert it to BPDE (= ultimate carcinogen)

however genetic variation in enzymes between individuals determines how much bpde you produce from a set amount of benzopyrene

so same level of exposure but different likelihood of developing cancer

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31
Q

what condition can inherited defects in the NER (nucleotide excision repair) pathway lead to?

A 
Xeroderma pigmentosum (XP)
- a rare autosomal recessive condition

extreme sensitivity to UV light (as damage cannot be repaired)
- with UV, get abnormal skin pigmentation and very high frequency of skin cancers, have to completely avoid sun!

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32
Q

what condition arises from inherited defects in the ATM gene?

A 
ataxia telangiectasia (AT)
- autosomal recessive

much increased risk of cancer
- haematological cancers in childhood and solid tumours as adults

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33
Q

what is lynch syndrome?

A

aka HNPCC (hereditary nonpolyposis colorectal cancer)

autosomal dominant condition

inherit faulty DNA mis-match repair genes

increadibly high risk of colorectal cancer 80%
(as well as endometrial 60%, ovarian 12% and others)

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34
Q

what 5 levels of defence does the body have against carcinogens?

A
  • dietary antioxidants (fruit/veg inactivates free radicals which –> DNA damage)
  • detoxification mechanisms
  • DNA repair enzymes
  • apoptotic response to unrepaired genetic damage
  • immune response to infection and abnormal cells
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35
Q

how are heavy metals carcinogenic?

A

not, in themselves, carcinogenic but they react with other molecules to form free radicals which then –> dna damage

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36
Q

name 5 carcinogens present in tobacco smoke

A
  • polycyclic aromatic hydrocarbons (PAHs)
  • acrolein (arid smell, potentially direct acting)
  • nitrosamines
  • radioactive lead + polonium (v. small level but accumulate over time)
  • heavy metals (cadmium, chromium)
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37
Q

HOW is alcohol carcinogenic?

5 reasons

A
  • converted into acetaldehyde, can –> DNA damage
  • increases levels of oestrogen + testosterone (both carcinogens)
  • increases uptake of other carcinogens into upper GI cells (eg cig smoke absorbs into bloodstream using alcohol as a solvent)
  • reduces levels of folate (needed for accurate DNA replication)
  • can kill surface epithelium –> unscheduled proliferation to replace dead cells (a potent promoting stimulus)
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38
Q

what increases a woman’s likelihood of breast cancer? (7)

A
  • early menarche
  • age of 1st pregnancy >30years
  • late menopause
  • post-menopausal obesity
  • oral contraception (combined, not progesterone only)
  • hormone replacement therapy (HRT)
  • high alcohol consumption

basically all of these are risk factors as they increase body’s exposure to OESTROGEN (= a complete carcinogen, initiates and promotes)

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39
Q

why does chronic inflammation often lead to cancer? (2)

A
  • DNA damage from release of free radicals by immune cells = INITIATION
  • growth factor induced cell division to repair tissue damage = PROMOTION

therefore inflammation is a complete carcinogen

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40
Q

what % of cancers are due to preventable causes?

A

over 50%

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41
Q

what is the difference between proto-oncogenes and oncogenes?

A

proto oncogenes - promote cell proliferation, survival and angiogenesis in a normal cell

oncogenes- mutated versions of proto-oncogenes
= uncontrolled proliferation, angiogenesis, inhibition of apoptosis etc,

nb oncogenes are DOMINANT GAIN-OF-FUNCTION: ie one mutant copy of the gene acts dominant to the remaining normal parental gene

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42
Q

what are the 4 mechanisms of oncogene activation?

A

TRANSLOCATION of an oncogene from a low to an active transcriptional site

POINT MUTATION - substitution of a single base within the amino acid sequence, produces a hyperactive oncoprotein

AMPLIFICATION by insertion of multiple copies of an oncogene - increased expression

INSERTION of a promoter or enhancing gene (by retroviruses) near an oncogene -> increased expression

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43
Q

what is an oncoprotein?

what are 3 different types of oncoprotein? and give an example for each

A

a growth factor that activates cell growth

a GROWTH FACTOR RECEPTOR that activates cell growth
(eg HER2 amplification in some breast cancers, a drug targets this)

BINDS DNA to STIMULATE TRANSCRIPTION and expression of other genes
(eg translocation/overexpression of c-myc - which stimulates transcription - is seen in a lot of cancers + is potential drug target)

cytoplasmic SECOND MESSENGER that ACTIVATES SIGNALLING for cell cycle progression and cell growth (eg KRAS and PI3K mutations - in lots of cancers)

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44
Q

what are the two different types of tumour suppressor genes (TSGs)?

A

GATEKEEPERS (antioncogenese)
- negative regulators of the cell cycle and proliferation and positive regulators of apoptosis

CARETAKERS
- can fix problems on genes which are caused by carcinogens

45
Q

what 4 types of mutations can cause the inactivation of TSGs?

A

inactivating point mutations

deletions

translocations

epigenetic silencing

46
Q

what is epigenetic silencing?

A

shutdown of gene expression via methylation of CpG sequences in promoter regions

47
Q

are mutations within TSGs recessive or dominant? why is this clinically relevant?

A

TSG mutations are recessive (protooncogene mutations are dominant)

both copies of a TSG have to be mutated (or epigenetically inactivated) for complete loss of function and cancer to develop

important for familial cancers, they inherit one mutated copy of the gene from parents so only need one more mutation to cause cancer (instead of 2 in normal people)

48
Q

what is an example of a familial cancer syndrome which is due to one inherited copy of a mutated TSG?

and how does it prevent differently to the sporadic equivalent of this cancer?

A

inherited retinoblastoma
- germline mutation: absence of one copy RB1 gene

predisposes individuals to developing retinoblastoma (as only have one more gene to mutate) - in sporadic cases there has to be 2 mutations, in the SAME CELL!

inherited retinoblastoma tends to be bilateral (in both retinas) whereas sporadic retinoblastoma tends to be unilateral

49
Q

what is Li-Fraumeni syndrome?

A

a cancer syndrome that is the inheritance of ONLY ONE copy of the TSG p53 (a gatekeeper)

thus predisposes patients to sarcomas and breast tumours

50
Q

what are BRCA1 + BRCA2?

A

caretaker TSGs

if one mutated copy of gene inherited then high likelihood of breast and ovarian cancer = familial breast cancer

51
Q

what specific genes are knocked out in HNPCC (aka lynch syndrome)?

A

hMLH1, hMSH2

these are caretaker TSGs

52
Q

how many mutations are generally needed in a cell for it to become cancer? (carcinogenesis)

A

minimum of 3 genetic changes are needed to transform a normal cell –> neoplastic cell

importance of mutation accumulation, rather than the sequential order of specific mutations (as this varies between patients)

53
Q

what is K-RAS

A

a proto-oncogene

54
Q

what are the 7 hallmarks of cancer cells?

A

self-sufficiency in growth signals

insensitivity to antigrowth signals

tissue invasion and metastasis

limitless potential for replication

sustained angiogenesis

evading apoptosis

genomic instability

55
Q

what does self-sufficiency in growth signals mean?

and what are some examples which lead to this quality?

A

normal cells require the stimulus of positive growth factors before they enter the cell cycle and divide.

tumour cells acquire the ability to GROW IN THE ABSENCE OF THESE FACTORS

  • EGFR overexpression
  • EGFR mutation
  • Ras mutation
  • B-Raf mutation

(all above examples are in MAPK/ERK pathway)

56
Q

what is an example of a mutation which leads to cells not responding to negative growth factors and leaving the cells cycle? (ie insensitivity to antigrowth signals)

A

Rb protein prevents progression of G1 –> S phase (in cell cycle) in normal cells

inactivation of Rb gene (common in cancer cells) –> resistance to -ve growth regulation

(lost the gatekeeper between G1 and S phase) –> uncontrolled proliferation

57
Q

what is meant by limitless potential for replication? (in cancer cells)

A

cells have a finite lifespan. During each cell division, they loose some DNA from the telomere. After the telomeres become very short the cell –> apoptosis

rapidly proliferating tumour cells can OVEREXPRESS the TELOMERASE enzyme to maintain normal telomere length

58
Q

what is an example of a mutation which leads to resistance to apoptosis in a tumour cell?

A

p53 inactivation
(present in >50% of tumours)

leads to loss of apoptotic response

(in normal cells transcription factor p53:

  • controls expression of >100 genes
  • pauses cell cycle to allow for DNA repair
  • induces apoptosis if too much damage)
59
Q

what cancer syndrome is due to an inherited loss of one copy of p53 gene?

A

Li-Fraumeni syndrome

increased risk of breast cancer and sarcomas

60
Q

what size can tumours grow to before they need their own blood supply?

A

2mm

any larger and the cells in the middle will die due to lack of nutrients/oxygen

61
Q

what mutations lead to angiogenesis in tumours?

A

stabilisation of HIF-1 transcription factor

this induces VGEF (vascular endothelial growth factor) - an angiogenic growth factor

this actively recruits endothelial cells that proceed to construct new capillaries and vessels

62
Q

what is the primary reason why tumours ‘want to’ induce angiogenesis and what is the side effect of this

A

primary reason: to get nutrients

side effect: metastasis

63
Q

how are tumours able to invade local tissue?

A

epithelial cells are held tightly together by ADHESION MOLECULE E-cadherin

many tumours show LOSS of E-CADHERIN through mutation/hypermethylation of the gene

this –> EPITHELIAL-MESENCYMAL TRANSITION (EMT)

these mesenchymal cells are motile and secrete proteases

this allows them to break through basement membrane and invade the underlying stroma

64
Q

what is PSA serum protein marker and what is it used to detect and how effective is it?

A

prostate-specific antigen

used to detect prostate cancer

but 1/3 of patients with high PSA do NOT have cancer!

65
Q

what is the serum antigen CA-125 used to detect?

is it effective?

A

ovarian cancer

not good at detecting early stage disease

66
Q

what predictive marker for prognosis is used for AML (acute myeloid leukaemia)?

A

gene expression profiling of AML subtypes

AML subtypes with different translocations are clearly distinguishable, match the translocation pattern with the known prognosis for each translocation

67
Q

how is HER2+ breast cancer treated and why?

A

with the drug Herceptin

HER2 gene codes for a positive growth factor receptor (HER2 receptor)

overexpression of HER2 found in 30% of breast cancers
- this makes cells more responsive to +ve growth factors

Herceptin is an antibody drug targeted to HER2 and so stops the overexpression, reducing the cancers response to positive growth factors

nb individuals whose cancers are HER2- will have no response to Herceptin treatment

68
Q

what is the difference between invasion and metastasis?

A

INVASION

  • invades adjacent normal tissue
  • destroys normal tissue

METASTASIS
- spreads from site of origin to distant sites and forms new tumours in these new areas

69
Q

do basal cell carcinomas often metastasise?

A

no, almost never

70
Q

what is the most lethal type of skin cancer?

A

malignant melanoma
- cancer of skin melanocytes (produce melanin)

often metastasises

71
Q

what % of adult cancer patients have metastatic disease?

A

50%

72
Q

what proportion of paediatric cancer patients have metastatic disease?

A

majority

73
Q

what proportion of lung cancer patients have metastatic disease?

A

majority

74
Q

what proportion of breast cancer patients have metastatic disease?

A

one third

75
Q

what are cadherins?

A

cell-cell adhesion molecules

“Caderins begin with a C, as does Cell”

76
Q

what are integrins?

A

cell to extracellular matrix adhesion molecules

“integrins INTERGRATE cells to the extracellular matrix”

77
Q

what do mutations in cadherins lead to?

A

loss of cell-cell adhesion AND loss of contact inhibition

78
Q

what do mutations in integrins lead to?

A

decreased cell-matrix adhesion

79
Q

why does EMT (epithelial - mesenchymal transition) in tumours lead to invasion and metastasis?

A

epithelial cells are tightly connected, polarised and tethered

mesenchymal cells are loosely connected and able to migrate

therefore invade

80
Q

how do tumour cells degrade extracellular matrix?

A

using matrix metalloproteinases

81
Q

what enzyme degrades collagen types 1, 2 and 3?

A

interstitial collagenases

82
Q

what enzyme degrades collagen type 4 and gelatin?

A

gelatinases

83
Q

what enzyme degrades collagen type 4 and proteoglycans?

A

stomolysins

84
Q

in normal tissues what counteracts matrix metalloproteinases to prevent excess extracellular matrix breakdown?

A

tissue inhibitors of metalloproteinases

85
Q

what are the 4 routes of metastasis?

A

lymphatic

blood

transcoelomic

implantation/direct seeding

86
Q

what does transcoelomic metastasis mean?

A

across peritoneal, pleural, pericardial cavities or in CSF

87
Q

what does implantation/direct seeding mean?

A

spillage of tumour during biopsy/surgery

88
Q

what are the 5 stages of metastasis?

A

detachment invasion

intravasation (goes into blood vessel)

survival against host defences (in blood stream)

adherence extravasation (goes from blood vessel to distant site)

growth

89
Q

what route of metastasis do carcinomas normally follow?

A

lymphatic spread

90
Q

what route of metastasis do sarcomas normally follow?

A

blood spread

91
Q

what route of metastasis do ovarian tumours often follow?

A

transcoelomic

92
Q

what are the two hypotheses of patterns of metastasis?

A

mechanical hypothesis
- dictated by anatomy (ie GI cancer spreads to liver as that’s where blood goes next)

seed and soil hypothesis
- bits of cancer spread everywhere but they only grow into full secondary tumours if the ‘environment’ is right!

93
Q

what are 3 promoters of angiogenesis (and what are they produced by)?

A

VEGF (vascular endothelial growth factor) - produced by tumour cells

PDGF (platelet-derived growth factor) - produced by stromal (connective tissue) cells

TGFB (transforming growth factor beta) - produced by inflammatory cells

“anything with growth factor (GF) in is likely to promote angiogenesis”

94
Q

what are 4 inhibitors of angiogenesis?

A

ECM (extracellular matrix) proteins

thrombospondin

canstatin

endostatin

“anything with ‘STatin’ in is likely to STop angiogenesis”

95
Q

what does the STAGE of a tumour measure?

what is a common staging tool?

A

how ADVANCED is the tumour? (has cancer spread and how?)

TMN
- tumour size
- metastasis
- spread to nodes
values from each calculated to give an overall stage of 1-4

nb stage can be clinical, radiological, pathological

so where, along the progression from normal towards killing the patient, is the tumour currently at

96
Q

what does the GRADE of a tumour measure?

A

how AGGRESSIVE is the tumour?

ie how different it looks from the tissue of origin

so how quickly the tumour is progressing towards killing person

97
Q

what staging system is used for colorectal cancer? and what do the stages mean?

A

DUKES

A = invades into, but not through, bowel wall

B = invades through bowel wall but with no lymph node metastases

C = local lymph nodes involved

D = distant metastases

98
Q

What four characteristics are used to GRADE tumours?

A

differentiation
(how much does tumour resemble tissue it originates from, poorly differentiated = looks very different from original)

nuclear pleomorphism and size

mitotic activity (incl. abnormal mitotic form)

necrosis

(also vascular proliferation)

nb grading is performed by histopathologists and is subjective

things are graded G1(near normal) –> G4 (very bad)

99
Q

what does a tumour have to do to be called malignant? (as opposed to benign)

A

invade local tissue

(doesn’t necessarily have to metastasise!!)

eg basal cell carcinomas invade but don’t metastasise! (so technically a malignancy but, in practise, often not called malignant)

100
Q

what’s more common, sarcomas or carcinomas?

A

carcinomas

101
Q

what is the staging system for lymphomas?

A

Anarbor

102
Q

what is the staging system for gynaecological cancers?

A

FIGO

103
Q

what two types of women are endometrial cancers more common in?

A
  • postmenopausal

- obese (as fat cells produce oestrogen)

104
Q

what are 5 cancers which often metastasise to bone?

A
  • lung
  • prostate (because venous drainage goes next to spine)
  • kidney
  • breast
  • thyroid
105
Q

what is a pathological fracture?

A

a bone fracture which occurred mainly due to a medical reason (as well as minor trauma)

eg osteoporosis or bone cancer

106
Q

what are 3 examples of oncogenes?

A

Ras

HER2

PI3K

107
Q

what is the most commonly mutated TSG?

A

P53

most cancers have loss of this gene

108
Q

what 4 things are used to assess prognosis in any cancer?

A
  • tumour type (and subtype)
  • stage
  • grade
  • molecular profile (happening more and more)

* Year 2 EMS (7 decks)

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