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Pathoma > Chapter 3.2 Carcinogenesis > Flashcards

Chapter 3.2 Carcinogenesis Flashcards

1
Q

What are carcinogens?

A

agents that damage DNA

oncogenic viruses

radiation can induce DNA damage

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2
Q

Aflatoxins are related to which carcinoma? Where do they come from?

A

important relationship to hepatocellular carcinoma

-derived from Aspergillus, which can contaminate stored grains

byproduct of Aspergillus would be aflatoxins which increase the risk of hepatocellular carcinoma

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3
Q

Alkylating agents increase the risk of what type of disease? Explain.

A

increase risk of leukemia/lymphoma

when we treat patients who have cancer with alkylating agent, one complication is increased risk of secondary lymphoma/leukemia years down the line (long term side effect of chemotherapy)

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4
Q

What cancers does alcohol cause? Explain the etiology.

A

related to squamous cell carcinoma of oropharynx and upper esophagus, pancreatic carcinoma, and hepatocellular

alcohol causes chronic pancreatitis which can lead to carcinoma

alcohol trashes liver, cirrhosis which increases risk for hepatocellular carcinoma

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5
Q

Exposure to arsenic leads to which cancers?

A

increases risk of squamous cell carcinoma of skin (women who used to work in England in field didn’t want people to see they had been working so they’d apply arsenic to skin which would lighten it; then they would develop squamous cell carcinoma

arsenic poisoning - test for it by clipping fingernails or remove hair and it can be found in fingernails and hair

increases risk for lung cancer (arsenic present in cigarette smoke)

angiosarcoma of liver

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6
Q

What two things can exposure to asbestos lead to? Which is more likely?

A

increases risk for lung cancer and mesothelioma (mesothelial cells of pleura)

exposure to asbestos is more likely to lead to lung cancer than mesothelioma !! IMPORTANT

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7
Q

What type of cancers does cigarette smoke lead to? Explain the etiology.

What is the most common carcinogen worldwide?

A

carcinoma of oropharynx, squamous cell carcinoma of esophagus, lung cancer, kidney and bladder (urothelium - kidney, bladder, ureters, part of urethra …key risk is cig smoke) carcinogens get into blood, filtered in kidney, concentrated in urine, hang out in bladder and entire collecting system is bathed in carcinogen constantly over period of years; key risk for kidney and bladder cancer

most common carcinogen worldwide; polycyclic hydrocarbons are particularly carcinogenic

(40 carcinogens in cigarette smoke but most important are polycyclic hydrocarbons)

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8
Q

What does the following carcinogen lead to?

Nitrosamines

Where is it found?

A

stomach carcinoma

found in smoked foods; responsible for high rate of stomach carcinoma in Japan

(intestinal type of stomach carcincoma or diffuse type… nitrosamines are related to intestinal type of stomach carcinoma and intestinal type is more common)

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9
Q

What does the following carcinogen lead to?

Naphthylamine
From what is this carcinogen derived?

A

urothelial carcinoma of bladder

derived from cigarette smoke

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10
Q

What does the following carcinogen lead to?

Vinyl chloride

Describe the population of patients most likely to be exposed.

A

angiosarcoma of liver (important study that det. this association; workers exposed and large amount developed this cancer)

occupational exposure; used to make polyvinyl chloride (PVC) (plastic type) for use in pipes

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11
Q

What does the following carcinogen lead to?

Nickel, chromium, beryllium, silica

A

lung carcinoma

occupational exposure

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12
Q

Describe the what exposure to the following oncogenic virus can lead to:

EBV

What is the typical patient affected? How does it present?

A

nasopharyngeal carcinoma, Burkitt lymphoma and CNS lymphoma in AIDS

classic patient is Chinese male or African individual,

classical presents at neck mass, metastasizes early to regional lymph nodes,

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13
Q

A Chinese male presents with a neck mass. Which oncogenic virus is most likely? What does this virus lead to?

A

EBV

nasopharyngeal carcinoma, Burkitt lymphoma and CNS lymphoma in AIDS

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14
Q

Describe the what exposure to the following oncogenic virus can lead to:

HHV-8

How do patients present?
What are the three patient subsets that are affected? Describe how to treat each.

A

karposi sarcoma (tumor of endothelial cells)

patients present with purple-ish raised lesions

patient subsets
1) older eastern European males -treatment is to excise the karposi sarcoma

  1. AIDS patients - treat virus by anti-retroviral agents to boost CD4 positive T cell count to allow immune system to destroy HHV-8 cells
  2. patients with transplants bc immunosuppressed - treat with reduces immunosuppression slightly to empower immune system to go kill those virally infected cells
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15
Q

Describe the what exposure to the following oncogenic virus can lead to:

Hepatitis B and C virus (HBV and HCV)

A

B- DNA virus
C- RNA virus

Hepatocellular carcinoma

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16
Q

Describe the what exposure to the following oncogenic virus can lead to:

HTLV-1

A

adult T cell leukemia/lymphoma

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17
Q

Describe the what exposure to the following oncogenic virus can lead to:

High risk HPV (16, 18, 31, 33)

A

squamous cell carcinoma of vulva, vagina, anus and cervix; adenocarcinoma of cervix

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18
Q

What type of cancer does ionizing (nuclear reactor accidents and radiotherapy) radiation lead to?
What is the mechanism?

A

AML, CML, papillary carcinoma of thyroid (children exposed to Chernobyl accident)

mechanism: generates hydroxyl free radicals (water within tissues hits with ionizing radiation and byproduct is hydroxyl free radicals)

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19
Q

What is the most common cause of non-ionizing radiation?

A

UVB sunlight is most common course

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20
Q

Non-ionizing radiation leads to what type of cancers? Explain the mechanism.

A

basal cell carcinoma of skin, squamous cell carcinoma of skin, melanoma of skin

results in formation of pyrimidine dimers (nicks in DNA) which are normally excised by restriction endonuclease, excessive exposure will produce exceessive damage and overrun ability to respond to damage

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21
Q

What does xeroderma pigmentosum lead to? Explain the mechanism.

A

xeroderma pigmentosum is mutation of restriction endonucleases that excise formation of pyrimidine dimers in DNA

without these endonucleases the dimers form and DNA damaged and not repaired; leads to basal cell carcinoma, squamous cell carcinoma, and melanoma of skin

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22
Q

What are the three key systems that can be disrupted by carcinogenic agents?

A

DNA mutations eventually disrupt key regulatory systems

allows for tumor growth and progression

  • proto-oncogenes
  • tumor suppressor
  • regulators of apoptosis
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23
Q

What are proto-oncogenes?

A

essential for cell growth and differentiation

mutations form oncogenes
lead to unregulated cell growth

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24
Q

What are the 5 categories of proto-oncogenes?

A 
growth factors
growth factor receptors
signal transducers
nuclear regulators 
cell cycle regulators
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25
Q

Describe the process normally of how a cell division is activated.

A

Growth factor on cell surface, when cell needs to divide (constant turn over or repair/ regeneration)

Growth factor comes in and binds Growth factor receptor, sends signal, signal transducer carries signal to nucleus, where cell cycle regulators activated so cycles through G1, S, G2, M

(each step involves proto-oncogenes)

26
Q

Give a clinical example of how growth factor mutation can lead to cancer. Describe the mechanism.

A

growth factor -Platelet derived growth factor (PDGFB), mutated gene associated with formation of a tumor

astrocytoma - tumor of astrocytes of brain (type of glial cell)

in this case, overexpression due to mutation of PDGFB, which drives formation of astrocytoma, autocrine loop

astrocyte overproduces PDGF which can result in over-growth of cell, extra PDGF keeps hitting receptor which will signal nucleus to divide, cell keeps growing in unregulated manner

27
Q

Explain the mechanism by with a growth factor receptor could lead to cancer.

A

if cell expressing growth factor receptor; (mutation and over expression of receptor, then simple stimulus of growth factor results in 100x or 1000x for cell to grow and divide

28
Q

What is ERBB2/HER2 neu?

A

epidermal growth factor receptor amplified in a subset of breast cancers
(mechanism is amplification)

designer antibody (trestomezab) designed against HER2/neu receptor;

29
Q

Patient with history of breast cancer comes to you having read an article about new treatment that is a designer antibody against a growth factor receptor. What test would be important to perform to determine whether should be treated with this antibody?

a. estrogen receptor
b. progesterone receptor
c. Her2/neu

A

Her2/neu

30
Q

If suspect MEN2A or MEN2B in a patient, then what might you explore as a next step in diagnosis or treatment?

A

RET studies

if RET mutation then prophylactic removal of thyroid before tumor can form bc medually carcinoma of thyroid can kill patient

(testing for RET is important in patients with familial MEN2B or A bc MEN2A/2B are associated w mutations in RET proto-oncogene and are passed down in an autosomal dominant manner )

RET is a neural growth factor receptor; point mutation can lead to cancer
(could lead to pheochromocytoma as well)

31
Q

What cancer is a mutation in the KIT receptor associated with?

A

gastrointestinal stromal tumor

stem cell growth factor receptor
point mutation

32
Q

What is RAS gene family?

A

commonly mutated in lots of cancers; up to 70-80 percent of human tumors have RAS mutation associated with it

seen in carcinoma, melanoma, and lymphoma

Signal transducer, GTP binding protein

point mutation can lead to cancer

33
Q

What can a mutation in RAS lead to? What types of cancers?

A

(commonly mutated in lots of cancers; up to 70-80 percent of human tumors have RAS mutation associated with it)

seen in carcinoma, melanoma, and lymphoma

34
Q

Describe the mechanism by which RAS can lead to carcinomcas, melanoma, and lymphoma.

A

Receptor; RAS usually intracellularly bound to GDP, as soon as GF binds the receptor, GDP gets kicked off and RAS gets associated with GTP; now this complex can send message down to nucleus

so you don’t want to much message sent to nucleus, RAs can cut away a phosphate and change GTP to GDP;

GAP (GTPase, associated protein) helps RAS cleave that phosphate and shut off active form;

mutation in GAP protein then RAS has hard time converting GTP to GDP and can’t shut off; (mutated ras inhibits activity of GTPase) means excess signal is sent to signal and causes cell to overgrow.

point mutation can lead to cancer.

35
Q

Describe the role of ABL. Describe the mechanism by which it can lead to cancer.

A

is a tyrosine kinase; when 9,22 translocation, there is overreaction

classically results in CML (and some types of all ALL)

9, 22 translocation DEFINES CML but is also seen in some types of ALL (in particularly adult forms; ALL usually ALL is form seen in children)
9,22 translocation also called Ph+ (Philadelphia chromosome

ALL w 9. 22 translocation has a relatively poor prognosis

36
Q

Describe the role of the MYC family and their function.

A

They are transcription factors go to nucleus and cause upregulation of genes necessary for growth

(nuclear receptors that lead to cancer)

37
Q

What is most important nuclear regulator?

A

MYC

38
Q

What are c-MYC, N-MYC, and L-MYC associated with?

A

c-MYC = Burkitt lymphoma- translocation 8/14

N-MYC=Neuroblastoma (amplification)
L-MYC= Lung carcinoma (small cell) (amplification)

39
Q

Explain the etiology of Burkitt’s lymphoma.

A

w c-MYC translocation will result in Burkitt lymphoma (lymphoma of B cells)

mechanism by which this happens is usually a translocation of chromosomes 8 and 14 involving Ig (heavy chain)

B cells usually express Ig heavy chain (which sits on chromosome 14)

translocation on MYC (sits on chromosome 8) … results in switching of Ig heavy chain with MYC… this will also turn on MYC (bc that location in chromosome is “ON” location in a B cell) so there is massive overproduction of MYC and result in massive growth of the tumor

40
Q

What is a key histological finding in Burkitt’s lymphoma?

A

A starry sky appearance; tumor cells represent sky (very blue) but stars (white areas) represent areas of macrophages eating cells that are dying

cells growing so rapidly that grow and die, macrophages consume as they’re dying

41
Q

Describe the cell cycle briefly.

A

cell cycle consisted of G1, S, G2, and M

The entire cell cycle is highly regulated; in particular G1 to S, G1 to S is most highly regulated, before you put cell to S phase where cell copied, make sure it should be going to S phase, make sure its not carrying any mutations in its DNA

42
Q

Explain the etiology of mantle cell lymphoma.

A

CCND1 (cyclin D1) - cell cycle regulator

mantle cell lymphoma
(basically due to 11/14 translocation)

Mantle cell lymphoma is a lymphoma of B cells. Within B area of lymph node (cortex) you have follicles, and outside follicle you have mantle, outside mantle you can develop region called margin; within each of these regions you can get a tumor (follicular cell lymphoma, mantle cell lymphoma, or marginal cell lymphoma)

mantle cell lymphoma driven by 11/14 B

B cells normally over-expressing Ig heavy chain which sits on C14, if CD gets translocated to Ig(H) spot then you get overexpression of cyclin D which allows cell to go from G1 to S

43
Q

Biopsy of lymph node is performed and shows expansion of the region next to the follicle. What genetic abnormality could cause this condition?

A

mantle next to follicle

mantle cell lymphoma caused by 11,14 translocation

B cells normally over-expressing Ig heavy chain which sits on C14, if CD gets translocated to Ig(H) spot then you get overexpression of cyclin D which allows cell to go from G1 to S

44
Q

On what chromosome is CCND1 (cyclin D1)?

A

14

…key translocation in mantle cell lymphoma is 11/14

45
Q

What role can CDK4 play in cancer?

A

CDK4 is a cell cycle regulator

cyclin-dependent kinase,
amplification
related to melanoma

46
Q

What type of mutation can lead to melanoma?

A

CDK4 amplification (a cell cycle regulator, a cyclin-dependent kinase) can lead to melanoma

47
Q

What pathological process is associated with a 8/14 translocation? 11/14 translocation?

9/22 translocation?

A

14 has heavy chain immunoglobulin …

8- c-MYC, translocation results in Burkitt lymphoma

11- cyclin D1 (CCND1), translocation leads to mantle cell lymphoma

9/22 (philadelphia chromosome)- ABL tyrosine kinase (signal transducer activated) leading to CML and some types of ALL

48
Q

What is the role of tumor suppressor genes?

A

regulate cell growth

-decrease “suppress” risk of tumor formation

p53 and Rb

49
Q

What is p53’s function? Explain its role and mechanism of action.

A

regulates cell cylce progression from G1 to S

if cell wants to go from G1 to S, it has to get past p53, p53 is like traffic cop, “okay, show me your DNA” if p53 looks at DNA and sees that it is mutated, will blow molecular whistle and call in repair enzymes to repair cell before S phase, or says “no way, we can’t repair” so then would blow another whistle and call in BAX, BAX will destroy Bcl2 (Bcl2 stabilizes the mitochondrial membrane so cytochrome c doesn’t leak out) when cytochorome c leaks out it will activate caspases to induce apoptosis (when severe DNA mutation in a cell)

so in response to DNA damage, p53 slows the cell cycle and up-regulates DNA repair enzymes
if not possible will induce apoptosis

50
Q

What is Knudson’s two hit hypothesis? Explain.

A

Both copies of p53 or Rb must be knocked out for tumor formation

Loss is seen in greater than 50% of cancers

Germline mutations of p53 results in Li-Fraumeni syndrome; increased risk for multiple types of carcinomas and sarcomas (bc inherit one bad copy from a parent)

51
Q

Describe the etiology of Li-Fraumeni’s syndrome. What causes it? What are patients at risk for?

A

Germline mutations in p53 results in Li-Fraumeni syndrome; increased risk for multiple types of carcinomas and sarcomas (bc inherit one bad copy from a parent)

52
Q

Explain the role of Rb.

A

regulates progression from G1 to S.

When cell wants to go from G1 to S, it needs E2F, E2F is normally bound to Rb; in order for it to be released Rb must be phosphorylated by cylcinD/CDK4 complex. When phosphorylated it releases E2F and now the cell can go from G1 to S

if mutation in Rb that E2F is free; that means cells can easily go from G1 to S and can result in a tumor.

53
Q

Who phosphorylates Rb?

A

cylcinD/CDK4

54
Q

What does Rb mutation result in?

A

constitutively free E2F; allowing progression through the cell cycle and uncontrolled growth of cells

55
Q

What are some ways that Rb can be knocked out?

A

if a patient has sporadic mutations, both copies of Rb being knocked out they develop unilateral retinoblastoma (v unlikely)

Germline- (familial retinoblastoma) -then can develop bilateral retinoblastoma leading to osteosarcoma.

56
Q

What are patients with a familial retinoblastoma at risk for?

A

Germline- (familial retinoblastoma) -then can develop bilateral retinoblastoma leading to osteosarcoma.

(easier to get that second hit if all their eye cells already have one bad copy of the gene)

57
Q

Explain the consequences of a 14/18 translocation and what disease process can ensue.

A

Bcl2 is overexpressed in follicular lymphoma

t(14; 18) on 14 is Ig(heavy chain) Bcl2 is on chromosome 18

when Bcl2 goes to IgH region, then Bcl2 is over-expressed, bc Bcl2 is over-expressed, apoptosis will not occur bc Bcl2 really stabilizing

in follicle you DO want a lot of apoptosis (B cells undergoing somatic hypermutation -random generation of mutations within B cell so you can increase the diversity of antibodies being produced by the B cell… so somatic hypermutation is desired state in lymph node; but if those mutations fail, you want those cells to die

B cells born in bone marrow, as naive B cells, go to college in lymph node, in lymph node they “fail” if they don’t generate new antibodies in somatic hypermutation. Failure = apoptosis. As B cells pile up will produce a folliclular lymphoma (B cells not apoptosing bc there is markedly increased Bcl2)

58
Q

Describe how tumor cells can achieve cell immortality.

A
  • telomerase
  • angiogenesis
  • evade immune surveillance (downregulating expression of MHCI)
59
Q

Describe how tumors use angiogenesis.

A

Angiogenesis is necessary for tumor growth and survivial

fibroblast growth factor (FGF) and VEGF are commonly produced by tumor cells to stimulate angiogenesis

60
Q

How do tumors avoid immune surveillance.

A

Avoiding immune surveillance

mutated, producing abnormal proteins, which will be expressed on MHC I.
when that happens CD8+ T cells can come in and kill the tumor

so tumors can evade immune surveillance by down-regulating expression of MHC I, so abnormal proteins being prod. by tumor wont be expressed on surface and CD8+ can’t come in and kill the tumor

immunodeficiency (primary and secondary) increase the risk for cancer

61
Q

How do tumors use telomerase?

A

Telomerase is necessary for cell immortality

Normally, telomeres shorten with serial cell divisions resulting in senescence (cell shuts down and stops dividing)

Cancers have upregulated telomerase; preserved telomeres (so cancer cells can keep dividing)

Pathoma (23 decks)

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