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Molecular Biology Exam 3 > Cancer 2 > Flashcards

Cancer 2 Flashcards

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1
Q

What are the two broad types of mutations that cause cancer?

A

(1) Overactivity Mutations - gain of function - oncogenes - involves single mutation event and activation of gene causing proliferation (dominant).
(2) Underactivity Mutations - loss of function - tumor suppressor genes - involve genes that inhibit growth. Mutation event: one gene - no effect; second mutation causes problems (recessive).

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2
Q

What are the effects of oncogenes on causing cancer?

A

Oncogenes = gas pedal

Mutation of a single copy of proto-oncogene converts it to an oncogene and has dominant effect.

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3
Q

What are the effects of oncogenes on causing cancer?

A

Tumor-suppressor genes = brakes

Tumor suppressor genes have changes causing cancer that is recessive - both copies must be mutated.

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4
Q

Activation of oncogenes are caused by dominant mutations, where only one allele needs to be present for activity. What are the 4 mechanisms in which an activation of oncogenes can cause cancer?

A
  • Deletion or point mutation in coding sequence.
  • Regulatory mutation
  • Gene amplification
  • Chromosome rearrangement
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5
Q

What is the normal function of tumor suppressor genes?

A

Generally encode proteins that inhibit cell proliferation.

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6
Q

What are the two major categories of tumor suppressor genes?

A

(1) Proteins that normally restrict cell growth and proliferation.

> intracellular proteins that inhibit progression through Gi in cell cycle (e.g., Rb, CKI)
receptors or components of a signaling pathway that inhibit cell proliferation
proteins that promote apoptosis (caspase)

(2) Proteins that maintain integrity of the genome.

> checkpoint control proteins (ATM, ATR - detect DNA damage - stops cell cycle)
Remember Ataxia Telangiectasia
DNA repair enzymes or pathways

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7
Q

What are the two forms of retinoblastoma?

A
  • Hereditary form

- Sporadic form

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8
Q

What percentage of retinoblastoma is familial, in which both eyes are affected (tumors)?

A

40%

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9
Q

What percentage of retinoblastoma is sporadic (no family history) - single tumor one eye?

A

60%

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10
Q

The hereditary form of Rb is the loss of function or deletion of one copy of Rb in every cell - because defect is inherited, thus these cells are predisposed to be cancerous. What event occurs in these patients to cause a loss of herterozygosity - leading to cancer?

A

Somatic event occurs - eliminates one good copy and tumor forms.

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11
Q

What hypothesis has been proposed that causes the sporadic form of Rb?

A

Two Hit Hypothesis - first Rb gene obtains mutation then need second mutation Rb.

Sporadic - 2 normal Rb genes, one hit then 2nd hit so more rare than hereditary form.

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12
Q

In a normal functioning cell the Rb protein interacts with E2F to inhibit it. What is the function of E2F?

A

Binds to promoters of G1/S cyclin and S cyclin genes + DNA synthesis protein genes - induces gene expression - drives cell cycle.

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13
Q

True or False:

Proto-oncogene is a normal gene, usually involved in regulation of cell proliferation that can be converted to a cancer-causing oncogene by a mutation.

A

True

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14
Q

What mouse model is used as a tool for studying oncogenes?

A

Transgenic mice - express transgene of oncogene in mice and determine if cancer occurs.

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15
Q

What are the four common signaling pathways that are relevant in cancer, thus known as cancer genes?

A

(1) regulate cell proliferation
(2) control cell growth
(3) control division
(4) control apoptosis

all can be involved in cancer

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16
Q

What are the two types of genes, that can cause cancer if mis-regulated, are involved in the Rb pathway?

A
  • Cdk or cyclin = proto-oncogene.
    Non-Proliferating Cell
    > active CKI (p16) stops Cdk-Rb binds E2F (regulatory protein) to block
    > cyclin or Cdk genes could be oncogenes
  • CKI or Rb = tumor suppressor gene.
    Proliferating Cell
    > CKI absent so Cdk always activated
    > Rb inactive and E2F drives S-Cdk activation by making more cyclins
    > CKI or Rb could be lost = causing cancer
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17
Q

How does a mutation in Bcl2 cause cancer?

A

Bcl2 mutation stops apoptosis.

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18
Q

What are the 4 mechanisms in which p53 in involved in?

A

(1) cell cycle arrest
(2) DNA repair
(3) apoptosis
(4) block of angiogenesis

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19
Q

What are the four functions that will be lost if you lose p53?

A

(1) loss of checkpoint control in cell cycle
(2) loss of cell cycle arrest in response to DNA damage
(3) loss of apoptosis in response to DNA damage
(4) loss of DNA repair activities

20
Q

What is the role of p53 in stopping the cell cycle?

A

Stimulates transcription of gene encoding CKI (Cdk inhibitory protein) called p21.

p21 binds to G1/S-Cdk and S-Cdk and so will stop cell cycle.

21
Q

Which pro-apoptotic proteins are activated by p53?

A

p53 also activates expression of pro-apoptotic proteins BH123 and BH-3.

22
Q

List 4 stimuli that activate p53 to trigger cell cycle arrest, senescence, and/or apoptosis.

A
  • hyperproliferative signals
  • DNA damage
  • telomere shortening
  • hypoxia
23
Q

How can DNA tumor viruses and tumor suppressor genes cause cancer?

A

> Papilloma viruses - cause warts and cervical cancer.

> Exist as latent phase extrachromosomal material (like plasmid in bacteria).

> Normally the replication of the viral DNA coincides with the replication of chromosomes.

> However, if tumor integrates with host DNA - interferes with control of cell division in basal cells - malignant tumor develops.

24
Q

Which viral proteins of the papilloma virus cause cells to replicate in an uncontrolled manner?

A

> Viral proteins of papilloma virus.

> The viral proteins that do this (cause malignancy) are E6 and E7.

> These bind to 2 tumor suppressor genes - Rb + p53.

> Cells can replicate in an uncontrolled manner.

25
Q

What happens in the activation of proliferation by DNA tumor viruses?

A

> Viral protein E7 binds to Rb and so E2F (gene regulatory protein) can cause overexpression of G1/S-Cdk and S-Cdk and cells grow and divide.

> AND viral protein E6 binds to p53 and inactivates it and so CKI is not produced and Cdk’s can act uncontrollably.

> Cell proliferation activated by DNA virus.

Thus, viral proteins inhibit tumor suppressor genes.

26
Q

The barriers to cancer cell metastasis is escape from parent tissue, travel through circulation, and colonization of remote site. Which of these areas are difficult for cancer cells to invade, and which are easy for cancers cells to invade?

A

> It is difficult for cancer cells to:

  • escape from parent tissue
  • colonization of remote site

> It is easy for cancer cells to:
- travel through circulation

27
Q

Cancer cells escape from parent tissue.

A

> Difficult:

  • local invasiveness
  • for most cancers that first step of metastasis is local invasion and only few cancer cells will pass this barrier.
28
Q

Cancer cells travel through circulation.

A

> Easy:

  • the initial entry into blood or lymphatic vessels is facilitated by angiogenesis of new blood or lymphatic vessels.
  • most cancer cells have acquired this ability before becoming invasive through mutations in genes that control apoptosis.
29
Q

Cancer cells colonization of remote site.

A

> Difficult:

  • many cancer cells survive in circulation and exit at remote sites.
  • however, some cells die after they enter a foreign tissue, others fail to proliferate, or only form micro-metastasis.
  • only a few metastasis-competent cells continue to proliferate in a foreign tissue (colonization) and form metastatic tumors.
30
Q

What is one of the most preventable cancers?

A

Colorectal Cancer

31
Q

What reveals early detection of colorectal cancer?

A

colonoscopy

32
Q

How long does it take for tumor progression in colorectal cancer?

A

10 years

start colonoscopy at age 50

33
Q

What are the characteristics of colorectal cancer?

A

> Arises in the epithelial lining of large intestine.

> Gut is renewed at a rapid rate (takes only a week to replace all of the epithelial sheet in your large intestine).

> Renewal is from stem cells.

> Highly organized epithelium in large intestine.

> Mutations that disrupt organization signals begin tumor progression for colorectal cancer.

> Colon cancer:

  • cancer: 600,000 deaths annually
  • 10% of total cancer deaths from colorectal cancer
  • Age: > 55 years.

> Colonoscopy can detect small, protruding benign tumor called a polyp: adenoma.

34
Q

What is a polyp a precursor of?

A

colorectal cancer

  • *cut off polyp = cure**
    • If left alone, malignant tumor develops from adenoma (polyp)**
35
Q

What is the cause of 40% of colorectal cancers?

A

Have point mutation in K-Ras.

early adenoma to intermediate adenoma

36
Q

What is the cause of 60% of colorectal cancers?

A

Inactivating mutation of p53.

from late adenoma to carcinoma

37
Q

What is the cause in greater than 80% of colorectal cancers that proceeds from normal epithelium to hyperplastic epithelium?

A

loss of Apc due to mutation

38
Q

What is the cause of hereditary colorectal cancer - familial adenomatous polyposis coli (FAP)?

A

Caused by inactivation of tumor suppressor gene APC.

  • hundreds of polyps
  • at least one polyp will certainly become malignant
39
Q

True or False:

Patients with FAP have inactivating mutations or deletions of one copy of Apc, however, most colorectal cancers are not hereditary but more than 80% of these cancers show inactivation of both copies of the Apc genes - acquired through lifetime.

A

True

** our best weapon against cancer is early detection **

40
Q

What is hereditary non-polyposis colorectal cancer (HPNCC)?

A

> These cancer cells are unusual.

> Most HPNCC cells have normal # or near-normal # of chromosomes.

> Colorectal cancer cells usually have mutiple copies of chromosomes.

41
Q

What is the difference between colorectal cancer and HNPCC?

A

(A) Colorectal cancer - usually has a chromosomal mess with chromosomal abnormalities such as translocations, deletions, and abnormal number of certain chromosomes.

(B) HNPCC - chromosomes look almost normal - but defects in DNA mismatch repair.

42
Q

What is the cancer strategy when using chemotherapy?

A

Give as strong a dose as possible to kill tumor and almost kill the patient.

Chemotherapy stops cell division - impact on rapidly dividing cells (cancer cells)

43
Q

What is the reciprocal translocation between chromosomes 9 and 22 responsible for?

A

Chronic Myelogenous Leukemia

44
Q

Why is Bcr-Abl the cause of chronic myelogenous leukemia (CML)?

A

> Abl is a tyrosine kinase for cell signaling.

> N-terminus Bcr makes it hyperactive.

> Coding sequence of Bcr is fused to Abl when chromosomal translocation occurs.

> Bcr-Abl makes highly active tyrosine kinases and is highly expressed.

> Causes cell proliferation - cancer CML.

> Treatment - Gleevec - inhibits tyrosine kinase activity.

> Gleevec causes disappearance of Philadelphia Chr in > 80% patients.

45
Q

What is the treatment for chronic myelogenous leukemia?

A

Gleevec - which functions to inhibit tyrosine kinase activity.

Gleevec takes place of ATP on Bcr-Abl - substrate not changed. Thus inhibiting the phosphorylation of the substrate proteins, thus, substrate protein is not activated - leading to no signal - NO leukemia.

causes disappearance of Philadelphia Chr in > 80% patients.

46
Q

What is the strategy for using combination therapy?

A

Treat patients with drugs simultaneously in an advantage for cancer therapy (CML).

47
Q

What’s is next in personalized medicine for cancer patients?

A

> Cancers can be extremely heterogenous - so how treat?

> Gene expression profile of a cancer can be analyzed by microarray to identify disregulated cancer - critical genes.

> Custom-driven treatments can be selected to target specific disregulated cancer - critical proteins.

Molecular Biology Exam 3 (9 decks)

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