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M2MWeek5 > Molecular Basis of Carcinogenesis I, II, III > Flashcards

Molecular Basis of Carcinogenesis I, II, III Flashcards

1
Q

What are the 5 characteristics of malignant/cancer cells?

A

1: Unresponsive to normal signals for proliferation control 2: De-differentiated (lack many of the specialized structures and functions of the tissue in which they grow) 3: Invasive 4: Metastatic (capable of shedding cells that can drift through the circulatory system and proliferate at other sites) 5: Clonal in origin (derived from a single cell)

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2
Q

Compare/contrast benign tumor cells and cancer cells?

A

Benign tumor cells are not invasive or metastatic; but like the cancer cells have lost many of the growth controls and specialized functions of normal cells. They are immortalized

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3
Q

In which two types of genes must mutations occur for tumor initiation?

A

Oncogenes and anti-oncogenes

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4
Q

What do oncogenes do?

A

Normally stimulate cellular proliferation (analogous to the gas pedal of your car). Must be activated in cancer cells

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5
Q

What do anti-oncogenes do?

A

Tumor suppressors; normally inhibit cellular proliferation (analogous to the brake pedal of your car). Must be inactivated in cancer cells

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6
Q

In BCR-ABL fusion protein (aka Philadelphia chromosome) what is different about it?

A

The ABL gene is normally not expressed in these tissues; but once it gets fused it is expressed to such high levels that it drives cell proliferation and tumor genesis.

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7
Q

What cancer is associated with BCR-ABL?

A

CML (chronic myelocytic leukemia)

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8
Q

What kinds of changes would you see in oncogenes?

A

Can see quantitative changes or qualitative changes

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9
Q

What occurs to inactivate tumor suppressors? Examples where this happens?

A

LOH (loss of heterozygosity). Ex retinoblastoma (RB) and APC gene in FAP (familial adenomatous polyposis)

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10
Q

What is “Knudson theory?”

A

Said 2 hits or events were needed to produce retinoblastoma (ie; both Rb genes must be mutated. In familial they already have 1 hit so they only need 1 more)

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11
Q

Does aneuploidy correlate with a good or poor prognosis in many cancers?

A

Poor

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12
Q

Name 4 cancers and their associated genes where susceptibility is inherited as autosomal dominant

A

1: Familial Adenomatous Polyposis (FAP-APC gene) 2: Familial Retinoblastoma (RB gene) 3:F amilial Breast and Ovarian Cancer (BRCA1 and BRCA2 genes) 4: Wilms tumor syndromes

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13
Q

Name 4 cancers and their associated genes where susceptibility is inherited as autosomal recessive

A

1: Xeroderma pigmentosa (XP genes) 2: Ataxia-telangiectasia (AT gene) 3: Bloom�s syndrome 4: Fanconi�s congenital aplastic anemia (FA genes)

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14
Q

What type of gene is the retinoblastoma gene (RB gene)?

A

It is a antioncogene aka a tumor suppressor gene. This particular gene is the best understood of the cancer susceptibility genes

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15
Q

What do cytogenetic analysis of cells from retinoblastomas show? (I think this is where RB is)

A

Region around chromosome 13q14 often have an abnormal structure

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16
Q

What goes wrong with RB (several different options)?

A

Some Pts lack RB completely. Some have partial deletions or rearrangemetns of RB

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17
Q

How are RB mutations detected?

A

PCR or Southern hybridization

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18
Q

Compare/contrast the RB gene in healthy vs. tumor cells in cases of inherited retinoblastoma?

A

The normal (nonmalignant) retinal cells are heterozygous for the RB gene (normal/mutant). But the tumor cells have descended as a clone from a single cell that has acquired homozygosity for the retinoblastoma susceptibility gene. This is the hallmark of a antioncogene or tumor suppressor gene (LOH)

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19
Q

When is the Rb protein normally hyper- and hypo-phosphorylated?

A

Hyperphosphorylated in rapidly proliferating cells at S or G2 of the cell cycle. Hypophosphorylated in non-proliferating cells in G0 of G1 of the cell cycle

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20
Q

How does hypophosphorylation of Rb protein normally regulate the cell cycle?

A

Hypophosphorylated form of the RB protein normally functions to repress the entry of cells into the S phase. When RB becomes hyperphosphorylated it no longer inhibits this transition and the cells begin a cell division cycle

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21
Q

What happens when there is no RB protein or is is all nonfunctional?

A

Cells cannot down regulate their cell division and grow out of control

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22
Q

What phosphorylates the RB protein?

A

CDKs (cyclin-dependent protein kinases). They inactive the RB protein with phosphorylation; thereby allow the cell to proceed from G1 to S phase

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23
Q

What is weird about RB inheritance pattern?

A

It is inherited in an AD way; but you have to lose the wild type gene for it to be cancerous (ie; it is actually recessive)

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24
Q

If a PT presents with bilateral retinoblastoma; is it familial or sporadic?

A

Familial. Sporadic will always only be in one eye. This PT will also be at increased risk for other cancers

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25
Q

What are 2 animal tumor viruses that target the RB protein?

A

SV40 and HPV

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26
Q

How do SV40/HPV work to target the RB protein?

A

They drive a quiescent cell into S phase/proliferation by producing viral proteins SV40 T antigen (T = transforming) or HPV E7 protein

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27
Q

What to SV40 T antigen/HPV E7 protein do?

A

Bind to and inactive the RB protein

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28
Q

Which two proteins do HeLa cells express that allows them to keep growing?

A

HPV E7 and E6

29
Q

What does E6 protein do?

A

inhibits p53

30
Q

What is p53?

A

An important tumor suppressor. Mutated p53 found in 50% of all cancers

31
Q

Which gene works as a tumor suppressor in FAP (Familial Adenomatous Polyposis)?

A

APC Gene

32
Q

How is APC gene inherited?

A

Like RB; it is AD which puts patients at higher risk for colon cancer. LOH must occur (must lose wild-type gene) to tun benign adenomatous polyps into malignant. Same AD inheritence but recessive in function

33
Q

Where is APC gene located?

A

5q

34
Q

How does APC perform its tumor suppression?

A

Encodes a cytoplasmic protein that causes the degradation of any unbound Beta-catenin in the cytoplasm

35
Q

What is Beta-catenin normally bound to? Where is normally located in the cell?

A

Normally it is kept at the membrane by being bound to E-cadherin. Any loose/cytoplasmic beta-catenin gets degraded by a protein coded for by APC gene

36
Q

What happens when APC is lost in FAP patients?

A

Beta-catenin goes to the nucleus to produce transcription of oncogenes like c-myc. Loss of APC tumor suppressor causes an overexpression of the c-myc oncogene; results in cancer

37
Q

What are the inherited genes that increase risk for breast and ovarian cancers?

A

BRCA1 and BRCA2

38
Q

What is BRCA1 involved with in the cell?

A

Regulates checkpoints/DNA repair through recomination

39
Q

What is BRCA2 invoved with in the cell?

A

Combined with RAD51; involved with homologous recomination used for DNA repair

40
Q

Compare/contrast inherited vs. acquired cases of breast/ovarian cancers

A

Inherited cancers display LOH and are homozygous for mutated BRCA1 or 2 genes. Acquired cases do not display the mutated genes. (Note this is different than in RB where both inherited and acquired tumors show the gene mutation)

41
Q

If you are born homozygous for mutated BRCA2 gene; what disease do you get?

A

Fanconi’s anemia. (Heterozygotes get breast cancer after losing wild-type allele)

42
Q

Explain 2 ways that p53 gene acts as the “guardian of the genome.”

A

1: Acts as a transcription factor important for the expression of genes and prevents cells from replicating damaged/foreign DNA. In p53 defective cells; damaged DNA is replicated. 2: p53 also required for apoptosis

43
Q

What are the p53 point mutation “hotspots” seen in all human cancers?

A

amino acids 248 or 273

44
Q

What is a mutation hotspot that is unique to lung cancer?

A

An alternation in amino-acid 157 of p53. Result of mutagenic chemicals from cigarette smoke

45
Q

What do human viruses (ex Adenovirus and HPV) do to overcome the action of p53?

A

The viruses have oncogenes that act by inactivating p53. Adenovirus has E1B and HPV has E6 proteins. (These viruses also inactivate RB protein)

46
Q

Is p53 an oncogene or anti-oncogene? Why was it originally thought to be the opposite?

A

Anti-oncogene (tumor suppressor). Although a mutated p53 gene can become oncogenic and produce a mutant p53 protein that binds to wild-type p53 and inactivates it (dominant-negative mutation)

47
Q

Where were oncogenes first discovered?

A

Oncogenic retroviruses

48
Q

What are the 3 genes in a retrovirus’ RNA genome that DO NOT lead to tumors?

A

gag gene (codes for internal virion proteins); env gene (codes for virus membrane glycoproteins; pol gene (codes for a virus polymerase)

49
Q

What gene segment in retroviruses causes the ability to rapidly transform cells into the malignant phenotype?

A

v-onc

50
Q

What is v-src?

A

The oncogene of Rous Sarcoma Virus. Causes fibrosarcomas in certain birds

51
Q

What is v-erb? What are two related genes?

A

The oncogene of avian erythroblastosis virus causes erythroblastosis in chickens. Two related genes: erb-A and erb-B.

52
Q

What is v-abl?

A

The oncogene found in Abelson leukemia virus from mice

53
Q

What is v-myc?

A

Usually fused with a portion of the gag gene. It appears that this gene is capable of eliciting neoplastic transformation of cells

54
Q

How does v-src function?

A

Codes for the protein (pp60v-src). A membrane bound protein kinase that phosphorylates tyrosine residues in several different proteins. Theses proteins then change the properties of the cells by affecting gene expression

55
Q

How does v-erb-B function?

A

Codes for a protein that is similar in structure to the cell surface receptor for epidermal growth factor (EGFR). This raises the possibility that this protein has growth stimulating properties like EGFR. This receptor is a member of a family of related proteins that (like pp60v-src) exhibit tyrosine-specific protein kinase activity

56
Q

How does v-abl function? What is it similar to?

A

Codes for a protein kinase that phosphorylates tyrosine residues on other proteins. It is similar to the human cellular gene (c-ABL) that is found in the BCR-ABL translocation in the Philadelphia chromosome and is overexpressed in BCR-ABL CML

57
Q

What is a proto-oncogene?

A

A normal gene which when altered by mutation becomes an oncogene that can contribute to cancer (c-onc genes)

58
Q

What is v-onc vs. c-onc?

A

v-onc is viral oncogene; c-onc is cellular oncogne. The v-onc is a homologue of a gene that is found in normal cells. The virus picks up this gene and mutates it to induce cells to proliferate. Some of nearly same DNA sequences but some are quite different

59
Q

c-src vs. v-src

A

c-src has a different carboxy-terminal amino acid sequence than v-src and has numerous introns that do not exist in v-src

60
Q

c-myc vs. v-myc

A

c-myc has many introns not present in v-myc; although the coding sequences are nearly identical (7 amino acid changes)

61
Q

What do mutated human bladder cancer cells show in regard to the c-ras gene?

A

Shows point mutation in either codon 12 or 61 of the ras gene product. These mutations produce a ras protein that is unregulated and is always �on�. Detection of these ras mutations indicates a poor prognosis.

62
Q

What gene has been found amplified in neuroblastoma?

A

N-myc. Member of c-myc family of oncogenes

63
Q

Which c-onc gene is found amplified in about 20% of breast cancers? What does it do?

A

Her2/neu oncogene (aka erbB2). Encodes a integral membrane protein kinase (v-erb-B)

64
Q

What do higher levels of amplification correlate to in prognosis?

A

Poor prognosis (translocations of c-onc genes also indicate poor prognosis)

65
Q

What is herceptin?

A

Humanized mouse antibody. It is specific for the protein product of the HER2/neu/erbB2 oncogene. Extend the life of breast cancer patients and makes radiation more effective

66
Q

Why does herceptin work with breast cancer?

A

Many breast cancer cells overexpress HER2. This targets HER2 gene (and turns it off?). Targeted treatment

67
Q

Remember the drug that targets BRC-ABL protein?

A

Gleevec. Mimcs ATP; binds to ABL very well and not to other enzymes. Worked on CML leukemia. Resistance does come

68
Q

How does a heat map work?

A

Uses hybridization to tumor DNA to show areas where there are lots of increases and areas with deletions/decreases. Red is increases; Blue/Green is decrease

69
Q

What makes targeted therapies effective/what makes cancer cells vulnerable?

A

Oncogene addiction (among other things)

M2MWeek5 (5 decks)

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