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CMBM exam 5 > CANCER GENETICS :) > Flashcards

CANCER GENETICS :) Flashcards

0
Q

Knudson’s ‘Two hit hypothesis’ of a single gene

A

two genetic alterations are required

  • one germline & one somatic
  • two somatic
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1
Q

BRCA1/2 seen what percent of breast cancer cases?

A

~5%

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2
Q

Haploinsufficiency of a single gene

A

loss of single copy of gene is sufficient

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3
Q

Some dominant cancer predisposition phenotypes

A

see elevated risk in heterozygotes
RB1 - inherited retinoblastoma
APC - familial adenomatous polyposis (FAP)
NF1, NF2

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4
Q

Tumor suppressor gene mechanisms

A

Regulates rate or cessation cell cycle
Regulate cell death/apoptosis
Repair DNA

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5
Q

Tumor suppressor genes

A

normal activity of gene is to suppress (or restrain) growth
when mutated and function is loss, growth (cell division) can occur uncontrollably
the number of identified tumor suppressors continues to expand

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6
Q

Mechanism of action: Tumor suppressor genes

A
  1. regulate rate or cessation of cell cycle
  2. Regulate cell death/apoptosis
  3. Repair DNA
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7
Q

cdk4/cyclin D

A

promote progression from G1 to S

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8
Q

cdk 2/cyclin E

A

commit to replication

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9
Q

cdk 2/cyclin A

A

initiate replication

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10
Q

cdk 1/cyclin B

A

promote mitosis

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11
Q

Retinoblastoma (Rb)

A

tumor suppressor, first one discovered
ubiquitously expressed
loss of finction = unscheduled cell proliferation
regulation of cell cycle progression via interaction with E2F to repress E2F dependent transcription of cell cycle genes
promotes cellular differentiation (cell cycle independent)
Rb heterozygotes have clear elevated cancer risk: Knudson’s Two hit hypothesis

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12
Q

Multiple phosphorylations of Rb

A

inhibits Rb-E2F complex formation and the ability of Rb to arrest the cell cycle

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13
Q

how can DNA viruses cause tumors?

A

via inactivation of Rb and p53
inhibiting Rb inhibits E2F leading to activation of genes for DNA replication
inhibiting p53 leads to inhibition of apoptosis

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14
Q

How can Rb be inactivated and what results?

A

results in molecular and functional consequences
occurs by:
-mutation (retinoblastoma, small cell lung cancer, osteosarcoma)
-phosphorylation (breast cancer, melanoma, colon cancer)
-viral oncoprotein (cervical cancer)

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15
Q

Deregulation of Rb pathway

A

is common in human cancer

some examples Glioma/blastoma, breast, lung pancreas, GI, endometrium, bone marrow, head and neck, liver

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16
Q

p53

A

tumor supressor
transcription factor induced by stress
promotes growth arrest, senescence and apoptosis

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17
Q

Mutant p53

A

highly expressed in cancer cells
wildtype is lacking
frequent in most of the common types of human cancer

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18
Q

over expression of wildtype p53

A

repressed oncogene (MYC, HRAS) transformation of cells

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19
Q

TP53

A

most frequently mutated gene in human cancer
about half of all tumor specimens studied have mutant p53
tumors that lack mutations in TP53 often have changes in upstream regulators that abrogate p53 function

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20
Q

Hallmarks of tumor suppressor gene

A
  1. absence of wildtype gene/protein in tumor cells
  2. Humans carrying germline mutations should exhibit increased cancer susceptibility (germline mutations in p53 are largely responsible for Li-Fraumeni syndrome)
  3. Loss of the gene in experimental animal model should confer a cancer prone phenotype - p53 null mice develop cancers (lymphomas) with a high penetrance, early onset
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21
Q

p53 mutant mice had

A

a short life span

confirms p53 has important role tumor suppression

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22
Q

Li-Fraumeni syndrome

A

hereditary syndrome that is characterized by early onset cancers of diverse types
-germline mutation in p53 usually the culprit

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23
Q

if MDM2 is overexpressed then

A

p53 is turned off

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24
Q

what sort of cellular responses does p53 mediate?

A 
Through regulation of p53 target genes 
-metabolic homeostaiss 
-antioxidant defense 
-DNA repair 
-Growth arrest 
-Senescence 
Protein-protein interaction 
-apoptosis (severe stress)
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25
Q

what sort of stress would active p53 signaling?

A

oxidative stress, nitric oxide, hypoxia, ribonucleotide depletion, mitotic apparatus dysfunction, oncogene activation, DNA replication, double-strand breaks, telomere erosion

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26
Q

What is the role of MDM2?

A

inhibits p53

its transcription is also regulated by p53

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27
Q

Some examples of tumors where amplification of MDM2 is seen?

A

Esophagus
Nasopharynx
Brain and nervous system
Prostate

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28
Q

Phosphorylating p53

A

stabilizes it.

29
Q

Mechanisms of mutant p53 function

A
  1. Mutant p53 binds DNA to alter gene expression
  2. Mutant p53 binds to transcription factors to enhance their function
  3. Mutant p53 forms a complex with transcription factors to prevent their function
  4. Mutant p53 interacts with proteins to change their function directly
30
Q

Explain what happens when mutant p53 binds DNA

A

interacts with DNA directly using mutant p53 binding elements or other regions on the DNA, including MARs, to regulate transcription. some cofactors and other proteins are involved.
ex: EGR1

31
Q

Explain mutant p53 binding to transcription factors to enhance their function

A

mutant p53 enhances transcription by forming a complex with TFs that can include transcriptional cofactors and other proteins
response to stimulus mutant p53 is recruited to a transcription regulatory complex that can include TFs, cofactors and other proteins. This mostly results in activation of target gene expression
Stimulated by: TPA, VIT D, DNA damage

32
Q

Explain how mutant p53 forms a complex with transcription factors to prevent their function

A

mutant p53 decreases transcription by binding TFs and/or transcriptional cofactors and other proteins, sometimes preventing their binding to DNA. This activity can also involve aggregation of mutant p53 with other proteins

33
Q

Explain how mutant p53 interacts with proteins to change their function directly

A

mutant p53 interacts with other proteins, not directly involved in transcriptional regulation, and enhances or blocks their function

34
Q

level of p53 activity impacts

A

cancer susceptibility and cancer resistance

mutations cause the mutant p53 function to lie on a continuum where it is not or nothing when a point mutation occurs

35
Q

what are some roles of p53 outside of cellular survival?

A 
Reproduction 
Prolonged organismal life span 
Antioxidant functions 
Autophagy 
Glucose metabolism 
Mitochondrial respiration 
Embryonic stem cell pools
36
Q

APC

A

adenomatous polyposis coli
tumor suppressor
functions in cell adhesion and signaling
loss of APC is among the earliest events in colorectal cancer
70-75% of colorectal tumors - one allele of APC is mutated
FAP - familial adenomatous polyposis, autosomal dominant disorder (APC is truncated) (almost 100% FAP develop cancer by age 60)

37
Q

What does APC regulate?

A

Beta catenin in normal and cancer cells
When APC is mutated is no longer able to bind b-catenin for degradation, instead b-catenin is free to translocate to the nucleus and induce gene transcription

38
Q

BRCA 1 and BRCA 2

A

Tumor suppressor genes
germline mutation in BRCA1 increases lifetime cancer risk to 85% for breast cancer and 50% ovarian
few sporadic cancers have mutation in BRCA 1
most mutations identified as result in truncated proteins
large nuclear proteins
potential role in repairing double stranded DNA breaks and transcriptional regulation
potential role in G1/S checkpoint control

39
Q

BRCA is associated with

A

DNA repair
when inactivated or truncated will see cannot interact properly
failed repair of most genes - leads to cell cycle arrest or apoptosis through functioning p53 and p21
failed repair of p53 or other checkpoint genes - cell proliferation

40
Q

Tissue type and context play a big role when considering functional loss of tumor suppressor genes (uterus v. prostate v. breast v. blood)

A

w/r/t PTEN
at ~ 80% of function will start to see dysplasia in the uterus and cancer in the breast and symptoms in blood but prostate remains normal
30% is when start to cancer in the prostate
With low to none PTEN, context becomes important. with Prostate cancer and p53 wildtype there is senescence but aggressive cancer with a mutated p53. Same seen with Blood when normal p53 cases see HSC exhaustion/BM failure while mutated p53 cases see Leukemia

41
Q

Pt with colon adenocarcinoma. Characterization of tumor after surgical resection finds high levels of mutant p53. This most likely indicates

A

that the cellular response to stress was abnormal

42
Q

Oncogenes

A

gain of function which is bad news
transition from regulated to unregulated cell growth
-chromosomal instability (defects in mitotic chkpts and chromo segregation)
-genomic instability (defective DNA repair and DNA damage chkpts)
-unscheduled proliferation (active mitogenic sensors, defecive mitogenic breaks, overcome oncogenic stress)
-aberrant mitogenic signaling

43
Q

Proto-oncogene

A

proteins that are involved in the control of cell growth
becomes excessively active (gain of function) and excessive activity results in uncontrolled cell growth, and now is an oncogene

44
Q

Five groups of oncogenes

A
  1. growth factors
  2. growth factor receptors
  3. signal transducers
  4. Transcription factors
  5. other -program cell death regulators, bcl2
45
Q

Growth factors

A

PDGF, EGF, FGF, NGF

46
Q

Growth factor receptors

A

typically receptor tyrosine kinases that consist of extracellular ligand binding, transmembrane, and kinase catalytic domains (inside the cell)
ex: erbB, erbB-2, fms, kit, met, ret, ros, trk

47
Q

Signal transducers

A

nonreceptor protein kinases, GTP binding proteins

ex: src, abl, raf-1, H-ras, K-ras, N-ras, gsp

48
Q

Transcription factors

A

nuclear proteins regulate expression of genes

ex: erbA, ets, fos, jun, myb, c-myc

49
Q

How do proto-oncogenes become oncogenes?

A

gain of function from mutations (point mutations and deletions)
result in structural rearrangements of the protein so that the protein is continuously active
a frequent mechanism in tumors that increases actiivty of K-ras, H-ras and N-ras

50
Q

Normal Ras signaling

A 
Bound to GEF and GDP
GDP exchanged for GTP 
this turns on Ras 
GAP removes Pi from GTP to make GDP on bound Ras
this turns off Ras 
Inactive form - Ras-GDP
51
Q

Ras signaling and cancer

A

point mutations (at G12 or Q61) convert Ras into GAP insensitive, GTP is constitutively bound and Ras is constitutively activated
when GTP is always bound then Ras is always on
Mutation in Ras results in inability of GAP to bind and cannot facilitate GTP -> GDP for inactivation of Ras
so this process leaves Ras more active

52
Q

Ras mutations correlate highly with what type of cancers?

A

Pancreatic cancer - 90%
papillary thyroid cancer - 60%
Colon cancer 50%

53
Q

Increases in what growth factors are seen with cancer?

A

EGFR overexpression - colorectal, pancreatic, lung cancer, non small cell lung
EGFR mutation - Glioblastoma
Ras mutation
B-Raf mutation - melanoma, papillary thyroid cancer, colon cancer

54
Q

Why is a mutation in a down stream cytoplasmic signaling molecule so bad?

A

little regulation at this level with cytoplasmic proteins

55
Q

Gene amplification

A

expansion of gene copy number within the cell (redundant replication of genominc DNA= increased expression of genes)
frequently seen with c-myc (transcription factor)
erbB-2 (HER2/neu) amplified in breast and ovarian cancers

56
Q

Briefly describe the EGF receptor

A

extracellular domain - on this there is an area for mAb inhibition
transmembrane domain
Intracellular domain - has a kinase domain where TK inhibition can occur

57
Q

HER2

A

orphan receptor (means do not know what binds and regulates)
with no extracellular ligand binding domain
so it is ALWAYS active
this can lead to breast cancer

58
Q

HER3

A

Dead kinase - no functional intracellular domain
no catalytic domain
inactive - no ATP binding

59
Q

HER2 overexpression

A

results in signaling abnormalities that contribute to tumorigenesis

60
Q

Heterodimer of EGFR and HER2

A

increased EGFR
activates Ras, PI3k, PLC
this leads to invasion and cyclin D1/p27
G1/S deregulation

61
Q

Homodimer of HER2

A

increased signaling
leads to PAR6 and aPKC activity
loss of polarity

62
Q

Interaction of HER2, HER3 and src

A

increased HER3 signaling
activates PI3K which acts on Akt
Leads to Cyclin D1/p27 and g1/s deregulation
see proliferation, survival, metabolism and invasion

63
Q

Redundant replication of genomic DNA

A

a section of chromosome that is chunked and duplicated
can amplify tumor ability depending on what genes are duplicated
which depends on proximity
ex: GRB7 seen in resistant HER2 tumors

64
Q

Chromosomal rearrangement

A

common in hematologic malignancies

some solid tumors

65
Q

Mechanisms by which chromosomal rearrangements produce malignancy

A
  1. transcriptional activation of proto-oncogenes

2. creation of fusion gene

66
Q

Transcriptional activation of proto-oncogenes

A

increased gene expression

most freq. expression of proto-oncogene is controlled by T cell receptor gene or immunoglobin regulatory elements

67
Q

Creation of fusion gene

A

portions of two different genes joined into single chimeric gene that has transforming activity
loss of normal regulation

68
Q

Example of transcriptional activation: c-myc translocations in Burkitts lymphoma

A

85% cases of Burkitts lymphoma t(8;14)(q24;q32)
this moves c-myc to locus of immunoglobulin heavy-chain gene resulting in constant transcription of c-myc
some cases the light chain chromosome sections (chr 22 or 2) are moved into closer proximity of c-myc (instead of c-myc being inserted into those chains)

69
Q

Fusion gene: Philadelphia chromosome (super famous-impt to know)

A

seen in CML - chronic myelogenous leukemia
t(9;22)(q34;q11)
c-abl gene fused to bcr gene which results in increased kinase activity and abnormal cellular localization
t(9;22) also found in 20% Acute lymphoblasitc leukemia (ALL)
there is a gain of function in Abl

70
Q

How does Abl transform cells?

A

-Mainly through activating Ras-Raf-CDKs pathway to E2F to increase S phase promoting genes and c-myc
-DOK pathway to activate Ras-Raf-MAPK & PI3K-Akt to E2F
-activate Rac-ERK&JNK to active AP1- mediated gene transcription (serum response)
-Activate JAK-STAT & cytokine dep transcription
Downstream - all of this affects the cell cycle and cytokine production

71
Q

Bcl-2 (B cell lymphoma-2)

A

Bcl-2 family has two subgroups

  • Prosurvival
  • Proapoptotic

CMBM exam 5 (19 decks)

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