d




 



 

c

 




u

 

u u
 



× Cancer is a disease in which some of the

body¶s cells become dysregulated in their
normal functions & properties:
‡ Increased replication
‡ Resistance to apoptosis
‡ ³Immortality´
‡ Destruction/remodeling of extracellular matrix
‡ Angiogenesis
‡ Metastasis
 c




 

× che human body is made up of ~1012 cells
whose replication, death, and
differentiation state is highly regulated.
× Cells respond to both positive and
negative extracellular regulators to
maintain normal physiology.
 






  
  

 

 
 
    


 

 

 
 
D
   
  


    

 

  

 
  

 






 


 
   
 


 



× Îhile tendencies to develop cancer can

be inherited, genetic changes of cancer
cells, both inherited, and somatic,
contribute to the malignant phenotype.
× Epigenetic changes to gene expression
are emerging as important to cancer as
well.
 


 



× Most genetic changes in cancer alter

the normal control mechanisms of
normal cell physiology.
× Few if any cancer genes have
developed entirely new functions.
 


 



× Most of the primary changes in gene activity are

due to structural alterations of genomic DNA:
‡ DNA nucleotide mutations
± Loss of function
± Change of function
‡ DNA strand breakage with subsequent loss of genes
‡ DNA strand breakage with rearrangement of genes
‡ Amplification of specific genes
 


 



× Mutations and other genetic alterations

are acquired during an individual¶s
lifetime in cells of the body (somatic
cells)
× Alterations are passed on to somatic
daughter cells, but not to gametes
(germline cells)
 


 








× Dnly a minority of cancer is familial

‡ Cancer-susceptibility gene passed through germline
DNA transmission (gametes)
‡ Study of cancer gene families can be quite
informative about how cancer originates
‡ Non-familiar cancer is referred to as sporadic
½
 


!

× Receptors
× Signal transduction constituents
× cranscriptional regulators
× DNA replication regulators
]



 

 
cytoplasm


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× Dncogenes
‡ Enhanced biochemical activity leads to altered
cell phenotype, usually increased proliferation
± Activation of a proto-oncogene
± Acquisition of a viral oncogene
× cumor suppressors
‡ Loss of activity leads to altered cell phenotype
± Mainly cell cycle regulators
× Genes that control genomic instability
‡ Loss of activity leads to many kinds of cell
mutations


&


× Cell with initial genetic mutation displays

growth advantage over neighboring cells

× Enhanced proliferation and/or survival

allows additional mutations that offer
additional growth and selective advantage
over surrounding cells (clonal selection)
 



„

„

]   

 
 
 


× All of the cancer cells in a tumor mass are

derived from a single progenitor
× „
 cancer cells will contain mutations that
occur early in cancer progression
× ü
cancer cells will be identical to others in
the tumor mass
× ‰  parts of the tumor mass may be non-
malignant cells responding to factors made
by the cancer cells
c 
 


× Step wise process that takes some time
× Accelerated by anything causing genetic
damage
‡ External exposure to carcinogens
‡ Internal genomic instability
× Incremental steps between normal and fully
malignant cells
‡ Precursor lesions seen in most cancer types that
are µneoplastic¶ but µbenign¶
‡ Established cancers display gradation in
aggressive growth behavior
 R


 

 


   
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× In general«..
‡ Cancer cells retain some characteristics of
the tissue in which they originated
± Show some morphologic and biochemical
features of differentiated cells
> e.g. lymphoma vs. adenocarcinoma



‡ Cancer cells resemble stem cells

 

± ? Infinite regenerative capacity

c


 






 



× Shope Papilloma
d



 
virus



 
× Causes benign
squamous
growths
 c



× 1911-Peyton Rous discovers a

³filterable agent´ (meaning a virus)
that can multiply in chickens and
causes tumors of muscle or soft tissue
(sarcomas)
× Virus is named Rous Sarcoma Virus
 c




× 1970- Steven Martin shows that unlike

avian leukemia viruses, RSV contains
a new gene (src) that is able to induce
tumor formation
× 1976- Bishop and Varmus show that
the src gene is minimally changed from
a normal gene present in non-
malignant cells (cellular, or c-src)
]

½

d



 



 
 c


 


DNA transfer Cell transfer

d



 



 

d



 



  d



 



 

Isolation of the
transforming EJ
Bladder cancer
oncogene, later
d



 



 

named RAS
 % 
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× Proto-oncogenes are normal genes with

required normal functions in
development and/or homeostasis, that
serve as precursors of genes that can
gain the ability to be dominant-acting
oncogenes
× Change in genetic coding sequence
leads to new or accelerated
biochemical activity
 % 
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]cR

× Example: ½ ‰
‡ Normal functions as a GcPase involved in signal
transduction from cell surface d



   
receptors to the MAP kinase pathway 
   



‡ cwo variants H, K, commonly mutated

in tumors
‡ Mutated in many kinds of cancers,
particularly carcinomas
‡ Mutation results in inactive GcPase, GcP bound
RAS protein stays in its active form
‡ Mutations are found in only a few codons,
especially codon 12
 R)
R )$*%+

× Missense mutations in codons 12, 13

and 61 alter gene product activity
codon number
 
DNA 

  

 

amino acids    

mutation


  
 
 
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#

× Example: c-src
‡ Normal function is tyrosine kinase that passes
growth stimulatory signals
‡ Mutation of C-terminal tyrosine removes
inhibitory regulation resulting in highly active
kinase in oncogenic viruses (v-src) and
occasionally in tumors
× Protein kinases are particularly important in
growth signal transduction
‡ Receptor tyrosine kinases particularly important
in cancer
 R
#
 

× About 500 distinct kinases in
genome
× Many have altered expression
in growing or malignant cells
× Many scientific careers have
been made studying kinases
× Very few kinases have been
found mutated in human
cancers (MEc, b-RAF)
× Several receptor tyrosine
kinases are amplified in
specific tumors (EGFR, ERB-
B2)
 c



 
 
#

× Kinases are inherently
µdruggable¶
‡ Drugs usually mimic AcP.
Modified for specific
kinases
d



× Îhile uncommonly  



 

mutated in cancer, many

oncogenic signals pass
  signaling kinases
such as AKc or
ERK/MAPK
% $
$


 
 % 
$$


 

× cwo mechanisms
‡ Places proto-oncogene under new
regulatory elements leading to increased
transcription of wild-type gene
‡ Splices two coding sequences together
leading to deregulation of biochemical
activity of one of the subunits
c 
  
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!
 

RNA *

DNA 








 



RNA
 



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DNA


 

RNA 

 



DNA 

 


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"
 

, 
,  !
!$$  

× che transcriptional enhancers of immunoglobulin (¦)

chains are highly active in B lymphocytes
× cranslocation of the 
 gene on chromosome 18 near
the enhancers of the immunoglobulin heavy chain gene
on chromosome 14 (t14;18) leads to inappropriately
high transcription levels of 


( - [ d
! - [ d
! ,
 
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 ÷.  

× Normally, lymphocyte subpopulations die

through apoptosis
× che bcl-2 protein inhibits a step in the
apoptotic pathway occuring in the outer
membrane of mitochondria
× Dverexpression of bcl-2 up-regulation
prevents apoptotic death of follicular
lymphoma cells contributing to lymphoma
 cNF or Fas
receptors

bcl 2
cyt 3

mitochondria
ù

Caspase Release of
Apoptosis activation cytochrome C
 [ 
 
"
 

,$
,$   #/ 

× cranslocation of ¦ enhancers to the  gene

(chr. 8) leads to inappropriately high transcription
levels of 
‡ t(8;14) Ig heavy chain (most common)
‡ t(2;8) D light chain
‡ t(8;22) light chain
× che myc protein is part of a transcription complex
that activates genes involved in cell replication
 [ 
 
"
 

0 #/. 
× Illustrates one reason why cancers arising from
different tissues have different genetic changes
‡ Ig transcriptional control elements are not active in
cells other than B lymphocytes
‡ Hence rearrangements between the Ig enhancers and
proto-oncogenes in other cell lineages would have
not have the same consequences
  



÷*

÷*$$%÷. 
#


× ³Philadelphia chromosome´ t(9;22) (q34;q11)

‡ Chronic myeloid leukemia (CML)
± Most cases
‡ Acute lymphocytic leukemia (ALL)
± Subset of cases

× che
 gene (9q34) encodes a tyrosine kinase

involved in signal transduction
 


 


÷*
÷*$$%÷. 
#

× che BCR/ABL fusion protein has
cytoplasmic localization
‡ Fusion appears to deregulate normal localization
of ABL kinase activity
× Activation of multiple signal transduction
pathways
‡ Major effect is increased cell proliferation
× che breakpoints between bcr and abl differ
in CML and ALL
‡ A shorter fusion protein results in ALL, probably
with different biological activity
 $$!


 




 
× Novartis Pharmaceutical discards kinase inhibitors
that weakly inhibit the VEGF receptor kinase
× Dncology fellow Brian Druker uses research
fellowship year to re-
re-test discarded drugs on ABL
kinase, identifies ScI571 as best compound
× ScI571/imatinib (GleeveccM) inhibits bcr-bcr-abl kinase
activity, is an oral agent, and has low toxicity
× 70% of CML patients in ³blast crisis´ have a clinical
response to Gleevec as a single agent
× Because of clinical safety, Gleevec is used
empirically on several types of cancers, notably GI
stromal tumors
 R!
  !
 

× Many CML patients relapse when treated with

imatinib
‡ Sequencing of the bcr
bcr--abl gene in resistant tumors
show that secondary mutations have occurred in the
AcP binding region of the kinase
‡ Dpportunity for complementary kinase inhibitor
strategy
 % 
$$


]

 
× Copying of normal genes and their
promoters many times
c


 




 
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 [ 


 
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×     
 gene amplified in ~20% of

breast carcinomas
× Gene encodes a growth factor receptor
× che result of gene amplification is an
abnormally high cell replication response to
normal levels of growth factor
‡ Increased cell replication
‡ Increased tumorigenicity
Ú[½$$ "

 

Ú[½
1



1


 ! 21,+Ú

Normal breast cells Cancer breast cells

Green probe: chromosome 17 centromere

Red probe: HER2/NEU gene locus
 Ú[½$$ "

 

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, 

"
 


3 

 Ú



 

45$$

 
45
× Herceptin (crastuzumab) is an anti-
Her2 humanized monoclonal antibody
‡ Administered by injection
× Potentiates standard chemotherapeutic
agents
‡ 15% increase in clinical response
‡ Longer survival times
 D


 
!

× A few cancer viruses (HPV, EBV,
HcLV) cause significant human
disease.
× Many, many rodent and avian viruses
have obtained oncogenes later found in
human cancers (e.g. Ras, Abl, Raf)
× DNA tumor viruses showed the
importance of tumor suppressor genes
in cancer
 À



× Integration of proto-oncogene (retroviruses)

‡ Receptors & signal transduction constituents
most common
‡ Common in animal tumors
‡ Not a major mechanism in human
carcinogenesis
± However, animal viral oncogenes have identified
human proto-oncogenes that are activated by other
mechanisms
> Ras

> Myc
 D





From: che Genetic Basis of Human Cancer, Vogelstein & Kinzler, eds., 1998
 (3%



× crue, viral encoded oncogenes

× Not analogues of mammalian genes
× Responsible for a few subtypes of human
cancer
× Example: Human papillomavirus (HPV) in
cervical carcinoma
‡ E6: Inactivates p53 tumor suppressor gene
‡ E7: Inactivates RB tumor suppressor gene
× Also, SV40, JC, polyoma, EBV
 ÚRÀ 



HPV Condyloma/ Additional Additional
virus low grade genetic hits genetic hits
infects dysplasia cause high cause
normal results grade invasive
squamous dysplasia to carcinoma
mucosa develop to develop

Anti-HPV immunization may prevent 70-95%

of cervical carcinoma in next two decades
 ÚRÀ



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From: Introduction to Dncogenes and Molecular Cancer Medicine, D.Î. Ross, 1998
 ÚRÀ
 !
 
 
   ½!

Adenovirus and SV40 oncogenes also

inactivate both p53 and pRb
 c 




× cumor suppressor genes are expressed

in normal cells and function to
interfere with the development of
cancer
× „ 
 





 
 

  

× Most significant are p53 and pRB
 ¦
 



× cumor suppressor gene alleles are
inactivated by some combination of:
‡ Intragenic mutation
‡ Gene deletion
‡ cranscriptional (epigenetic) silencing
 c 


 

!# 


× Normal cells express two copies of a

tumor supressor gene
× Both alleles of a tumor suppressor gene
must be inactivated in order to achieve
the ³cancer phenotype´
1

½
!

× 1 in 20,000 children
× Most common eye tumor in
children
× Dccurs in heritable and
nonheritable forms
× Identifying at-risk infants
substantially reduces morbidity
and mortality
3
!
Ú
!
½
!

Feature Nonheritable Heritable

cumor Unilateral Usually bilateral
Family history None 20% of cases
Average age at dx ~2 years <1 year
Increased risk of No Dsteosarcoma, other
second primaries sarcomas, melanoma,
others
 ]

1


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!
½
!
× Autosomal dominant
transmission
Bilateral RB, 1 yr × ½
 gene on chr 13 (first
d. 78 tumor suppressor gene
discovered)
× Penetrance >90%
× u   at organismal
Bilateral RB, Bilateral RB, 1 yr
6 mo osteosarcoma, 16 level, but 

 at
cellular level (mutant form
lacks function, overridden
by unmutated allele)
Bilateral RB,
1 mo
 ´ /4c $Ú5


½
!

Normal Predisposed Affected

2 intact copies 1 intact copy Loss of both
1 mutation copies
Modified from c 
Dct.

Dct. 27, "'
1986
 ´ /   






3
  
Replication cycles Replication cycles
Diploid
genome
protects
individual
 from
cancer
formation

Inactivating mutations occur infrequently during cell replication during lifetime

 ´ /   
  



 
 

Replication cycles Replication cycles

Rarely, inactivating mutations will occur in both cS gene alleles in a cell

 ´ /   
 

 ½
!
  
  
    
   
 Replication cycles  
  
  
   


  
  
Individuals with only one active cS allele have a higher probability of developing
tumors, and of developing more than one tumor
1
½
! 




  

× Most tumors occur in utero, in infancy or
early childhood
× Retinoblastoma is a tumor of ocular neurons,
and neurons stop replicating soon after the
post-natal period
× pRb is involved in cell cycle regulation
× Nonreplicative cells essentially never
develop cancers
× Retinoblastomas must therefore arise during
the time that the ocular neurons are still
replicating
 ½
½




! p16

u *#+ 
  
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u *#+   !
 
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%(
G1 R
G2
P P P P

 


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)& factor )& factor
M
 XÚ

2
 


Normal allele x x Mutant allele

Loss of normal allele

Chromosome Deletion Unbalanced Loss and Mitotic Point

loss translocation reduplication recombination mutation

x x x x x x x x x x

rare rare
In most cases, polymorphisms (x) near tumor suppressor
genes are lost (LDH). chis can be used to discover or
analyze tumor suppressor genes
  



× Perhaps the most commonly mutated gene in
human cancer
× A nuclear phosphoprotein with transcriptional
regulatory function
  
  

× Îild type p53 protein does not have high

levels of expression and has a short half life
‡ Not usually detected by immunohistochemistry
× Mutant p53 protein, while inactive, has a
longer half life
‡ Increased cellular accumulation allows
detection by immunohistochemistry

In other words: when p53 is visible, p53 function is absent!

3 
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7



  



DNA damage (radiation, chemotherapy) sensor

- 
./ ' 
S

Cell Death G1 R

High DNA damage M

Low DNA Damage
Die by apoptosis Repair damage and survive
(!  
  


    
 ()3%"78 



× Cyclin-dependent kinase inhibitor
‡ Acts on CDK4 and CDK6
‡ Prevents phosphorylation of the RB protein
‡ Blocks progression of cell through G1 of the
cell cycle
× Inactivated in many types of carcinoma
and in melanoma
 ½
(´3%"




! p16 
  

 ,

u *#+

' 
! S

u *#+   !
 
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%(
G1 R
G2
P P P P

 


trans. trans.


)& factor )& factor
M


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78 


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78 c   $
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× Usually must be inactivate both alleles, like
tumor suppressor genes
‡ Some consider these ³caretaker genes´ as a
form of tumor suppressor genes
× Usually don¶t directly cause ³cancer
phenotype´ but allow cancer-causing
genetic changes to occur/accumulate
× Dften involved in hereditary cancer
 1
 

(3%

2


× Disease genes usually cause increased incidence

of a few specific types of cancer
× Usually inherited in an autosomal dominant
manner
× Affected individuals usually develop cancers
earlier in life than the general population
× Affected individuals usually are at risk for
multiple neoplasms
3



3[½




 

× che NER pathway removes a variety of DNA
base damages induced by UV irradiation and
chemicals
× Xeroderma pigmentosum (XP) is an
autosomal recessive genetic disorder
characterized by defects in the NER pathway
× Mutations in many different genes (at least 7
groups) can cause this syndrome
‡ Pathway requires coordinated effort of many gene
products
 (3%

:À 

× UV irradiation causes
the formation of
chemical cross links
between adjacent
pyrimidine bases in
DNA (C & c)
‡ C more mutagenic than
c
‡ DNA polymerase
usually substitutes A
for ³uninstructed´
nucleotide
3[½  
   -
 







 
 
;


3[½


× In NER-deficient cells non-repaired dimers
lead to missense mutations during DNA
replication
‡ Activating oncogene mutations
‡ Inactivating tumor suppressor gene mutations
× UV radiation does not penetrate past the skin
× XP patients have marked increase in skin
cancer
‰#


 R
 1

Ú3R
Hereditary Non-Polyposis Colon Carcinoma

× Autosomal dominant inheritance

× Penetrance ~80%
× Genes belong to DNA mismatch repair
(MMR) family
× Genetic heterogeneity („
„‰

„‰
„‰
„‰)
 1

Ú3R
× Early but variable age at
CRC diagnosis (~45
years)
× cumor site in proximal
colon predominates
× Extracolonic cancers:
endometrium, ovary,
stomach, urinary tract,
small bowel, bile ducts,
sebaceous skin tumors
 1Ú¦´

(Ú3R

CRC
dx 50s

CRC CRC CRC Dvarian

dx 45 dx 61 dx 75 Ca, dx
64

CRC CRC Endometrial 45 CRC

dx 48 dx 52 Ca, dx 59 dx 42
 
½#Ú3R

100

% 80 Colorectal 78%
with
cancer 60

40 Endometrial 43%
Stomach 19%
20 Biliary tract 18%

0 Dvarian 9%
0 20 40 60 80
Aarnio M et al. ¦

   64:430, 1995
Age (years)
"'
Ú3R½
11

 
½


½]



Normal '% '

Base pair DNA repair
mismatch
%'%

 ' '

%'%

Defective DNA  ' ' ' '

repair (MMR+)
%'% % %

 ½
1
X
 



¦!
‰¦

Normal

Microsatellite
instability Addition of
nucleotide repeats



¦!
‰¦
× 10%±15% of sporadic tumors have MSI
× 95% of HNPCC tumors have MSI at
multiple loci
× Routine MSI assays soon available
Normal MSI tumor

Electrophoresis gel
 ‰

½

½#


Ú3R1


No surveillance
% of Surveillance
subjects 20
with CRC
11.9%
10

4.5%
0
0 3 6 9
Years of follow-
follow-up
Jarvinen HJ et al. ]
 108:1405, 1995 "'
 [ 





× Epigenetics:
‡ Mechanisms of gene expression control
that can be passed from one cell to its
offspring, that are not reflected in changes
in DNA sequence
× Examples:
‡ DNA methylation
‡ Histone modification
‡ Noncoding RNAs
 (3%
 

× Some growth suppressing proteins are

found to be absent from cancers, but
the promoter and coding region are
intact
× Examples:
‡ p16
‡ RASSF1/NDRE1
× Local regions of DNA,
usually in gene
promoters (CpG rich
regions) maintain C-
methylation during
DNA replication

× DNA methyltransferase

 

 

 
d

 




 

 

    
  

  
 (3%

 

× DNA methylation can be detected by

DNA sequencing after 5Me-dC
deamidation to dU (using bisulfite)

× Reversal of DNA methylation (e.g.

restoring expression of tumor
suppressor genes) is being attempted
using 5-aza Cytidine
 Ú


× Generally, histone acetylation is
associated with transcriptionally active
genes
× Histone acetylation is effected by
Histone acetyl transferase (HAc) and
deacetylation by HDACs
 Ú(% 
 





× Several cancer-related gene products

are HAc¶s
‡ BRCA1, p300(viral oncoprotein target)
× Pharmacologic inhibitors of HDACs
show anti cancer effects
‡ Na Butyrate
‡ cricostatin
× HDAC
inhibtors make
you smarter too
 ½3%
× Rapidly emerging field
× Certain, but complex
mechanisms of gene
expression control d



 

× Some miRNAs (e.g. 



 

miR15) have
associations with
cancer
 ‰
  




× Cancers arising in hormonally-responsive tissues
often retain a hormone-responsive proliferation drive
‡ ³normal´
‡ increased hormone sensitivity
× Hormone receptors tend not to be mutated as
oncogenes in early tumor progression
× Anti-hormone therapy is however effective in
treating hormonally-responsive tumors
‡ Anti-estrogen therapy in breast cancer
‡ Anti-androgen therapy in prostate cancer
 ‰
  




× Abnormal levels of hormones may predispose to
cancer due to increased cell replication
‡ Breast cancer, endometrial cancer
‡ Hormone drive may be endogenous or exogenous

Hormone



Ú


  


 
  



!  
"  Ú
$ 
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$
#



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cytoplasm




 








nucleus

"


 





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 %$ 

 




× Patients with metastatic prostate cancer

are treated with androgen deprivation
therapy
‡ Surgical therapy with orchiectomy
‡ Medical therapy with hormone antagonists
× Most cancers respond initially
× Most cancers recur with disease that no
longer requires normal androgen levels
(³androgen independent´)
% 




 



 


'

× Some studies suggest that AR gene changes

occur in subpopulations of advanced prostate
cancer prior to hormone therapy
× chese subpopulations are selected for and
expand after hormone therapy
× An example of continued ³tumor progression´
× Similar ³Darwinian selection´ of subpopulations
of cancer thought to occur in the selection of
cancer resistant to other therapies, particularly
chemotherapy
 
 



 

 


    








  !
;

 

   





 %



× Cells require blood vessels to carry oxygen and

nutrients
× Cancers must either grow along existing vessels
or create new ones
 %


× Many cancers secrete angiogeneic cytokines
‡ Vascular endothelial growth factor (VEGF)
‡ Basic fibroblast growth factor (bFGF)
‡ Platelet derived endothelial cell growth factor
(PD-ECGF)
× Stimulate endothelial cell proliferation,
migration, vessel formation and vessel
maintenance
× Anti-angiogenesis therapy may be a useful
way of controlling cancer
Î 





× Proteases to allow
invasion through
basement membrane
× Factors to allow survival
in isolation in blood and
remote tissue
× Adhesion and migration
factors to leave
bloodstream
× c

  



 

  

 
  
 ¦

× Somatic cells, from which most

cancers originate, only have a limited
number of cell replication cycles
before they become senescent and stop
replicating
× Many cancers have mechanisms to
avoid senescence, hence have
unlimited replication capability
 c




× celomeres are the ends of the chromosomes

made up of thousands of ccAGGG repeats
‡ DNA repeats plus specific telomere proteins
stabilize the ends of linear chromosomes
× celomeres become shorter with each cell
replication (~100 bp)
 c






 

× Cells with short telomeres usually
‡ Are blocked from entering replication, or
‡ Undergo apoptosis
× chis ³programmed senescence´ is responsible
for many of the effects of aging
‡ Limited capacity for cell regeneration
± Brittle skin, slow healing
‡ Atrophy of many organs
 c



× celomerase can elongate telomeres in a

³non-template-directed´ manner
× celomerase is not expressed in most
somatic cells
‡ Expressed in germ cells and some stem
cells
 


Ú  


'
Environment
‡ Radiation (UV, Xray, gamma rays, etc)
‡ Chemical (tobacco tars, nitrosamines, etc.)
‡ Hormones/hormone mimics
‡ Infectious agents (Helicobacter pylori, hepatitis
viruses)
× Products of the body
‡ Inflammatory byproducts (free radicals,
peroxides)
‡ Hormones
 




× Many chemical compounds can promote

cancer formation
‡ Direct DNA damage-
± ³Alkylation´
± DNA strand breaks
‡ Increase cell proliferation
 




× Some compounds must act in concert in a specific

sequence to efficiently cause cancer in animal models
‡ Initiator: Must interact with cells first
± Damage DNA (e.g. µcoal tar¶)
‡ Promoter: Must interact with cells secondarily
± Promote cell replication to ³fix´ DNA damage as gene mutations,
and to allow for additional genetic changes to occur
± (e.g. phorbol ester)
× In general DNA damage and cell replication work
together in cancer formation
 

 

× Polycyclic aromatic hydrocarbons
‡ Carbon fuel combustion, tobacco smoke
× Aflatoxin
‡ Food contaminated with
 



× Aromatic amines & azo dyes
‡ Dccupational exposure
× Nitrosamines
‡ Dietary exposure in preserved meats
 [ 

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× Causes double strand DNA breaks

‡ Chromosomal translocations are a major
consequence
‡ Increased risk of all types of cancers, but
lymphoma/leukemia, sarcomas, and thyroid
neoplasms most common
± chese neoplasms often require specific chromosomal
translocations, which are promoted by DNA breaks
½

;
45





X-ray induced
double strand break DNA replication
of chromosome & cell division

No loss Genetic
of genetic deletion
material
 c






× che most actively replicating cells in the

body are the most likely to form cancers
‡ Epithelial cells from continuously regenerating
structures develop common cancers: skin
carcinoma, colon carcinoma, etc.
‡ Neurons, which are terminally differentiated,
non-replicating cells, rarely form malignant
cancers
 (


 
 





 

× Lymphomas and sarcomas tend to have specific
translocations, carcinomas do not.
‡ che detection of specific gene rearrangements are
often diagnostic of a particular type of lymphoma or
sarcoma
× Carcinomas tend to be aneuploid, with
complex, non-uniform genomic changes
‡ Genomic instability and/or telomere crisis


 




 


 Î 


 


'

× Electrophiles
× Dften found in food
‡ Broccoli-isothiocyanates
‡ cea-ECGC
‡ Garlic-diallyldisulfide
× Many are sulfur redox-active
Ú  

 


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× Induce transcription of ³Phase 2 genes´

‡ chis requires the Electrophile Response
element, similar to AP1
‡ Phase 2 gene products may inactivate
carcinogens, e.g. through GSH
modification and excretion in bile
× However chemoprevention works on
radiation induced cancers and on
injected cancers (xenografts) too


 

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× Chemopreventives may covalently

modify cell proteins that control cell
death.
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'
× Humans and insects share innate
immunity
× Immune regulators in humans are
involved in cancer generation
× At least one target of cancer
chemoprevention is both a cancer
regulator and immune regulator in
humans.
 

‰
× DNA damage is associated with cancer risk
‡ Gene mutation/deletion is required for
± Dncogene activation
± cumor suppressor gene inactivation
× Mechanisms of DNA damage can be:
‡ Chemical and physical carcinogens, and other replication
errors
± Deficiency of DNA repair enzymes
× Cell replication is required to make DNA damage
permanent
× Cancer Chemopreventives may neutralize
carcinogens or sensitize mutated cells to cell death


 

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‡ Note:
‡ ³small round blue cells´
‡ Cells surrounding empty spaces
‡ ³Homer Îright rosettes´
‡ Samples of fresh tissue were sent for for
cytogenetic analysis.
 

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× Joe Fraumeni, a medical resident, cares

for a 7 year old girl with a sarcoma. He
notes that the girl¶s sister has been
treated for lymphoma, and takes an
extended family history
× Eventually, this and similar families
prove to have a provocative genetic
mutation«
 Li-Fraumeni Family

Bilateral breast, 40 Noncarrier

c -mutation
c -
carrier
50 Breast, 40 Leukemia
Dsteosarcoma, 42 , 33

Affected
with cancer
Breast, 35
Brain tumor, 32
Soft tissue
sarcoma, 7 Leukemia, 6
 X$1
 Syndrome

× Rare autosomal dominant syndrome

× Early onset of bone and soft tissue sarcomas, breast
cancer, brain cancer, leukemia, adrenocortical carcinoma,
and other tumors
× Multiple primary tumors
× c  germline mutations associated with most cases
× cesting in children and adults raises important ethical
and psychosocial issues
 cumor Sites in Families with c 

Germline Mutations
Breast 0*
Bone &0+
Brain &0
Soft tissue &&+
GI 1
Gynecol ./
Hematol *0
Adrenal /+
Dther &*&

( . &( &. 0( 0. /(
% of all tumors
Kleihues P et al. 


150:1, 1997 "'
 %







× A pathology resident receives a
surgical specimen labled ³colon´ from
a 35 year old man.
× che patient sought medical treatment
because of a history of colon cancer in
his family
1%
R 

d



 



 
 Clinical Features of FAP

× Estimated penetrance
for adenomas >90%
× Risk of extracolonic
tumors (upper GI,
desmoid, osteoma,
thyroid, brain, other)
× Untreated polyposis
leads to 100% risk of
cancer

"'
 ]

1%R
× Autosomal dominant inheritance
× Caused by mutations in  tumor suppressor gene on
chromosome 5q, participates in beta-catenin activation
× Up to 30% of patients have 
 
germline mutations
× Most families have unique mutations
× Most mutations are protein truncating
× Genotype/phenotype relationships emerging
 
Ú


‰
!½

Sporadic
(65%±
85%) Familial
(10%±30%)

Rare CRC
syndromes Hereditary
(<0.1%) nonpolyposis colorectal
Familial adenomatous cancer (HNPCC) (5%)
polyposis (FAP) (1%)

Adapted from Burt RÎ et al.    


 

u   

½

½,, 1996 "'
 1%R%
 (

 

%
 ½

uu
FAP
Adenomas
u CRC
% of
patients u
with
neoplasia
u
General population
u

u
20 40 60 80
Bussey HJR. ü 







,

, 1975 Age
Petersen GM et al. ]
 100:1658, 1991 "'
 1%R1Î %R


CRC d. 45

FAP 25, CRC d. 31 Age 59 Age 52

FAP, 22
colectomy

Age 40 Age 42
Negative Mutation carrier
±±
 FAP 38, 
++
sigmoidoscopies
(age 33) FAP

Age 16 Age 14
FAP and CRC
+
 + ±
 ±
  Gene Mutations Dccur Early
in Colorectal cumorigenesis

Loss of Activation Deletion Loss of Dther

 of 
of 18q c  alterations

Hyper-
Hyper- Inter-
Inter-
Normal Early Late
proliferative mediate Carcinoma Metastasis
epithelium adenoma adenoma
epithelium adenoma

Adapted from Fearon ER. 

61:759, 1990 "'

%   

 
× A 27 year old woman presents with a
swelling in the neck
× PE reveals an enlarged thyroid gland with
multiple, bilateral nodules. Radioiodine
uptake is elevated bilaterally.
× Cc examination reveals a 5 cm mass at the
superior pole of the right kidney
× Blood is sent for a genetic study«
× Surgery is scheduled to remove the
abdominal mass, which is«?

[3 !
× Medullary thyroid
carcinoma;
Pheochromocytoma,
variable d



 



 
hyperparathyroidism
× Point mutations of the
REc oncogene (a
receptor tyrosine
kinase)

[3

× MEN2b is far more aggressive, with

metastatic McC common at
presentation
× Prophylactic thyroidectomy can
prevent lethality
× Is anti-tyrosine kinase therapy
appropriate?