Genetic change that lead to development of cancer

Carcinogenesis is a multistep process, interaction between environment and genetic factors. It consist of three stages.
Carcinogen such as physical(UV ray), biological (virus-HIV,EB,bacteria) and chemical (bezene) with the inherited gene cause
Initiation, promotion -further acquisition of genetic errors and defect.Progression- gain metastatic potential lead to genome
instability or become cancer.
Hallmark of cancer
(a) evading apoptosis
(b) self sufficiency in growth signal
(c) insensitivity to antigrowth signals
(d) sustained angiogenesis
(e) tissue invasion and metastasis
(f) emerging hallmarks- deregulating cellular energetics,avoiding immune destruction
(g) enabling character- genome instability and mutation,tumor promoting inflammation
Common genetic changes that occur in cancer
(A) Mutation (deletion,duplication,amplification,truncation)
(B) DNA damages to a small set of gene that control cell proliferations and cell death- oncogene,tumor suppressor gene and DNA
repair pathways gene.
Imbalance between oncogene and TS result in cancer.
Oncogene are mutated form of normal cellular gene (proto-oncogene), due to gain of function; their protein product stimulate cell
division and/or inhibit cell death.
Cell environment signal regulate the activity of protooncogene, oncogene are defective and they are on even when they do not
receive the appropriate signals.they help ignore negative signals that would prevent the cell from dividing.
TSG protein product prevent directly or indirectly cell division or lead to cell death .eg. p53, RB,APC,BRCA (PRAB)
P53- regulate gene control cell division and death
Rb- regulate altering TF activity.inhibitor of cell division.
APC- protein bind and stimulate degradation of TF
BRCA- repair DNA damage and regulation of gene expression.

cancer cells/tumors arise from ancestral cell acquiring 7-12 genetics changes over 20-50 years.

Oncogenes are derived from the normal viral or chromosomal genes
-become ACTIVATED by mutation (e.g. a constitutively active growth receptor in absence of growth factor) or
ENHANCED by mutation (e.g. simple over-expression of normal growth factor receptors makes them much more
sensitive to growth factor) or self-expression of growth factors
Mutant gene function is dominant to WT gene (proto-oncogene)
Principally, they are intracellular signal transduction proteins (receptors), or transcription factors.
Oncogene are functionally defined by transformation assays,by increasing the plating efficiency of P rat embryo fibroblasts and in
combination with other oncogene cause transformation of cells(immortalisation).
Alteration in GF regulatory control circuit cause ligand independent firing.
All components of signalling pathway are potential oncogenes,when they are over expressed,mutated or fused with other genes.
Five class of oncogene
secreted growth factor
growth factor receptor
intracellular signal transduction
DNA binding protein/TF
cell cycle proteins -cyclins,cyclin dependent kinases and CDK inhibitors

18/12/2012
1
Cancer CeneLlcs - an overvlew
ur. S.M. lcksley
(s.m.plcksley[bradford.ac.uk)
14
Learnlng Cb[ecLlves
undersLand cancer ls a !"#"$%& dlsease, whereby a slngle
progenlLor cell has acqulred 6-12 geneLlc (!"#$%& ()*+("(,*-)
evenLs LhaL affecL proLo-oncogenes & Lumour suppressors. Some
progress has been made ln ldenLlfylng Lhese successlve geneLlc
evenLs (e.g. colon cancer)
undersLand proLo-oncogenes, oncogenes & Lumour suppressors,
and Lhelr funcLlonal deflnlLlon.
undersLand Lhe common geneLlc evenLs LhaL affecL proLo-
oncogenes & Lumour suppressors.
undersLand LhaL lndlvldual oncogene acLlvaLlon ls noL sufflclenL Lo
cause cancer (several defense mechanlsms are ln place)
undersLand LhaL all agenLs lncludlng vlruses LhaL cause cancer
resulL ln geneLlc changes LhaL affecL oncogene or Lumour
suppressors (dlrecLly or lndlrecLly)
8eferences
1he lecLure was adapLed from Lhe course
recommended LexL Puman Molecular
CeneLlcs", Chp 17 by 1. SLrachan & 8ead (4
Lh
LdlLlon). lL ls a wealLh of lnformaLlon and ls
hlghly recommended, - a source of exLra
readlng
Some maLerlal was also sourced from 8lology
of Cancer" 8.A. Welnberg
()* %++,-$*.$%)# )#+/
CANCER CELLS / TUMOURS ARISE
FROM A SINGLE ANCESTRAL CELL
ACQUIRING 7-12 GENETIC CHANGES
OVER 20 to 50 YEARS!
Alms of cancer geneLlcs
1o Lo ldenLlfy Lhe
muLaLlons wlLhln
paLhways LhaL allow
normal cells Lo
found/produce a
populaLlon of
prollferaLlng and
lnvaslve cancer cells.
1o evaluaLe wheLher
Lhese geneLlc evenLs
have LherapeuLlc or
dlagnosLlc or
prognosLlc poLenLlal
()* %++,-$*.$%)# )#+/
Some progress ldenLlfled ln molecular geneLlcs of some
cancers, e.g. colon cancer (buL really a slmple overvlew)
A useful flgure!

1 genomic instability cause gene amplification

Tumor suppresor gene encode protein that restore the growth control function to cancer cells by
-prevent inappropriate entry into cell cycle
-promote cancer cell death by apoptosis
-maintainance of genomic stability (accurate replication,DNA repair,segregation of daughter DNA molecules)
Both allele LOST/INACTIVAATED to see changes in cell properties,WT function is dominant to mutant.
Knudsons 2 hit hypothesis on Rb gene studies.
TS are inactivated by - Mutation followed by loss of remaining WT allele through deletion, known as LOH
- Mutation followed by loss of remaining WT allele by epigenetic silencing
DNA is methylated at CG sequences known as CpG island. Sometimes these regions are methylated in tumour suppressor promoters
and is known to switch off OR silence gene expression.
Activation of oncogenes is not enough to cause cancer,it is in turn control by TSG and other cell cycle regulatory proteins.
Viral protein also target and inactivate TSG.
All DNA tumour viruses have viral trans-acting genes that target the pRB and p53 tumour suppressors
How virus interact with genetics factors contributing to cancer.

Instability of genome EITHER chromosomal instability or microsatellite instability that occur during tumorigenesis
microsatellite instability, ie, alterations in the length of short repetitive sequences (microsatellites) e.g. colon cancers
A change in chromosome number, or aneuploidy, is a defining characteristic of many types of cancer. The other common
chromosomal abnormalities identified in cancers include translocations, deletions, and amplifications.
The loss or gain of whole chromosomes results from defective mitosis, involving chromosomal nondisjunction in which sister
chromatids are not properly segregated to the daughter cells.
CML 95% pt bcr-abl reciprocal translocation long arm of chromosome 9,22
Gleevec (imitinib mesylate) tyrosine kinase inhibitor,successful development of rationally designed drug

18/12/2012
4
vlral mechanlsms !"# avlan sarcoma
carry oncogene ln genome
lnserL sLrong vlral promoLer ALv vlrus avlan model
nexL Lo proLo-oncogene lnserL nexL Lo myc
Make vlral proLelns LhaL Sv40 MesoLhellomas
lnacLlvaLe Lumour suppressors 1Ag
!"#$ &"'($) "* +,$ -$.$/
01$23) +"
&".)+(+4+(5$ 2&+(5(+6 "* )(-.21
+#2.)34&+(". )6)+$7/8
1. AcLlvaLlon of oncogenes by gene ampllflcaLlon
Cncogenes can be acLlvaLed by gene ampllflcaLlon LhaL
arlses from genome lnsLablllLy.
1hese exLra coples of genes are presenL on small palred
mlnuLe chromosomes (double mlnuLe chromosomes)
LxLra coples = greaL lncrease ln [gene producL]
llSP sLudy showlng:
$%#& gene ampllfled on
double mlnuLe chromosomes
ln neuroblasLoma
9"# (114)+#2+(". ".16
Molecular Cncology volume 4, lssue 3 2010 233 -266
2. AcLlvaLlon of oncogenes by polnL muLaLlon
CrowLh facLor slgnallng Lrlggers C1 Lo blnd Lo 8AS proLeln.
C1-8AS complex ls an acLlve Lyroslne klnase LhaL acLlvaLes
downsLream molecules by a slgnallng cascade. Pydrolysls of C1
leaves a Cu-8AS complex LhaL ls lnacLlve as a Lyroslne klnase.
MuLaLlons are common aL aa12, 16 or 61 ln 8AS proLeln ln many
cancers (colon, lung breasL and bladder) and all decrease Lhe
lnLrlnslc C1ases acLlvlLy of 8AS proLeln, so LhaL Lhe 8AS proLeln
remalns ln an acLlve complex wlLh C1 for longer.
9"# (114)+#2+(". ".16
3. AcLlvaLlon of oncogenes by formaLlon of a chlmerlc proLeln
vla chromosomal LranslocaLlon
1he hlladelphla Chromosome, h1, represenLs a balanced
LranslocaLlon beLween chrm 9 & 21 Lo generaLe a fuslon gene LhaL
encodes a fuslon proLeln 8CL-A8L1 LhaL ls a Lyroslne klnase wlLh
abnormal Lransformlng properLles found ln Chronlc Myelold Leukemla.
9"# (114)+#2+(". ".16
!usL for reference only
18/12/2012
4
vlral mechanlsms !"# avlan sarcoma
carry oncogene ln genome
lnserL sLrong vlral promoLer ALv vlrus avlan model
nexL Lo proLo-oncogene lnserL nexL Lo myc
Make vlral proLelns LhaL Sv40 MesoLhellomas
lnacLlvaLe Lumour suppressors 1Ag
!"#$ &"'($) "* +,$ -$.$/
01$23) +"
&".)+(+4+(5$ 2&+(5(+6 "* )(-.21
+#2.)34&+(". )6)+$7/8
1. AcLlvaLlon of oncogenes by gene ampllflcaLlon
Cncogenes can be acLlvaLed by gene ampllflcaLlon LhaL
arlses from genome lnsLablllLy.
1hese exLra coples of genes are presenL on small palred
mlnuLe chromosomes (double mlnuLe chromosomes)
LxLra coples = greaL lncrease ln [gene producL]
llSP sLudy showlng:
$%#& gene ampllfled on
double mlnuLe chromosomes
ln neuroblasLoma
9"# (114)+#2+(". ".16
Molecular Cncology volume 4, lssue 3 2010 233 -266
2. AcLlvaLlon of oncogenes by polnL muLaLlon
CrowLh facLor slgnallng Lrlggers C1 Lo blnd Lo 8AS proLeln.
C1-8AS complex ls an acLlve Lyroslne klnase LhaL acLlvaLes
downsLream molecules by a slgnallng cascade. Pydrolysls of C1
leaves a Cu-8AS complex LhaL ls lnacLlve as a Lyroslne klnase.
MuLaLlons are common aL aa12, 16 or 61 ln 8AS proLeln ln many
cancers (colon, lung breasL and bladder) and all decrease Lhe
lnLrlnslc C1ases acLlvlLy of 8AS proLeln, so LhaL Lhe 8AS proLeln
remalns ln an acLlve complex wlLh C1 for longer.
9"# (114)+#2+(". ".16
3. AcLlvaLlon of oncogenes by formaLlon of a chlmerlc proLeln
vla chromosomal LranslocaLlon
1he hlladelphla Chromosome, h1, represenLs a balanced
LranslocaLlon beLween chrm 9 & 21 Lo generaLe a fuslon gene LhaL
encodes a fuslon proLeln 8CL-A8L1 LhaL ls a Lyroslne klnase wlLh
abnormal Lransformlng properLles found ln Chronlc Myelold Leukemla.
9"# (114)+#2+(". ".16
!usL for reference only