Upload
bandita-datta
View
223
Download
0
Embed Size (px)
Citation preview
8/17/2019 Kras Cancer Pres
1/34
Investigating Cancer
KRAS Activity
8/17/2019 Kras Cancer Pres
2/34
What is cancer?
• All cancers derive from singlecells that have acquired thecharacteristics of continuallydividing in an unrestrainedmanner and invading
surrounding tissues.• Cancer cells behave in thisabnormal manner because ofchanges in the DNA sequenceof key genes, which are knownas cancer genes. Therefore allcancers are genetic diseases.
Human melanoma cell undergoing celldivisionCredit: Paul Smith & Rachel Errington, Wellcome Images
8/17/2019 Kras Cancer Pres
3/34
Cancer information
• One in three eole in the !estern world develocancer and one in "ve die of the disease
• There are aro#imately $%% tyes of cancer, eachwith di&erent causes, symtoms and treatments
• 'n $%%(, $)(,))* eole were newly diagnosed withcancer in the +
• An individual-s risk of develoing cancer deends onmany factors, including age, lifestyle and geneticmakeu
Cancer Research UKhttp://info.cancerresearchuk.org/cancerstats/incidence/?a=5441
8/17/2019 Kras Cancer Pres
4/34
The 20 most common causes of
death from cancer, UK, 2008
Cancer Research UK. Accessed u!" #$1$
http://info.cancerresearchuk.org/cancerstats/%orta!it"/cancerdeaths /
8/17/2019 Kras Cancer Pres
5/34
Cancer cells have alteredgenomes
aryotye illustrating structural abnormalities in cancer
Credit : Mira Grigorova and Paul Edwards, Department of Pathology, University of Cambridge, unpublished
&ource: '''.path.ca%.ac.uk/(pa'efish/)reastCe!!*ine+escriptions/,CC-.ht%!
8/17/2019 Kras Cancer Pres
6/34
What is a mutation?
• Germline mutation
A change in the DNA sequence thatcan be inherited from either arent
• Somatic mutation
A change in the DNA sequence in cellsother than serm or egg
The mutation is resent in the cancercell and its o&sring, but not in theatient/s healthy cells
8/17/2019 Kras Cancer Pres
7/34
Mutations &cancer genes
• Cancer genes are causally imlicated inoncogenesis
• 0utations in cancer genes can occur somaticallyor can be inherited.
• 0utations in some cancer genes can be inheritedfrom arents, in which case they are resent inevery cell of the body. 1uch eole are at ahigher risk of develoing cancer.
• 1omatic mutations can occur in any of the cells ofthe body e#cet the germ cells 2serm and egg3and therefore are not assed on to children.
8/17/2019 Kras Cancer Pres
8/34
Importance of somaticDNA changes in humancancer
&o%atic
0nherited
)oth
n!" 5 1$2 of cancer cases ha3e a c!ear hereditar" co%ponent
e.g. BC!" and BC!# in reast cancer
63en in those cases 'here susceptii!it" is c!ear!" inherited so%atic
changes are re7uired for cancer to de3e!op
8/17/2019 Kras Cancer Pres
9/34
Cancer genes
• There are two tyes of cancer genes4 umour suppressor genes
!ncogenes
• To date, we know of aro#imately 5%% somatic
6cancer genes7 8 but there are almost certainlymore to be found
• CO10'C is a catalogue of somatic mutationsfound in cancer genes in human tumours and is
available at4htt499www.sanger.ac.uk9genetics9C:;9cosmic9
82CO10'C v5(release.
8/17/2019 Kras Cancer Pres
10/34
umour suppressor gene
TS
Cancer
8hese genes nor%a!!" function to 9R66;8ce!! gro'th/di3ision
8/17/2019 Kras Cancer Pres
11/34
!ncogene
Cancer
Ras
8/17/2019 Kras Cancer Pres
12/34
"#amples of mutations
Se$uence% Se$uence 'pe
ACTCGTTAGGCA 1ubstitution
ACTCGTTAGGCA ACTCGGCA Deletion
ACTCGTTAGGCAACTCGTTATCAGGCA 'nsertion
ACTCGTTAGGCA ACTTTGCAGGCA 'nversion
ACTCGTTAGGCA Dulication
ACTCCTTAGGC
A
ACTCGTTAGTTAGGCA
8/17/2019 Kras Cancer Pres
13/34
Cancer progression
=enign
TumourIn situ cancer
'nvasive
cancer
0etastaticcancer
Mutations in multiple cancer genes are required for the
development and progression of a single cancer
8/17/2019 Kras Cancer Pres
14/34
www. >ickr.com4 laste#it
Eternal causes of cancer!
ultraviolet radiation
8/17/2019 Kras Cancer Pres
15/34
Eternal causes of cancer!
to"acco smo#e
8/17/2019 Kras Cancer Pres
16/34
$ifest%le factor! diet
8/17/2019 Kras Cancer Pres
17/34
(iological factor) virus
• ?;@ is a cause ofcervical cancer
• ;roteins from the virusactivate and deactivate
cancer genes• The role of ?;@ in
cervical cancer has ledto the develoment ofvaccines
&'( in cervical epitheliumCredit: MC $%M, &ell'ome %mages
8/17/2019 Kras Cancer Pres
18/34
Activit'Activit'
• The KRAS gene codes for a signalling molecule
• 0utations in KRAS are resent in manycancers, including ancreatic cancer
• ou have to look for the mutations bycomaring healthy DNA sequence with tumourDNA sequence
• Not all of you will "nd a mutation
8/17/2019 Kras Cancer Pres
19/34
*our Wor+sheets
f , d
8/17/2019 Kras Cancer Pres
20/34
If 'ou ,nd amutation
B C A 0 ; D B O N D
8/17/2019 Kras Cancer Pres
21/34
Ho- to use the codon-heel
1tart from thecentre and move
outwards
8/17/2019 Kras Cancer Pres
22/34
Mar+ up 'our se$uence
8/17/2019 Kras Cancer Pres
23/34
Hetero.'gous mutations
+;A change
in cancer
;or%a! +;A
se7uence
)R*+ gene mutation ature -./, 01/ 34une 20025
A dou!e peak
indicates a %utation
on one chro%oso%e
and not the other i.e.
a hetero>"gous%utation
8 A
A
8/17/2019 Kras Cancer Pres
24/34
/esults
AminoAcidNum0er
Health'DNASe$uence
umourDNASe$uence
Health'Amino Acid
umourAmino Acid
*$ ::T :TT : 2glycine3 @ 2valine3
*E ::C :AC : 2glycine3 D 2asartic
acid3E% :AC :AT D 2asartic
acid3D 2Asarticacid3
F* CAA C:A G2glutamine3
H 2arginine3
*5F :CA CCA A 2alanine3 ; 2roline3*(E :AT :AC D 2Asartic
acid3D 2Asarticacid3
AminoAcidNum0er
Health' DNASe$uence
umour DNASe$uence
Health' AminoAcid
umourAminoAcid
*$ ::T : T T : 2glycine3 @ 2valine3
*E ::C :AC : 2glycine3 D 2asarticacid3
E% :AC :A T D 2asarticacid3 D 2asartic acid3
F* CAA C:A G 2glutamine3 H 2arginine3
*5F :CA CCA A 2alanine3 ; 2roline3
*(E :AT :AC D 2asartic acid3 D 2asarticacid3
8/17/2019 Kras Cancer Pres
25/34
Signi,cant mutations
Amino AcidNum0er
Health'DNASe$uence
umourDNASe$uence
Health'Amino Acid
umourAmino Acid
*$ ::T :TT : 2glycine3 @ 2valine3
*E ::C :AC : 2glycine3 D 2asaraticacid3
F* CAA C:A G2glutamine3
H 2arginine3
*5F :CA CCAA 2alanine3 ; 2roline3
8/17/2019 Kras Cancer Pres
26/34
Ho- common?
AA 1#1-@4
AA 1-#111
AA 1#1#
AA 14--
Source: C&0C (uly
#)")
RB1 t
8/17/2019 Kras Cancer Pres
27/34
RB1) tumour suppressorgene
Source: C&0C (uly
#)")
H d thi 1 t th
8/17/2019 Kras Cancer Pres
28/34
Ho- does this a1ect the2/AS protein?
8/17/2019 Kras Cancer Pres
29/34
Amino acid %
8/17/2019 Kras Cancer Pres
30/34
Amino acid %3
8/17/2019 Kras Cancer Pres
31/34
Amino acid 4%
8/17/2019 Kras Cancer Pres
32/34
Amino acid %54
8/17/2019 Kras Cancer Pres
33/34
Amino acid %54
8/17/2019 Kras Cancer Pres
34/34
What6s the impact?
•HA1 hels to transmit e#ternal growth signals to thecell nucleus, driving normal cell growth. 't is4
Activated when it binds :T;
'nactivated or 6switched o&7 when :T; is
hydrolysed to :D;