kras cancer pres

Upload: bandita-datta

Post on 06-Jul-2018

223 views

Category:

Documents


0 download

TRANSCRIPT

  • 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    Credit : Mira Grigorova and Paul Edwards, Department of Pathology, University of Cambridge, unpublished 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;