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Investigating Cancer

KRAS Activity
What is cancer?
All cancers derive from single
cells that have acquired the
characteristics of continually
dividing in an unrestrained
manner and invading
surrounding tissues.
Cancer cells behave in this
abnormal manner because of
changes in the DNA sequence
of key genes, which are known Human melanoma cell undergoing cell division
as cancer genes. Therefore all Credit: Paul Smith & Rachel Errington, Wellcome Images

cancers are genetic diseases.


Cancer information
One in three people in the Western world develop cancer and
one in five die of the disease

There are approximately 200 types of cancer, each with different


causes, symptoms and treatments

In 2007, 297,991 people were newly diagnosed with cancer in


the UK

An individual's risk of developing cancer depends on many


factors, including age, lifestyle and genetic make-up

Cancer Research UK
http://info.cancerresearchuk.org/cancerstats/incidence/?a=5441
The 20 most common causes of
death from cancer, UK, 2008

Cancer Research UK. Accessed July 2010


http://info.cancerresearchuk.org/cancerstats/mortality/cancerdeaths /
Cancer cells have altered genomes
Karyotype illustrating structural abnormalities in cancer

Credit : Mira Grigorova and Paul Edwards, Department of Pathology, University of Cambridge, unpublished
Source: www.path.cam.ac.uk/~pawefish/BreastCellLineDescriptions/HCC38.html
What is a mutation?

Germline mutation
A change in the DNA sequence that can be
inherited from either parent
Somatic mutation
A change in the DNA sequence in cells other
than sperm or egg
The mutation is present in the cancer cell and its
offspring, but not in the patients healthy cells
Mutations & cancer genes

Cancer genes are causally implicated in oncogenesis


Mutations in cancer genes can occur somatically or can
be inherited.
Mutations in some cancer genes can be inherited from
parents, in which case they are present in every cell of
the body. Such people are at a higher risk of
developing cancer.
Somatic mutations can occur in any of the cells of the
body except the germ cells (sperm and egg) and
therefore are not passed on to children.
Importance of somatic DNA
changes in human cancer
Both
Inherited

Somatic

Only 5 10% of cancer cases have a clear hereditary component,


e.g. BRCA1 and BRCA2 in breast cancer

Even in those cases where susceptibility is clearly inherited, somatic


changes are required for cancer to develop
Cancer genes
There are two types of cancer genes:
Tumour suppressor genes
Oncogenes
To date, we know of approximately 400 somatic
cancer genes * but there are almost certainly more
to be found
COSMIC is a catalogue of somatic mutations found in
cancer genes in human tumours and is available at:
http://www.sanger.ac.uk/genetics/CGP/cosmic/
*(COSMIC v47release. July 2010)
Tumour suppressor gene
These genes normally function to PREVENT
cell growth/division

TS

Cancer
Oncogene
Genes which normally function to PROMOTE cell
growth/division in a controlled manner

Ras

Cancer
Examples of mutations
Sequence 1 Sequence 2 Type
ACTCGTTAGGCA ACTCCTTAGGCA Substitution

ACTCGTTAGGCA ACTCGGCA Deletion

ACTCGTTAGGCA ACTCGTTATCAGGCA Insertion

ACTCGTTAGGCA ACTTTGCAGGCA Inversion

ACTCGTTAGGCA ACTCGTTAGTTAGGCA Duplication


Cancer progression
Mutations in multiple cancer genes are required for the
development and progression of a single cancer

Benign Tumour

In situ cancer

Invasive cancer

Metastatic
cancer
External causes of cancer:
ultraviolet radiation

www.flickr.com: lastexit
External causes of cancer:
tobacco smoke
Lifestyle factor: diet
Biological factor: virus
HPV is a cause of
cervical cancer
Proteins from the virus
activate and deactivate
cancer genes
The role of HPV in
cervical cancer has led
to the development of HPV in cervical epithelium
Credit: MRC NIMR, Wellcome Images

vaccines
Activity
The KRAS gene codes for a signalling molecule

Mutations in KRAS are present in many cancers,


including pancreatic cancer

You have to look for the mutations by comparing


healthy DNA sequence with tumour DNA sequence

Not all of you will find a mutation


Your Worksheets
If you find a mutation
How to use the codon wheel

Start from the centre


and move outwards
Mark up your sequence
Heterozygous mutations

Normal DNA
sequence

A double peak
A indicates a mutation
on one chromosome
DNA change and not the other i.e.
in cancer a heterozygous
mutation
T A

BRAF gene mutation Nature 417, 906-7 (June 2002)


Results
Amino Acid Healthy DNA Tumour DNA Healthy Amino Tumour Amino
Number Sequence Sequence Acid Acid
12 GGT GTT G (glycine) V (valine)

13 GGC GAC G (glycine) D (aspartic acid)

30 GAC GAT D (aspartic acid) D (aspartic


(Aspartic acid)
acid)

61 CAA CGA Q (glutamine) R (arginine)

146 GCA CCA A (alanine) P (proline)

173 GAT GAC D (aspartic


(Aspartic acid)
acid) D (aspartic
(Asparticacid)
acid)
Significant mutations

Amino Acid Healthy DNA Tumour DNA Healthy Amino Tumour Amino
Number Sequence Sequence Acid Acid
12 GGT GTT G (glycine) V (valine)

13 GGC GAC G (glycine) D (asparatic


acid)

61 CAA CGA Q (glutamine) R (arginine)

146 GCA CCA A (alanine) P (proline)


How common?

AA 12
13,894

AA 13
2,111
AA 61 AA 146
212 33

Source: COSMIC July 2010


RB1: tumour suppressor gene

Source: COSMIC July 2010


How does this affect the
KRAS protein?
Amino acid 12
Amino acid 13
Amino acid 61
Amino acid 146
Amino acid 146
Whats the impact?
KRAS helps to transmit external growth signals to the cell nucleus,
driving normal cell growth. It is:
Activated when it binds GTP
Inactivated or switched off when GTP is hydrolysed to GDP