This document provides an overview of the molecular foundations of cancer. It discusses how cancer arises from genetic and epigenetic aberrations that accumulate in cells and lead to altered gene expression and the acquisition of hallmark capabilities that allow tumors to form and progress. Key points covered include the types of genomic changes like mutations and chromosome defects that occur; the roles of oncogenes and tumor suppressor genes; how cancer risk can be inherited; and the uses of genomics in cancer diagnosis and targeted treatment.
2. Overview
1. Understand the principles of the Hallmarks of Cancer
2. Discuss the types of genomic changes that occur during cancer development
3. Understand the roles of oncogenes and tumour suppressor genes
4. Account for the fact that cancer risk can be inherited
5. Identify the uses of genomics in cancer diagnosis and treatment
6. New directions
3. At the cellular level,
cancer is a disease of the genome
• Cancer arises from the accumulation of genetic aberrations in somatic cells
• These aberrations consist of mutations and chromosome defects
• Epigenetic aberrations are also present
• Together, they lead to altered gene expression
• Over 500 genes are now known to be involved in cancer development
4. Advances in cancer “omics”
Whole Genome SequencingExome Sequencing
RNA Sequencing
Protein
Sequencing
mRNA
ncRNA
proteins
DNA
Methylated
DNA
Methylated
DNA
sequencing
TRANSCRIPTOME
PROTEOME
GENOMEEXOME
METHYLOME
8. 1. Understand the principles of the Hallmarks of Cancer
Cancer
• A disease of extraordinary diversity and complexity
• But - disparate malignancies share fundamental qualities
• The complexity merely reflects different solutions to the
same challenge:
Cancer cells must overcome multiple barriers used by
the organism to prevent expansive cell proliferation
Hanahan & Weinberg 2000, 2011
9. Hanahan & Weinberg 2000, 2011
The Hallmarks are acquired capabilities that allow
tumours to overcome these barriers
10. Hanahan & Weinberg 2011
The Hallmarks are acquired capabilities that allow
tumours to overcome these barriers
11. Mechanisms for acquiring the Hallmarks of Cancer
Hanahan & Weinberg, 2000 & 2011
Sustaining
proliferative
signaling
Evading
growth
suppressors
Avoiding
immune
destruction
Enabling
replicative
immortality
Tumor-
promoting
inflammation
Activating
invasion &
metastasis
Inducing
angiogenesis
Genome
instability
& mutation
Resisting
cell death
Deregulating
cellular
energetics
Activate
cellular
oncogenes
Inactivate
TP53
Produce IGF
survival
factor
Switch on
telomerase
Inactivate
DNA repair
genes
Induce
VEGF
Secrete TGFβ
Inactivate E-cadherin
Induce aerobic
glycolysis
Redirect
Inflammation-
promoting cells
13. Genetic and epigenetic aberrations give rise
to the hallmarks of cancer
If we know which genes are involved, we can:
• Have a better understanding of cancer biology
• Develop diagnostic and prognostic markers
• Follow the clinical course
• Develop targeted treatment
14. Genetic aberrations affect the DNA sequence
in the cells that give rise to cancer
2. Types of genomic changes that occur during cancer development
MUTATIONS
CHROMOSOME
DEFECTS
can also be described
as “mutations”
15. Causes of genetic aberrations in cancer
DNA damage by radiation & carcinogenic agents
DNA repair defects
Defects in the mitotic machinery
Recombinase machinery
Telomere dysfunction
Adapted from
Essential Cell Biology, Alberts et al, 3rd Ed.
16. Mutation
• Change in the DNA sequence
• Germ-line or somatic
• Rate in humans ~5x10-9 /nucleotide / generation
= 25 mutations /cell /generation
• Neutral, favourable, or non-favourable
17. Types of mutation
Missense
TGC GTG TTT
TGC CTG TTT
C V P
C L P
Silent
TGC GTG TTT
TGC GTA TTT
C V P
C V P
Nonsense
TGC GTG TTT
TGA GTA TTT
C V P
stop V P
Frame shift TGC GTG TTT
TGC AAG TGT TT
C V P
C K Y
C = cysteine
V = valine
P = proline
L = leucine
K = lysine
Y = tyrosine
24. Many layers of epigenetic regulation
All can be disrupted in cancer
Gene Expression
Non-coding RNA
DNA methylation
Histone modifications
N.Tsankova,
Nat Rev Neurosc 2007
25. 3. Oncogenes and tumour suppressor genes
ONCOGENES
• First identified in transforming retroviruses
• Act by gain of function
• Dominant (activation of one allele sufficient)
• Activated by
• mutation
• chromosome translocation
• gene amplification
• retroviral insertion
26. RAS genes – H-RAS, K-RAS, N-RAS
Activated by mutations which change amino acids 12, 13 or 61 in ~30% of tumours
RAF
MEK1/2
ERK1/2
RAS
P
P
Proliferation
NF1
ONCOGENES
RAS
- Mutation
Receptor
Tyrosine
Kinases
Extracellular
Signals
34. TUMOUR SUPPRESSOR GENES
• First identified for inherited Retinoblastoma and Wilm’s
Tumour
• Act by loss of function
• Recessive (inactivation of both alleles necessary)
• Inactivated by
• mutations
• deletions
• DNA methylation (epigenetic)
• Cause predisposition to cancer
35. TUMOUR SUPPRESSOR GENES
Knudson’s Two-Hit Model
Adapted from Knudson, Proc Natl Acad Sci 1971
deletion / mutation:
inherited or somatic
Mutation
Loss Loss &
duplication
Chromosome
deletion Recombination
36. TUMOUR SUPPRESSOR GENES
RB - retinoblastoma
• Crucial regulator of the cell cycle
• Ubiquitously expressed
• Inactivating mutations and deletions in sporadic tumours
• Germ-line defects cause retinoblastoma and osteosarcomas
13
38. TUMOUR SUPPRESSOR GENES
• Transcription factor
• Crucial role in the cell’s response to stress
• Frequently mutated or deleted in cancer
• Germ-line defects in the Li-Fraumeni syndrome cause bone
and soft tissue sarcomas, brain tumours
17
p53 (TP53)
41. Skin Cancer
Lung Cancer
Liver Cancer
High frequency of C->T transitions at dipyrimidine sites
High frequency of transversions; hotspots at codons 157,158
High frequency of transversions; hotspot at codon 249
http://p53.free.fr/
TUMOUR SUPPRESSOR GENES
p53 (TP53)
44. The six most frequently mutated genes in selected malignancies
45. 4. Account for the fact that cancer risk can be inherited
Inherited genetic defects can cause predisposition to cancer
Adapted from Knudson, Proc Natl Acad Sci 1971
deletion / mutation:
inherited or somatic
Mutation
Loss Loss &
duplication
Chromosome
deletion Recombination
47. 4. Identify the uses of genetics in cancer diagnosis and treatment
Adapted from Stratton 2011
Biology of
neoplastic change
Drug targets
Monitoring
cancer burden
Early
diagnosis
Evolution of
the cancer clone
Metastasis
Drug resistance
Progression &
response to therapy
Classification
of cancer
DNA repair
processes
Mechanisms
of DNA damage
48. Cancer Diagnosis
Many tumours have specific genetic abnormalities
x ABL
xPML RARA
PML-RARA
BCR-ABL
IgH-MYC
IgH MYCx
Chronic myeloid leukaemia
Acute promyelocytic
leukaemia
Ewing’s sarcoma
Burkitt’s lymphoma, B-cell
acute lymphoblastic leukaemia
BCR
t(15;17)
t(9;22)
t(8;14)
xEWS FLI1
EWS-FLI1
t(11;22)
50. Examples of targeted treatment
Genetic changes indicate which processes and pathways
can be targeted
GLEEVEC/STI571
RETINOIC ACID
x ABL
xPML RARA
PML-RARA
BCR-ABL
Chronic myeloid leukaemia
Acute promyelocytic
leukaemia
BCR
t(15;17)
t(9;22)
51. Targeted treatment of the MAPK pathway
Proliferation
RAF
MEK1/2
ERK1/2
RAS
NF1
Specific inhibitors
P
P
Receptor
Tyrosine
Kinases
Extracellular
Signals
52. G Bollag et al. Nature 467, 596-599 (2010)
Targeting mutated BRAF in metastatic melanoma
BRAF
MEK1/2
ERK1/2
RAS
NF1
Proliferation
PLX4032
P
P
53. Hanahan & Weinberg (2000) Hallmarks of Cancer.
Cell 100: 57-70
Hanahan & Weinberg (2011) Hallmarks of Cancer: The Next Generation.
Cell 144: 646-674
Weinberg (2014) The Biology of Cancer, 2nd edition.
Garland Science, Taylor & Francis Group, LLC
Stratton et al (2009) The Cancer Genome
Nature 458: 719-724
Stratton (2011) Exploring the Genomes of Cancer Cells: Progress & Promise.
Science 331: 1553-1558
McDermott et al (2011) Genomics and the Continuum of Cancer Care.
N Engl J Med 364(4): 340-50
Vogelstein et al (2013) Cancer Genome Landscapes.
Science 339(6127): 1546-58
Garraway & Lander (2013) Lessons from the Cancer Genome.
Cell 153(1): 17-37
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