cancer genetics - denise sheer
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Denise Sheer ~ Barts & The London School of Medicine & Dentistry ~ Mar 2014
Molecular Foundations of Cancer
~ Genetics ~
Professor Denise Sheer
Blizard Institute
Overview
1. Principles of the Hallmarks of Cancer
2. Types of genetic changes that occur during cancer development 3. Tumour Suppressor Genes and Oncogenes
4. Cancer risk can be inherited
5. Uses of genetics in cancer diagnosis and treatment
Denise Sheer ~ Barts & The London School of Medicine & Dentistry ~ Mar 2014
1. Hallmarks of Cancer
Cancer • A disease of extraordinary diversity and complexity
• But - disparate malignancies share fundamental qualities
• The complexity 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 Denise Sheer ~ Barts & The London School of Medicine & Dentistry ~ Mar 2014
Hanahan & Weinberg 2000, 2011
The Hallmarks are acquired capabilities that allow tumours to overcome these barriers
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
Denise Sheer ~ Barts & The London School of Medicine & Dentistry ~ Mar 2014
At the cellular level, cancer is a genomic disease
• 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
Denise Sheer ~ Barts & The London School of Medicine & Dentistry ~ Mar 2014
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 treatments
Genetic and epigenetic aberrations give rise to the key features of cancer
Denise Sheer ~ Barts & The London School of Medicine & Dentistry ~ Mar 2014
Cancer “omics”
Whole Genome Sequencing Exome Sequencing
RNA Sequencing
Protein Sequencing
mRNA ncRNA
proteins
DNA
Methylated DNA
Methylated DNA
sequencing
TRANSCRIPTOME
PROTEOME
GENOME EXOME
METHYLOME
Denise Sheer ~ Barts & The London School of Medicine & Dentistry ~ Mar 2014
Genetic aberrations affect the DNA sequence in the cells that give rise to cancer
2. Types of genetic changes that occur during cancer development
MUTATIONS CHROMOSOME
DEFECTS
Denise Sheer ~ Barts & The London School of Medicine & Dentistry ~ Mar 2014
Causes of genetic defects 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. Denise Sheer ~ Barts & The London School of Medicine & Dentistry ~ Mar 2014
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
Denise Sheer ~ Barts & The London School of Medicine & Dentistry ~ Mar 2014
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
Denise Sheer ~ Barts & The London School of Medicine & Dentistry ~ Mar 2014
Chromosome defects
STRUCTURAL
translocation
inversion
insertion
duplication
amplification
deletion
NUMERICAL loss or gain of whole
chromosome
loss of gain of whole chromosome set
Leukaemias tend to have simple karyotypes
Many carcinomas and high grade brain tumours have complex karyotypes
Denise Sheer ~ Barts & The London School of Medicine & Dentistry ~ Mar 2014
Chromosome defects
Metaphase spread Karyotype
Denise Sheer ~ Barts & The London School of Medicine & Dentistry ~ Mar 2014
Chronic Myeloid Leukaemia
Philadelphia Chromosome
9;22 translocation – t(9;22)
Denise Sheer ~ Barts & The London School of Medicine & Dentistry ~ Mar 2014
Chronic Myeloid Leukaemia 9;22 translocation – t(9;22)
9 22 Philadelphia Chromosome
Recurrent translocations that give rise to specific gene fusions are common in leukaemias, lymphomas and sarcomas.
They are also found in some carcinomas and brain tumours.
ABL
BCR-ABL
BCR
Denise Sheer ~ Barts & The London School of Medicine & Dentistry ~ Mar 2014
Chromosome aberrations Chromosome aberrations
Metaphase spread Karyotype
Denise Sheer ~ Barts & The London School of Medicine & Dentistry ~ Mar 2014
Glioblastoma
Complex karyotype, multiple chromosome defects: -Translocations, insertions, deletions +++ -Chromosome gains Denise Sheer ~ Barts & The London School of Medicine & Dentistry ~ Mar 2014
Vogelstein et al, Science 2013
Number of mutations across human cancers Genome-wide sequencing
Denise Sheer ~ Barts & The London School of Medicine & Dentistry ~ Mar 2014
Vogelstein et al, Science 2013
Total alterations affecting protein coding genes
Indels: Insertions & Deletions SBS: Single base substitutions
Denise Sheer ~ Barts & The London School of Medicine & Dentistry ~ Mar 2014
3. Oncogenes and tumour suppressor genes
ONCOGENES • Act by gain of function • Dominant (activation of one allele sufficient) • Activated by - mutation - chromosome translocation - gene amplification - retroviral insertion
• Some were first identified in transforming retroviruses, e.g. - HRAS (rat/mouse Harvey sarcoma virus) - KRAS (rat/mouse Kirsten sarcoma virus) - ABL (mouse abelson leukaemia virus) - MYC (avian myelocytoma virus)
Denise Sheer ~ Barts & The London School of Medicine & Dentistry ~ Mar 2014
RAS genes – HRAS, KRAS, NRAS Activated by mutations that change amino acids 12, 13 or 61 in ~30% of tumours
RAF
MEK1/2
ERK1/2
RAS
P
P
Proliferation
NF1
ONCOGENES - Mutation
RAS RAS
Receptor Tyrosine Kinases
Extracellular Signals
Denise Sheer ~ Barts & The London School of Medicine & Dentistry ~ Mar 2014
Incidence of HRAS, KRAS & NRAS gene mutations
Adapted from Downward, Nature Rev Cancer 2003, & The Biology of Cancer (© Garland Science 2007)
ONCOGENES - Mutation
Denise Sheer ~ Barts & The London School of Medicine & Dentistry ~ Mar 2014
ONCOGENES - Mutation
MYC MYC
MYC genes – MYC, MYCN, MYCL Activated by mutations, chromosome translocation and amplification
Note: MYC is also called c-MYC
Transcription factor
Proliferation
MYC
Denise Sheer ~ Barts & The London School of Medicine & Dentistry ~ Mar 2014
Chronic Myeloid Leukaemia
BCR-ABL gene fusion
x ABL BCR-ABL
BCR
Philadelphia Chromosome
9 22
BCR ABL
9;22 translocation – t(9;22)
ONCOGENES - Chromosome
translocation
BCR-ABL
Denise Sheer ~ Barts & The London School of Medicine & Dentistry ~ Mar 2014
- Gene Amplification multiple copies
ONCOGENES
Neuroblastoma
MYCN
MYC MYC MYC MYC
MYC MYCL MYCN
MYC MYC MYC or
Denise Sheer ~ Barts & The London School of Medicine & Dentistry ~ Mar 2014
- Gene Amplification multiple copies
ONCOGENES
EGFR EGFR or EGFR EGFR EGFR
EGFR EGFR EGFR
7 cen EGFR
Glioblastoma
Denise Sheer ~ Barts & The London School of Medicine & Dentistry ~ Mar 2014
Frequencies of mutations across human tumours
Thomas et al,Nat Genet 2008
ONCOGENES
Denise Sheer ~ Barts & The London School of Medicine & Dentistry ~ Mar 2014
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
Denise Sheer ~ Barts & The London School of Medicine & Dentistry ~ Mar 2014
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
Denise Sheer ~ Barts & The London School of Medicine & Dentistry ~ Mar 2014
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
Denise Sheer ~ Barts & The London School of Medicine & Dentistry ~ Mar 2014
13
TUMOUR SUPPRESSOR GENES RB – retinoblastoma – RB hyperphosphorylation allows the cell to enter late G1
The Biology of Cancer (© Garland Science 2007)
A: cyclin A B: cyclin B D: cyclin D E: cyclin E
Denise Sheer ~ Barts & The London School of Medicine & Dentistry ~ Mar 2014
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
p53 (TP53)
17
Denise Sheer ~ Barts & The London School of Medicine & Dentistry ~ Mar 2014
17
The Biology of Cancer (© Garland Science 2007) Denise Sheer ~ Barts & The London School of Medicine & Dentistry ~ Mar 2014
Distribution of mutations over the p53 gene
The Biology of Cancer (© Garland Science 2007)
Hotspots in Glioblastoma
http://p53.free.fr/ Denise Sheer ~ Barts & The London School of Medicine & Dentistry ~ Mar 2014
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)
Denise Sheer ~ Barts & The London School of Medicine & Dentistry ~ Mar 2014
TUMOUR SUPPRESSOR GENES
p53 (TP53) – response to stress
The Biology of Cancer (© Garland Science 2007) Denise Sheer ~ Barts & The London School of Medicine & Dentistry ~ Mar 2014
4. 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
Denise Sheer ~ Barts & The London School of Medicine & Dentistry ~ Mar 2014
Examples of tumour suppressor genes and associated cancer syndromes
Adapted from The Biology of Cancer (© Garland Science 2007)
TF: transcription factor
Denise Sheer ~ Barts & The London School of Medicine & Dentistry ~ Mar 2014
5. Uses of genetics in cancer diagnosis and treatment
Adapted from Stratton, Science 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
Denise Sheer ~ Barts & The London School of Medicine & Dentistry ~ Mar 2014
Cancer Diagnosis Many tumours have specific genetic abnormalities
Examples
x ABL
x PML
RARA PML-RARA
BCR-ABL
IgH-MYC IgH
MYC x
Chronic myeloid leukaemia
Acute promyelocytic leukaemia
Burkitt’s lymphoma, B-cell acute lymphoblastic leukaemia
BCR
t(15;17)
t(9;22)
t(8;14)
Denise Sheer ~ Barts & The London School of Medicine & Dentistry ~ Mar 2014
Opportunities for targeted treatment
Hanahan & Weinberg, 2011 Denise Sheer ~ Barts & The London School of Medicine & Dentistry ~ Mar 2014
Examples of targeted treatment Genetic changes indicate which processes and pathways
can be targeted
GLEEVEC/STI571
RETINOIC ACID
x ABL
x PML
RARA PML-RARA
BCR-ABL Chronic myeloid leukaemia
Acute promyelocytic leukaemia
BCR
t(15;17)
t(9;22)
Denise Sheer ~ Barts & The London School of Medicine & Dentistry ~ Mar 2014
Targeted treatment
MAPK pathway
Proliferation
RAF
MEK1/2
ERK1/2
RAS NF1
Specific inhibitors P
P
Receptor Tyrosine Kinases
Extracellular Signals
Denise Sheer ~ Barts & The London School of Medicine & Dentistry ~ Mar 2014
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
Denise Sheer ~ Barts & The London School of Medicine & Dentistry ~ Mar 2014
Minimal residual disease Genetic changes can be used to monitor response to treatment
e.g. BCR-ABL in CML
Tumour biology Genetic changes indicate defects in cancer-specific processes
e.g. p53 in many cancers and other examples given in this lecture
Denise Sheer ~ Barts & The London School of Medicine & Dentistry ~ Mar 2014
Hanahan & Weinberg (2000) Hallmarks of Cancer. Cell 100: 57-70
Weinberg (2007) The Biology of Cancer.
Garland Science, Taylor & Francis Group, LLC
Stratton et al (2009) The Cancer Genome Nature 458: 719-724
Hanahan & Weinberg (2011) Hallmarks of Cancer: The Next Generation.
Cell 144: 646-674
McDermott et al (2011) Genomics and the Continuum of Cancer Care. N Engl J Med 364(4): 340-50
Stratton (2011) Exploring the Genomes of Cancer Cells: Progress & Promise
Science 331: 1553-1558
Garraway & Lander (2013) Lessons from the Cancer Genome Cell 153: 17-37
Vogelstein et al (2013) Cancer Genome Landscapes
Science 339: 1546-1558
For more information (and really great to read!)
Denise Sheer ~ Barts & The London School of Medicine & Dentistry ~ Mar 2014
Contact me if you have any questions
d.sheer@qmul.ac.uk
Denise Sheer ~ Barts & The London School of Medicine & Dentistry ~ Mar 2014
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