cancer gil mcvean, department of statistics, oxford
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Cancer
Gil McVean, Department of Statistics, Oxford
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Questions about cancer
• What is cancer?
• What causes unregulated cell growth?– What regulates cell growth?
• What causes DNA damage?
• What are the steps in the development of cancer?
• How do cancer therapies work?
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What is cancer?
• No single disease
• Characterised by– Unregulated cell growth (compared to benign tumours)– Invasive properties– Metastasis (migration to new tissues)
• Mutations in oncogenes give new properties – Hyperactive growth and division, protection against programmed cell
death (apoptosis), loss of respect for normal tissue boundaries, ability to become established in diverse tissue environments
• Mutations in tumour-suppressor genes lose normal functions– Accurate DNA replication, control over the cell cycle, orientation and
adhesion within tissues, interaction with immune system
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Some terminology
• Tumour– Cell masses – usually neoplastic – can be malign or malignant
• Many types of cancer– Carcinoma: From epithelial cells– Melanoma: From melanocytes– Lymphoma: From lymphocytes (B, T and NK cells)– Leukaemia: From WBC in bone marrow– Blastoma: From precursor cells (e.g. in retina)– Neuroma: From nervous system– Sarcoma: From connective/supporting tissue– …
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Incidence in UK
• 1 in 3 develop cancer during their lives
• 1 in 4 people die from cancer
• 3 out of 4 cases of cancer occur in people aged > 60
• Age-corrected incidence of cancer has increased by 21% in males and 41% in females over last 30 years
• Survival rates vary hugely between cancers – From <5% for lung cancer to
>80% for breast cancer
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Cervical cancer
• Carcinoma (cancer of epithelial cells)
• Human papillomavirus responsible for almost all cases– STD
• Produces proteins which inhibit key tumour suppressor genes
• P53– Activates DNA repair – Holds cell cycle at G1/S check point till repair carried out– Initiates apoptosis
• Rb (Retinoblastoma)– Holds cell cycle at G1/S check point till DNA repair carried out
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The cell cycle
G1/S checkpoint
G2/M checkpoint
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What causes DNA damage?
• Spontaneous damage
Hydrolysis
Free radical attackfrom reactive oxygen species (O and H2O2)
Loss of G base
C > U mutation (1000 per cell per day)
Alkylation of G
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What causes DNA damage?
• DNA replication errors– Mis-pairing (AC, GT) from rare tautomeric shifts– Errors in proof-reading– Polymerase slippage– Template strand dislocation
Polymerase site – preferentially binds AT and GC matches
Exonuclease site – preferentially binds AC and GT mis-matches
Actively identifies mismatchesAutoreverse on stallingAssociated proof-readingLater MMR105/106 to 109/1011 accuracy
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What causes DNA damage?
• Environmental mutagens
– UV produces cyclobutane pyrimidine dimer
– Ionising radiation produces clustering of oxidative-stress like damage (from ROS)
– Chemicals (e.g. Benzopyrene – responsible for ‘sooty warts’ in 18th C. chimney sweeps, major mutagen in tobacco smoke)
‘Intercalates’ in DNA preventing correct DH formation leading to G > T mutations in p53 transversion hotspots
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How is damaged DNA detected?
• Double-strand breaks– Homologous recombination repair
• Single-stranded DNA– Stalled replication forks– Nucleotide excision repair– Homologous recombination repair
• Chemically modified bases
• Recognition of damage leads to– Cell cycle checkpoint activation– DNA repair– Gene transcription– Apoptotic cell death
ATM
ATR
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DNA damage repair and classic tumour suppressor genes
Exact activation pathway unknown
Breast, Ovarian, Prostate cancer
Li-Fraumeni syndrome
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Rous sarcoma virus
• RSV is retrovirus with standard gag, pol, and env genes
• Also has v-src gene – tyrosine kinase. Like host gene (chicken), but lacks inhibitory site so is constantly ‘on’ leading to cell proliferation
• Mutation of normal src gene can have same phenotype– Led to notion of oncogene
• Oncogene = Mutant form of normal gene (proto-oncogene) that over-rides regulatory controls and/or gains new functions
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Oncogene activation
• Translocation– 8/14 translocation of B cells in
Burkitt’s lymphoma– 9/22 Philadelphia chromosome in
Chronic Myelogenous Leukaemia
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Oncogene activation
• Amplification– Extra-chromosomal segments to form
‘double minutes’– Integration to form HSRs
• Regions associated with palindromic sequence– Hairpin structures
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Oncogene activation
• Point mutation
• Single base changes in– Growth factors (TGF-)– Cell surface receptors (EGFR)– Cellular messengers (RAS oncogene mutated in 30% all human tumours)– Transcription factors (MYC)
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Genetic progression of cancer
Stratton et al. (2009)
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Cancer genomes are often (though not always) highly mutated
This makes identification of driver mutations difficult
Genome sequence of small-cell lung cancer
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A quick calculation
• There are maybe 1012 - 1013 cells in the human body
• DNA polymerase has an error rate of one in 109-1011
• RBCs last about 120 days – other cells are maybe longer lasting (say a year on average)
• Every year you would expect 10 – 10,000 mutations in your body at any given nucleotide position
• The average gene is about 1500 nucleotides long – so each gene experiences 104 -107 point mutations per year
• Why aren’t we dead?
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6 or 7 steps to cancer
• In the early 1950s epidemiological studies showed that cancer incidence increases with the 6th power of age– Though risk from mutagen exposure is linear (but also delayed)
• Armitage and Doll (1954) showed that this can be explained if transformed cell lineages require 6-7 events in a particular order
Age
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What are the steps?
• Immortalisation (avoidance of apoptosis)
• Loss of DNA repair
• Activation of cell growth
• Changes in cell shape/motility/adhesion
• Changes in cell metabolism
• Recruitment of vascularisation
• Suppression of immune system
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The right mutation at the right time
• Tumours can be differentiated according to patterns of gene expression– Relates to stem cell population in which driver mutations occured and
the driver mutation(s) – e.g. Oncogene activation
Ependymomas can be differentiated into 9 subtypes based on gene expression, which correspond to 9 different stem cell populations. Johnson et al (2010)
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Therapies
• Surgery– Other therapies often used in combination
• Radiotherapy– Problems with hypoxia in solid tumours
• Non-specific chemotherapy– Targets cell division, so greater effect on fast-growing cells (includes
hair, epithelial lining)– Usually not specific to cancer cells
• Specific chemotherapy– E.g. Imatinib targets TK domains of 3 oncogenes (e.g. specific to CML)
• Monoclonal antibodies– Rituximab is a modified monoclonal targeting B cell leukaemias
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Chemotherapies from natural products
• Paclitaxel (tradename Taxol)– From Pacific Yew Tree– Used to treat ovarian and breast cancer– Promotes microtubule assembly
• Camptothecin– From Chinese ornamental tree– Used to treat colon, lung and ovarian cancer– Inhibits topoisomerases
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The future
• Use antibodies to target specific chemicals– Immune activators (cytokines such as Interleukins)– Lethal chemicals
• Use antibodies to target radiotherapy
UK survival rates (1999 – 2003)
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Genetic predisposition
• Many cancers have strong heritable component
• Sometimes this is due to highly penetrant mutations– BRCA1, BRCA2
• Genome-wide association studies are identifying other loci with much weaker effects– Though still explains no more than 5% of genetic risk
• Familial aggregation of different cancers points to common genetic risk factors– Breast and prostate cancer– Melanoma and squamous cell carcinoma