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Cancer Genetics - Denise Sheer

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Hallmarks of Cancer, Cancer Genetics, Genomics, Mutations, Chromosome Defects, DNA Damage, Oncogenes, Tumour Suppressor Genes, Cancer Risk, Diagnosis, Prognosis, Targeted Treatment, CML, Philadelphia Chromosome, ABL, HRAS, KRAS, MYC, EGFR, RB, TP53, BRAF, Molecular Pathology
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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
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Page 1: Cancer Genetics - Denise Sheer

Denise Sheer ~ Barts & The London School of Medicine & Dentistry ~ Mar 2014

Molecular Foundations of Cancer

~ Genetics ~

Professor Denise Sheer

Blizard Institute

Page 2: Cancer Genetics - Denise Sheer

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

Page 3: Cancer Genetics - Denise Sheer

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

Page 4: Cancer Genetics - Denise Sheer

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

Page 5: Cancer Genetics - Denise Sheer

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

Page 6: Cancer Genetics - Denise Sheer

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

Page 7: Cancer Genetics - Denise Sheer

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

Page 8: Cancer Genetics - Denise Sheer

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

Page 9: Cancer Genetics - Denise Sheer

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

Page 10: Cancer Genetics - Denise Sheer

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

Page 11: Cancer Genetics - Denise Sheer

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

Page 12: Cancer Genetics - Denise Sheer

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

Page 13: Cancer Genetics - Denise Sheer

Chromosome defects

Metaphase spread Karyotype

Denise Sheer ~ Barts & The London School of Medicine & Dentistry ~ Mar 2014

Page 14: Cancer Genetics - Denise Sheer

Chronic Myeloid Leukaemia

Philadelphia Chromosome

9;22 translocation – t(9;22)

Denise Sheer ~ Barts & The London School of Medicine & Dentistry ~ Mar 2014

Page 15: Cancer Genetics - Denise Sheer

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

Page 16: Cancer Genetics - Denise Sheer

Chromosome aberrations Chromosome aberrations

Metaphase spread Karyotype

Denise Sheer ~ Barts & The London School of Medicine & Dentistry ~ Mar 2014

Page 17: Cancer Genetics - Denise Sheer

Glioblastoma

Complex karyotype, multiple chromosome defects: -Translocations, insertions, deletions +++ -Chromosome gains Denise Sheer ~ Barts & The London School of Medicine & Dentistry ~ Mar 2014

Page 18: Cancer Genetics - Denise Sheer

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

Page 19: Cancer Genetics - Denise Sheer

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

Page 20: Cancer Genetics - Denise Sheer

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

Page 21: Cancer Genetics - Denise Sheer

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

Page 22: Cancer Genetics - Denise Sheer

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

Page 23: Cancer Genetics - Denise Sheer

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

Page 24: Cancer Genetics - Denise Sheer

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

Page 25: Cancer Genetics - Denise Sheer

- 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

Page 26: Cancer Genetics - Denise Sheer

- 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

Page 27: Cancer Genetics - Denise Sheer

Frequencies of mutations across human tumours

Thomas et al,Nat Genet 2008

ONCOGENES

Denise Sheer ~ Barts & The London School of Medicine & Dentistry ~ Mar 2014

Page 28: Cancer Genetics - Denise Sheer

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

Page 29: Cancer Genetics - Denise Sheer

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

Page 30: Cancer Genetics - Denise Sheer

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

Page 31: Cancer Genetics - Denise Sheer

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

Page 32: Cancer Genetics - Denise Sheer

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

Page 33: Cancer Genetics - Denise Sheer

The Biology of Cancer (© Garland Science 2007) Denise Sheer ~ Barts & The London School of Medicine & Dentistry ~ Mar 2014

Page 34: Cancer Genetics - Denise Sheer

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

Page 35: Cancer Genetics - Denise Sheer

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

Page 36: Cancer Genetics - Denise Sheer

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

Page 37: Cancer Genetics - Denise Sheer

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

Page 38: Cancer Genetics - Denise Sheer

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

Page 39: Cancer Genetics - Denise Sheer

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

Page 40: Cancer Genetics - Denise Sheer

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

Page 41: Cancer Genetics - Denise Sheer

Opportunities for targeted treatment

Hanahan & Weinberg, 2011 Denise Sheer ~ Barts & The London School of Medicine & Dentistry ~ Mar 2014

Page 42: Cancer Genetics - Denise Sheer

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

Page 43: Cancer Genetics - Denise Sheer

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

Page 44: Cancer Genetics - Denise Sheer

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

Page 45: Cancer Genetics - Denise Sheer

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

Page 46: Cancer Genetics - Denise Sheer

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

Page 47: Cancer Genetics - Denise Sheer

Contact me if you have any questions

[email protected]

Denise Sheer ~ Barts & The London School of Medicine & Dentistry ~ Mar 2014


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