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Genetic Basis of Cancer

PowerPoint for lecture, 1500 Monday 6th December 2004

Andrew Read

Dept of Medical Genetics

The bad news..

You are absolutely inevitably all going to get

cancer .

(unless something else gets you first)

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The argument from natural selectionThe argument from natural selection

Applies equally well to the population of cells that make up a

multicellular organism as it does to a population of whole

organisms

Multicellular organisms are formed by repeated mitosis,

so every cell contains the same genes and DNA

Mutations happen to somatic cell DNA just as much as to germ

line DNA

Inherited vs. somatic geneticInherited vs. somatic geneticdiseasedisease

Exactly the same mutations can occur in germ line or somatic

cells, but the observed spectrum is different because:

many mutations seen in somatic cells would be lethal

if constitutional (e.g. trisomy 8)

most inherited mutations would have no observable

consequences if present in a small number of somatic cells

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Inherited vs. somatic geneticInherited vs. somatic genetic

diseasedisease

Somatic mutations can be clinically significant when:

they occur early in embryogenesis, so that the person

ends up with a significant clone of mutant cells

(e.g. mosaic Down syndrome, Duchenne dystrophy etc.)

they give the cell a growth advantage so that it forms atumour

Cancer is the major somatic genetic disease

The natural selection argumentThe natural selection argument

Cell proliferation is under genetic control

Mutations will inevitably arise that give a cell a

proliferative advantage

The daughters of that cell will take over the organism

Cancer is the natural and inevitable end-state of

all multicellular organisms

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Natural selection and cancer:Natural selection and cancer:

two competing forcestwo competing forces

.Resist.

cancer

Develop

cancer

Timescale 75 years

Evolution within a species

Timescale 1,000,000,000 years

Evolution within an organism

The good news..

Its statistically impossible for anybody ever

to get cancer

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Mutation and selection in theMutation and selection in the

development of tumoursdevelopment of tumours

Age-of-onset data suggest the common epithelial

cancers require 4-7 successive events to convert a

normal epithelial cell into a malignant tumour cell

If typical mutation rates are 10-6 per cell generation,the chance of this happening to any of the 1013 cells

in a person is 10-11 - 10-29

i.e. 4-7 independent defences must be knocked out

Successful carcinogenesis requires

Or mutations that destabilise the genome, so as toincrease the subsequent mutation rate

Either mutations that increase the rate of cellproliferation, so as to provide an expanded target for

subsequent mutations

So how do we get cancer?

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General features of cancer: clonal

evolution

Implications of clonal evolution of cancers

Multistage process with each stage driven by genetic changes

some stages may be clinically or histologically identifiable

genetic changes precede morphological changes thus may

serve as early markers

Occurs over a relatively long period - early intervention

may be possible

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Implications of genomic instability

Very complex genotypes in cancer:

grossly abnormal karyotypes

many genes mutated, deleted or amplified

Cancers may consist of multiple clones with

different genetic lesions

Corrective gene therapy for common cancers unlikely

Tumour Suppressor Genes:

Oncogenes:

Genes that gain function in cancer development

Dominant (one copy of the gene needs to be activated)

Accelerator - normal function favours cell proliferation

Genes that sustain loss of function in cancer development

Recessive (both copies need to be inactivated)

Brakes - normal function restrains cell proliferation

Genes involved in tumorigenesis

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Functions of Oncogenes Secreted growth factors

Cell surface receptors

Signal transduction system components

Nuclear proteins, transcription factors

Cyclins/Cyclin-dependent kinases

PDGF

ERBB, RET, MET

RAS, ABL

MYC, JUN

CYCLIN D1, CDK

Functions of Tumour Suppressor Genes

DNA-binding transcription factors (p53, WT1)

Transcriptional regulators (Rb, APC, ?BRCA1)

Signal transduction system components (NF1, p16, DPC4, Patched)

Phosphatases (PTEN)

DNA repair and genome stability (p53, BRCA1 & BRCA2)

Structural protein (NF2)

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Cancer: the six capabilitiesCancer: the six capabilities

become capable of indefinite replication

become independent of external growth signals

become insensitive to external anti-growth signals

become able to avoid apoptosis

become capable of tissue invasion and metastasis

become capable of sustained angiogenesis

A successful cancer cell must:

Hanahan & Weinberg Cell 100 57-70 ; 2000

Activation of oncogenesActivation of oncogenes

By point mutation

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Signalling Signalling

TM

Cyto

Mutation

GDNF

RETreceptor tyrosine kinase

Activation of RET oncogene by point mutationActivation of RET oncogene by point mutation


By point mutation

By amplification

By chromosomal translocation that up-regulates

expression

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Activation of MYC oncogene by anActivation of MYC oncogene by an

8:14 translocation8:14 translocation

Result is Burkitts lymphoma


By chromosomal translocation that creates a novel

chimaeric gene

By point mutation

By amplification

By chromosomal translocation that up-regulates

expression

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Activation of ABL oncogene by aActivation of ABL oncogene by a

9:22 translocation9:22 translocationResult is a novel chimaericgene

Gene encodes an over-activegrowth signalling molecule

Causes chronic myeloidleukaemia

Gleevec is a specificinhibitor of the novel kinase

Inactivation of tumour suppressorInactivation of tumour suppressor

genesgenes

By point mutation (missense, nonsense, frameshift )

By deletion of all or part of the gene

By loss of all or part of the relevant chromosome

By silencing a structurally intact gene by methylation of

the DNA of its promoter

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Familial vs. sporadic cancersFamilial vs. sporadic cancers

99% of cancers are sporadic, no inherited susceptibility

1% involve inherited susceptibility :

manifest as rare mendelian dominant syndromes

increased cancer susceptibility

may be associated with other abnormalities

may be associated with multiple tumour types

Risk of Neoplasia in Cancer Syndromes

Syndrome Neoplasia Lifetime risk (%)

NF1

FAP

VHL

AT

MEN2A

Melanoma

BRCA1

HNPCC

Plexiform neurofibroma

Optic glioma

Bowel cancer

Cerebellar H'angioblastoma

Retinal angioma

Renal cell carcinoma

Lymphoma

Leukaemia

Medullary thryoid carcinoma

Phaechromocytoma

Melanoma

Breast

Ovary

Colon

Prostate

Colon and endometrium

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KnudsonKnudsons twos two--hit hypothesishit hypothesis

The same genetic changes cause the common sporadic

and rare familial forms of the disease

Oncogenesis requires two successive mutations in one cell

In the familial form the first hit is inherited, the

second is acquired

The familial condition is dominant at the pedigree

level but recessive at the cell level

Inactivation of Tumour Suppressor

Genes in familial cancers

First hit (mutation of one copy of the gene)

occurs in the GERMLINE

Second hit (mutation of the second copy of the gene)

occurs in the SOMATIC cells

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Germ cellGerm cell Somatic cellsSomatic cells

1st1stHITHIT

2nd2ndHITHITTumour cellsTumour cells

Inactivation of Tumour Suppressor Genes

in sporadic cancers

First hit (mutation or loss of one copy of the gene)

occurs in a SOMATIC cell

Second hit (mutation or loss of the second copy of the gene)

occurs in the SOMATIC cell carrying the first hit

or in one of its descendants

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2nd2nd

HITHITTumour cellsTumour cells

Somatic cellsSomatic cells Somatic cellsSomatic cells

1st1stHITHIT

Tumour Suppressor Genes

Familial Cancer:

Early onset

Multiple tumours of same

type

Other tumours

Tumour cells have both

copies of TSG inactivated

All other cells one copy of

TSG inactivated

Sporadic Cancer:

Later onset

Single tumour usually

No other tumours usually

Tumour cells have both

copies of TSG inactivated

All other cells normal

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22--hit hypothesis for retinoblastomahit hypothesis for retinoblastoma

Suppose there are 107 target cells and the chance of a mutationhappening to a given cell is 1 in 106

The incidence of sporadic retinoblastoma will be 107 x10-6x10-6

The risk of retinoblastoma in somebody inheriting one mutationwill be 107 x10-6 i.e familial Rb has a high penetrance

Retinoblastoma as model ofKnudsons two hit hypothesis

Familial form:

Onset:

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Colorectal cancer

Conversion to malignancy occurs in a multistage

process

Stages recognisable as distinct entities

Normal epitheliumNormal epithelium

AberrantAberrant dysplasticdysplastic crypt focuscrypt focus

Early adenomaEarly adenoma

Intermediate adenomaIntermediate adenoma

Late adenomaLate adenoma

CarcinomaCarcinoma

MetastasesMetastases

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Familial Adenomatous Polyposis Inheritance: Autosomal Dominant

Gene: APC

Incidence: ~1 : 8000 - 10000

Features: Colonic and Extracolonic

Familial Adenomatous Polyposis

Colon:

Many polyps (adenomas)

develop, usually after

puberty

One or more polypstransform to

adenocarcinoma, usually

in 3rd / 4th decades.

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Familial Adenomatous Polyposis

Extracolonic features

Dento-osseous changes

Congenital hypertrophy of retinal pigmentary

epithelium (CHRPE)

Desmoids

Sebaceous cysts

Extracolonic polyposis and carcinoma

Genetic changes in FAP and sporadiccolorectal cancers

Familial adenomatous polyposis (FAP)

APC mutation:

inherited germline mutation of one copy of APC

somatic mutation of second APC allele

occurs early in the multistage process

multiple polyps (adenomas)

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Genetic changes in FAP and sporadic

colorectal cancers

Sporadic CRC

APC mutation:

somatic mutation of one copy of APC

somatic mutation of second APC allele in the clone

of cells carrying the first hit

single polyp (adenoma)

Normal epitheliumNormal epithelium

AberrantAberrant dysplasticdysplastic cryptcryptfocusfocus

APCinactivation x2

Early adenomaEarly adenomaAlterations in DNA methylation

Intermediate adenomaIntermediate adenomaKRASactivation x1

Late adenomaLate adenomaSMAD4inactivation x2

CarcinomaCarcinoma

TP53inactivation x2

Genetic events in colorectal carcinogenesis

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Genetic changes in FAP and sporadic

colorectal cancers Mutation of both oncogenes and TSGs (other than

APC)

KRAS; TP53, SMAD4

Sequence of events appears to be important:

APC: early change - GATEKEEPER

KRAS: early change

SMAD4: intermediate change

TP53 late change

Progressive loss of proliferation control

Cancer Genetics- Summary (1)

All cancers are genetic diseases

Some cancers are familial diseases

Most cancers are sporadic diseases

Carcinogenesis is driven by Clonal selection

Genomic instability

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Two groups of genes involved in cancer

Oncogenes

Tumour suppressor genes

Most common cancers arise through a

multistage process

Alteration of 4-7 genes necessary Both oncogenes and tumour suppressor genes

involved

Think pathways and capabilities,Think pathways and capabilities,

not genes !not genes !


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