Julian Pe To

7/28/2019 Julian Pe To

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An epidemiological perspective on

the biology of cancer

Julian PetoCollaborating in Cancer Research

Cardiff 8th March 2006

London School of Hygiene and Tropical Medicine

and Institute of Cancer Research


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Bradford Hill Richard Doll


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Tobacco

Elimination of tobacco would prevent one third of all

cancers worldwide

Increased risk for cancers of lung, pancreas, bladder,kidney, larynx, mouth, pharynx, oesophagus

Recent evidence links smoking to increased risk of

stomach, liver and cervical cancers


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Cancer rates in migrants become similar to

those in the local population

0

5

10

15

prostate colon (m) stomach (m) breast (f)

Cumulativeratebyage75(%)

Osaka 1970-71

Osaka 1988-92

Hawaiian Japanese

1988-92

Hawaiian Caucasian

1968-72

Hawaiian Caucasian

1988-92


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Viruses, bacteria & parasites

Infections cause about 4% of cancers in the UK but 20%of all cancers worldwide

The most important are:

Helicobactor pylori (a chronic gastric bacterial

infection) causes stomach cancer

Human papillomaviruses (HPV) cause cervical cancer

Hepatitis B and C viruses cause liver cancer


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Cancers linked to obesity (Calle et al.,NEJM April 24 2003)

Oesophagus, colon, rectum, liver,gallbladder, pancreas, kidney, non-

Hodgkins lymphoma, myeloma

Prostate, breast, uterus, ovary, cervix


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Breast cancer and breastfeeding: collaborative

reanalysis of individual data from 47 epidemiological

studies in 30 countries, including 50 302 women with

breast cancer and 96 973 women without the disease

Collaborative Group on Hormonal Factors in Breast

Cancer Lancet (2002) 360:187-195

Reduction in risk:

3.0% per year for earlier age at first birth

7.0% per birth4.3% per year of breastfeeding


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Predicted reduction in Western breast cancer rates if women

had 6 or 7 children and breastfed each child for 2 yearsLancet (2002) 360: 187-95


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Percentage of US cancer deaths that would be

avoided by eliminating known risks

(Peto (2001) Nature 411: 390-395)

Cause Currentsmokers

Non-smokers

Smoking 60 -

Known infections 2 5Alcohol 0.4 1Sunlight 0.4 1

Air pollution 0.4 1Occupation 0.4 1Lack of exercise 0.4 1DietOverweight(BMI>25kg m

2)

Other dietary factors

4

4 - 12?

10

10 - 30?Presently unavoidable About a quarter At least half


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Collaborative cancer research

Epidemiology Avoidable causes Prevention

Genetics Mechanisms Better treatment

Biology Better screening

Epidemiology, genetics and biology

Clinical research

Evaluation of treatment,

screening and prevention


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Pre-molecular cancer epidemiology

1950s and 1960s:Cancer rates in adults suggest a series of

rate-limiting heritable steps in multi-stage

carcinogenesis.

Armitage and Doll (1954) Br J Cancer 8: 1-12

The age distribution of cancer and a multi-stage theory of

carcinogenesisReprinted in Int J Epid (2004) 33: 1174-79


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The tumour suppressor gene hypothesis for

polyposis coli and familial retinoblastoma

Cancers in apparently autosomal dominant

syndromes such as polyposis coli and familial

retinoblastoma appear as a result of

subsequent somatic mutations in which

individual cells become homozygous for a

recessive neoplasm-causing gene.

DeMars 1969


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Colon cancer

incidence isproportional to

the cube of age

in familial

polyposis coli,

and to the fifth

power of age in

the general

population

Ashley (1969)

J Med Genet 6,378


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USA (Connecticut)

0

50

100

150

200

250

300350

20 40 60 80

Denmark

0

50

100

150

200

250

300

350

20 40 60 80

Iceland

0

50

100

150

200

250

300

350

20 40 60 80

Japan (Osaka)

0

20

40

60

80

100

20 40 60 80

Age distribution of breast cancer incidence


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Model of rate of breast tissue ageingPike et al (1983) Nature 303, 767

0 10 20 30 40 50 60 70

Age

Bre

asttissue

ag

eing

rate

Menarche

First birth

Start of

perimenopausal

period

Last menstrual

period


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Stem cells and cancerCancer is caused by the accumulation of several genetic or

epigenetic changes in a single cell.

Teenage exposure (e.g. smoking or cervical HPV infection)greatly increases your cancer risk 50 years later.

The only cells that survive for 50 years are stem cells.

Therefore most cancers develop in very long-lived stem cells.

Stem cells must have evolved to minimise theaccumulation of multiple mutations in a single cell.

To understand cancer we have to understand stem cellbiology.

Shackleton et al (2006) Nature 439: 84-88. Generation of afunctional mammary gland from a single stem cell

Frank and Nowak (2004) Bioessays 26: 291-9. Problems of

somatic mutation and cancer


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Stem cell mechanisms to prevent mutationCairns (1975) Nature 255: 197-200

1. The immortal strand. When a stem cell

divides, the original DNA stays in the stem celldaughter, and the new copy (containing copying

errors) goes into the differentiating daughter

and is discarded within a week or two.

Copied DNA in differentiating daughter

Original DNA in stem cell

daughter


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Stem cell mechanisms to prevent mutation

2. DNA damage causes stem cell death rather

than error-prone repair

3. Mutant stem cells cannot escape from the

stem cell niche.


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Stem cell mechanisms to prevent mutation

4. Stem cell hierarchy. With four successive layers of

stem cells that divide 12 times and then die, the

maximum number of divisions in any cells ancestry is

reduced from ~20,000 to 48 in a human lifespan

12 divisions in 20 days (every 40 hours)

12 divisions in 8 months (every 20 days)

12 divisions in 8 years (every 8 months)

12 divisions in 100 years (every 8 years)


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Stem cell theorem

How many times should a stem cell divide,

contributing a daughter to the next level in

a hierarchical stem cell compartment, to

minimise the number of divisions any cellcan undergo?

Answer: e (= 2.7, the base of natural logs)


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Intestinal crypt

Leedham et al (2005) J Cell Mol Med 1:11-24


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Lung cancer mortality in continuing smokers

and ex-smokers. Halpern et al (1993) JNCI 85, 457

01

2

3

4

5

6

7

40 45 50 55 60 65 70 75

Age

D

eath

rate

per1000

Age stopped

60-64

55-59

50-54

40-49


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The stem cell perspective

What is the last step in lung cancer? It cannot becaused by smoking, as the incidence rate doesnot fall when smokers give up. The division of along-lived mutant stem cell seems plausible.

Do most mutagens cause cancer mainly by killingstem cells, causing stem cell proliferation, ratherthan by direct mutagenesis?

Cairns (2002) PNAS 99: 10567-70

Are stem cell proliferation (hormones, childhoodcancers) and chromosomal damage (Bloomssyndrome, asbestos) more important causes ofmost cancers than point mutation (XP)?

Cairns (1998) Genetics 148: 1433-40


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0

5

10

15

20

25

30-34 35-39 40-44 45-49 50-54 55-59 60-64 65-69

Age

An

nualdeath

ratep

er100,0

00

British cervical cancer mortality before screening

began (1920 birth cohort)


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CIN3 and cervical cancer

Almost 10% of British women develop CIN3 byage 50.

The prevalence of CIN3 in unscreened middle-

aged women is never much more than 1% evenpopulations where ~5% will eventually developcancer.

The cervical cancer incidence rate in unscreened

populations is constant from ages 50 to 85.Therefore most undiagnosed CIN3s musteventually regress cytologically but remain atconstant risk of malignant progression for at

least 35 years.


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15 25 35 45 55 65 75 85

0

10

20

30

40

50

60

70

80

Age (years)

Cum

ulativemortality

(%)

Genetic Rb

Sporadic Rb

General population

Cumulative lifetime cancer mortality for general

population, unilateral sporadic retinoblastoma survivors

and genetic retinoblastoma survivors.

Fletcher et al. (2004) J Natl Cancer Inst 96:357-63


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Cancer mortality after age 25 in hereditary

retinoblastoma survivors

Fletcher et al. (2004) J Natl Cancer Inst 96:357-63

Number of deaths SMR

Bone & sarcomas 5 74.3

Melanoma 2 23.3

Brain 2 6.6

Lung 14 7.0

Bladder 5 26.3

Breast 3 3.7Skin (non-melanoma) 1 58.5

Other cancer 9 2.2


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Apart from adrenocortical carcinoma in p53

carriers and retinoblastoma in Rb1 carriers, the

same early onset cancers are associated with

germline p53 or Rb1 mutation (osteosarcoma,

soft tissue sarcomas, breast cancer and brain

cancer).

Most of the adult-onset cancers in Rb1 carriers

are caused by DNA-damaging agents


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Breast cancer and percent mammographicdensity. Boyd et al. (1995).

Adjusted

Density Cases Controls odds ratio

None 10 25 1.0


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Correlates of breast density

Breast cancer risk

Sister with dense breasts

HRT

Late age at first birth

No breast feeding

Nulliparity

IGF-I


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3% 10% 20%Lifetime risk (log scale)

Polygenic model for breast cancer riskPharoah et al (2002) Nat Genet 31, 33

Peto (2002) Cancer Cell 1, 411

Lifetime risk General population Breast cancer patients

20% 0.03 0.25

C l ti b t i k f fi t d l ti f


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Cumulative breast cancer risks for first degree relatives of

CHEK2*1100delCheterozygotes with bilateral breast cancer,

first degree relatives ofCHEK2wild types with bilateral breast

cancer, and the expected rate in the general population

Johnson et al. (2005) Lancet 366: 1554-7


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Familial site-specific cancer risks in SwedenDong and Hemminki (2001) Int J Cancer 92 144

Parent or sibling affected Parent and sibling affected

SIR (N) SIR (N)

Breast 1.9 (1577) 2.4 (42)

Colon 2.0 (182) 27.6 (13)

Rectum 1.8 (47) 32.8 (2)Ovary 2.6 (88) 25.5 (4)

Prostate 2.7 (134) 23.7 (6)

Thyroid 6.9 (69) 292.0 (18)

Other endocrine 3.3 (84) 70.3 (8)

Lung 1.7 (112) 13.7 (3)Kidney 1.8 (45) 28.4 (2)

Melanoma 2.7 (256) 10.4 (7)

Brain & CNS 1.8 (188) 11.4 (6)

Leukaemia 2.3 (74) 33.3 (4)

Lymphoma 1.8 (76) 12.7 (2)


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The damage done to British medicalresearch by influential ethical experts


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In the late 1980s Ian Kennedy told a Select

Committee that HIV testing of the anonymiseddiscarded residue of blood samples from pregnant

women was unethical because a test must confer

some benefit on the patient.

This illogical assertion was accepted by the Select

Committee and delayed the introduction of HIV

monitoring, despite the pleas of many eminentscientists including Black, Cox, Doll, Bodmer,

Hoffenberg and Weiss. Black et al. (1987) Lancet ii 1277


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Data can be used for any medical research purposeunder the [Data Protection] Act, without the need for

the consent of individuals. So Professor Julian Peto is

simply wrong when he states that the Data Protection

Act is preventing data from being passed to medicalresearchers.

(Lord Falconer. Letter to The Times, May 17th 2001.)


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The Data Protection Act in the real world

The General Medical Council instructed doctors thatthey might face litigation under the Data Protection

Act if they notified their patients to cancer registries

without obtaining fully informed consent.


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The increasing bureaucratic burden imposed by

ethicists causes harm to patients and does

enormous damage to British cancer research.

Legislation is needed to restore the followingprinciple:

'Consent is not required for access to medical

records for non-commercial medical research that

has no effect on the individuals being studied and

has been approved by an accredited research ethics

committee.

93% of the audience voted for this proposed law at a

Parliamentary Group on Cancer public meeting

(Nov 5th

2002)


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Olivia Fletcher

Nikki JohnsonClare Palles

Maribel Almonte

Isabel dos Santos Silva

John Cairns

Richard Doll


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