An epidemiological perspective on the biology of cancer

Julian Peto
Collaborating in Cancer Research Cardiff 8th March 2006
London School of Hygiene and Tropical Medicine and Institute of Cancer Research

Bradford Hill

Richard Doll

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

Cancer rates in migrants become similar to those in the local population

15

Cumulative rate by age 75 (%)

Osaka 1970-71
10

Osaka 1988-92 Hawaiian Japanese 1988-92 Hawaiian Caucasian 1968-72 Hawaiian Caucasian 1988-92

prostate

colon (m)

stomach (m)

breast (f)

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

Cancers linked to obesity (Calle et al., NEJM April 24 2003) Oesophagus, colon, rectum, liver, gallbladder, pancreas, kidney, nonHodgkins lymphoma, myeloma

Prostate, breast, uterus, ovary, cervix

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 birth 4.3% per year of breastfeeding

Predicted reduction in Western breast cancer rates if women had 6 or 7 children and breastfed each child for 2 years
Lancet (2002) 360: 187-95

Percentage of US cancer deaths that would be avoided by eliminating known risks

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

Cause
Smoking Known infections Alcohol Sunlight Air pollution Occupation Lack of exercise Diet Overweight (BMI>25kg m 2) Other dietary factors Presently unavoidable

Current smokers
60 2 0.4 0.4 0.4 0.4 0.4 4

Nonsmokers
5 1 1 1 1 1 10

4 - 12? 10 - 30? About a quarter At least half

Collaborative cancer research

Epidemiology Genetics Avoidable causes Mechanisms Prevention Better treatment

Biology

Better screening

Epidemiology, genetics and biology Clinical research Evaluation of treatment, screening and prevention

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

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

Colon cancer incidence is proportional 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

Age distribution of breast cancer incidence

USA (Connecticut)
350 300 250 200 150 100 50 0 20 40 60 80 350 300 250 200 150 100 50 0 20 40 60 80

Denmark

Iceland
350 300 250 200 150 100 50 0 20 40 60 80
100 80 60 40 20 0 20

Japan (Osaka)

40

60

80

Model of rate of breast tissue ageing

Pike et al (1983) Nature 303, 767
Breast tissue ageing rate

Menarche

Start of perimenopausal period First birth

Last menstrual period

10

20

30

40

50

60

70

Age

Stem cells and cancer

Cancer 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 the accumulation of multiple mutations in a single cell. To understand cancer we have to understand stem cell biology. Shackleton et al (2006) Nature 439: 84-88. Generation of a functional mammary gland from a single stem cell Frank and Nowak (2004) Bioessays 26: 291-9. Problems of somatic mutation and cancer

Stem cell mechanisms to prevent mutation

Cairns (1975) Nature 255: 197-200

1. The immortal strand. When a stem cell divides, the original DNA stays in the stem cell daughter, 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

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.

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)

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 cell can undergo? Answer: e (= 2.7, the base of natural logs)

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

Lung cancer mortality in continuing smokers and ex-smokers. Halpern et al (1993) JNCI 85, 457
7
Death rate per 1000

6 5 4 3 2 1 0 40 45 50 55 60 65 70 75
Age stopped 60-64 55-59 50-54 40-49

Age

The stem cell perspective

What is the last step in lung cancer? It cannot be caused by smoking, as the incidence rate does not fall when smokers give up. The division of a long-lived mutant stem cell seems plausible. Do most mutagens cause cancer mainly by killing stem cells, causing stem cell proliferation, rather than by direct mutagenesis?
Cairns (2002) PNAS 99: 10567-70

Are stem cell proliferation (hormones, childhood cancers) and chromosomal damage (Blooms syndrome, asbestos) more important causes of most cancers than point mutation (XP)?
Cairns (1998) Genetics 148: 1433-40

British cervical cancer mortality before screening began (1920 birth cohort)
25
Annual death rate per 100,000.

20

15 10

5 0 30-34 35-39 40-44 45-49 Age 50-54 55-59 60-64 65-69

CIN3 and cervical cancer

Almost 10% of British women develop CIN3 by age 50. The prevalence of CIN3 in unscreened middleaged women is never much more than 1% even populations where ~5% will eventually develop cancer. The cervical cancer incidence rate in unscreened populations is constant from ages 50 to 85. Therefore most undiagnosed CIN3s must eventually regress cytologically but remain at constant risk of malignant progression for at least 35 years.

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
80 70

Cumulative mortality (%)

60 50 40 30 20 10 0 15 25 35 45 55

Genetic Rb

Sporadic Rb

General population
65 75 85

Age (years)

Cancer mortality after age 25 in hereditary retinoblastoma survivors

Fletcher et al. (2004) J Natl Cancer Inst 96:357-63
Number of deaths Bone & sarcomas Melanoma Brain Lung Bladder Breast Skin (non-melanoma) Other cancer 5 2 2 14 5 3 1 9 SMR 74.3 23.3 6.6 7.0 26.3 3.7 58.5 2.2

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

Breast cancer and percent mammographic density. Boyd et al. (1995). Adjusted odds ratio 1.0 1.2 2.2 2.4 3.4 5.3

Density None <10% 10%25%50%75%+

Cases 10 29 65 94 90 66

Controls 25 61 73 97 67 31

Correlates of breast density

Breast cancer risk Sister with dense breasts HRT Late age at first birth No breast feeding Nulliparity IGF-I

Polygenic model for breast cancer risk

Pharoah et al (2002) Nat Genet 31, 33 Peto (2002) Cancer Cell 1, 411

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

Lifetime risk <3% 3-10% 10-20% >20% General population 0.50 0.38 0.09 0.03 Breast cancer patients 0.12 0.38 0.25 0.25

Cumulative breast cancer risks for first degree relatives of CHEK2*1100delC heterozygotes with bilateral breast cancer, first degree relatives of CHEK2 wild types with bilateral breast cancer, and the expected rate in the general population

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

Familial site-specific cancer risks in Sweden

Dong and Hemminki (2001) Int J Cancer 92 144
Parent or sibling affected SIR (N) Breast Colon Rectum Ovary Prostate Thyroid Other endocrine Lung Kidney Melanoma Brain & CNS Leukaemia Lymphoma 1.9 2.0 1.8 2.6 2.7 6.9 3.3 1.7 1.8 2.7 1.8 2.3 1.8 (1577) (182) (47) (88) (134) (69) (84) (112) (45) (256) (188) (74) (76) Parent and sibling affected SIR (N) 2.4 27.6 32.8 25.5 23.7 292.0 70.3 13.7 28.4 10.4 11.4 33.3 12.7 (42) (13) (2) (4) (6) (18) (8) (3) (2) (7) (6) (4) (2)

The damage done to British medical research by influential ethical experts

In the late 1980s Ian Kennedy told a Select Committee that HIV testing of the anonymised discarded 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 eminent scientists including Black, Cox, Doll, Bodmer, Hoffenberg and Weiss. Black et al. (1987) Lancet ii 1277

Data can be used for any medical research purpose under 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 medical researchers. (Lord Falconer. Letter to The Times, May 17th 2001.)

The Data Protection Act in the real world

The General Medical Council instructed doctors that they might face litigation under the Data Protection Act if they notified their patients to cancer registries without obtaining fully informed consent.

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 following principle: '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)

Olivia Fletcher Nikki Johnson Clare Palles Maribel Almonte Isabel dos Santos Silva
John Cairns Richard Doll