What is the epidemiological evidence linking early life events and cancer risk and what are the potential critical windows for cancer prevention? By Professor Ricardo Uauy, University of Chile, London School of Hygiene and Tropical Medicine World Cancer Congress, Saturday 6 December 2014

1. What is the epidemiological evidence linking early life
events and cancer risk and what are the potential critical
windows for cancer prevention?
World Cancer Congress, Saturday 6 December 2014
Professor Ricardo Uauy
University of Chile
London School of Hygiene and Tropical Medicine

2. Outline

Life course and cancer prevention

The evidence linking early life exposures to cancer

Mechanisms

Example; early life exposures and breast cancer

Data from a Chilean cohort

Conclusions

3. A life course approach is key in cancer prevention
 Cancer process takes decades; there may be as much as 40 years
between exposure to carcinogen and diagnosis
 Cancer occurrence may be determined in very early life by:
 Maternal hormones & vaginal cancer in offspring
 Early diet and carcinogen exposure
 Birth weight
 Early growth
 Dietary preferences
 Attained height
 Obesity
 Breast feeding
 Adult diet and physical activity behaviors are established in early life
 Early life is most sensitive to cancer inducing processes (eg relatively
high cancer risk in under tens exposed to radiation or carcinogens;
smoking in adolescence)

4. Annual cancer rates 1970-2006 in all races (rates per 100,000)

5. Mouth, pharynx, larynx
Nasopharynx
Oesophagus
Lung
Stomach
Pancreas
Gallbladder
Liver
Colorectum7
Breast premenopause
Breast postmenopause
Ovary
Endometrium
Prostate
Kidney
Skin
Foods containing dietary fibre
Aflatoxins
Non-starchy vegetables1
Allium vegetables
Garlic
Fruits2
Foods containing lycopene
Food containing selenium3
Red meat
Processed meat
Cantonese-style salted fish
Diets high in calcium4
Salt, salted and salty foods
Glycaemic load
Arsenic in drinking water
Maté
Alcoholic drinks5
Coffee
Beta-carotene6
Physical activity
Body fatness
Adult attained height
Greater birth weight
Lactation
Convincing decreased risk
Probable decreased risk
Probable increased risk
Convincing increased risk
Substantial effect on risk unlikely
Continuous Update
Project matrix of
strong evidence

6. Continuous Update Project – strong evidence
Early life exposures and cancer risk
Prostate
cancer
(total)
Pancreatic
cancer
Colorectal
cancer
Premenopausal
breast cancer
Postmenopausal
breast cancer
Ovarian
cancer
Adult
attained
height
Per 5 cm
Probable
RR = 1.04
(1.03-1.05)
Probable
RR = 1.07
(1.03-1.12)
Convincing
RR = 1.05
(1.03-1.08)
Probable
RR = 1.09
(1.05-1.12)
Convincing
RR = 1.10
(1.07-1.13)
Convincin
g
RR = 1.08
(1.05-1.10)
Greater
birth
weight
- - - Probable - -
Lactation - - - Convincing Convincing -
Increased risk
Decreased risk

7. Effect of in vitro culture media of human embryos on
birth weight of newborns
Human Reproduction, Vol.25, No.3 pp. 605–612, 2010

8. Nutritionally induced epigenetic imprinting
Isogenic Avy/a animals, the five
coat colors used to classify
phenotype. Avy mutation results
from the insertion of a murine LTR
retrotransposon into an exon of the
agouti gene
Pseudo
agouti
Heavily
Mottled
Mottled
Slightly
Mottled
Yellow
betaine
choline
Folic ac
vit B12.
Waterland and Jirtle Nutrition 20:1 2004
Avy alleles of yellow mice are
hypo-methylated, allowing
maximal agouti expression.
Avy hyper-methylation silences
ectopic agouti expression in
pseudo -agouti animals,
recapitulating the agouti
phenotype.

9. Dutch Hunger Winter
 Individuals prenatally exposed to famine during the Dutch Hunger
Winter in 1944–45 had, 6 decades later, less DNA methylation of
the imprinted IGF2 gene compared with their unexposed, same-sex
siblings
 The association was specific for peri conceptional exposure,
reinforcing that very early development is a crucial period for
establishing epigenetic marks
 These data are the first to contribute empirical support for the
hypothesis that early-life environmental conditions can cause
epigenetic changes in humans that persist throughout life
Heijmansa BT et al PNAS 105:17046–17049 2008

10. DIET
ENVIRONMENT
BODY FAT DISTRIBUTION AND
CANCER RELATED OUTCOMES

11. Mechanisms of breast cancer development

12. 1200 Chilean children born in 2002 attending nursery schools in 2006
2002 -2003
0y
Growth and Obesity Cohort Study (GOCS):
2007
4y
2006
3.5y
2008
5.5y
2009
6.5y
2012
9.5y
GOCS I GOCS II
2500-4500gr
n= 14330
n= 1196
n= 313
n= 1196 n= 1050

13. Growth and Obesity Cohort Study is a concurrent cohort of
mothers-children in Chile
Socio-economic status = low-middle
Maternal height = 156.3 ± 5.6 cm
Pre-pregnancy BMI = 24.2 ± 4.3 kgm2
Pregnancy weight gain = 12.4 ± 4.8 kg
Smoking during pregnancy = 15%
Diabetes during pregnancy = ~ 5% (20-40%)
Preeclampsia = 9.1%
Breastfeeding* at 4 mo = 64%
* Exclusive or predominant

14. Body Mass Index Z score 0-84 months by Body Mass
Index status at 7 years (n=1096)
BAZ; WHO 2006
Age (months)
Adjusted for current age and sex
Points connected for ease of reading
BAZ ≥2
1≤ BAZ <2
-1≤ BAZ <1
BAZ ;WHO 2006-7

15. Timing of adiposity rebound in 805 Chilean children born in 2002, by Body
Mass Index status at 7 years
%
Timing of Adiposity Rebound
<2y
2-4y
4-5y
5-7y
Body Mass Index Z-scores based on WHO 2007
18.9
10.5
48.1
22.6
27.7
38.7
25.0
8.6
52.7
24.8
20.7
1.7
Body Mass Index
g/m2
Age (months)
BAZ >2
1 <=BAZ <=2
BAZ <1

17. Ultrasound bone age in 936 Chilean children categorized by
Body Mass Index status at 7 years of age
Months
BAZ <1
1<=BAZ <2
BAZ =>2
Body Mass Index
Z-scores
WHO 2007

18. Early Determinants of Fruit and
Vegetable Acceptance
Catherine A. Forestell, PhD, Julie A.
Mennella, PhD Monell Chemical Senses
Center, Philadelphia, Pennsylvania
Examples of types of facial
expressions displayed during the
first 2 minutes of feeding: brow
lowerer (A), inner brow raise (B),
squint (C), nose wrinkle (D), upper-lip
raise (E), and gape (F).
www.pediatrics.org/cgi/doi/10.1542/
peds.2007-0858 doi:10.1542/peds.2007-0858

19. What is “healthy growth”?
 Growth standards reflect nutrition and feeding practices of a given
community where reference data was obtained (none measure long term
health)
 Global growth standards are based on current (breast feeding + weaning
nutrition) guidelines
 Paradigm of “bigger” or “taller” is better has never been tested critically
(benefits vs potential risks).
 “Healthy” growth should be validated relative to measures that are
predictors of long term health… such as cancer risk

20. Cancer prevention : a Life Course Approach
Age
Fetal
Life
Adult Life
Infancy and Adolescence
Childhood
Older ages
Established adult risky behaviours
Diet/Physical activity. Tobacco.
Alcohol. Carcinogens
OBESITY
Biological risks
Socioeconomic status
Environmental conditions
Cumulative
incidence
Genetic susceptibility to Cancer
Breast Feeding
SES
Infections/PEM
Micronutrients
Contaminants
(air. food. water.)
Growth rate
Stature
Physical Activity
Food and Play
Behaviours
Smoking
Contaminants
(air. food. water.)
Time of Puberty
Obesity
Exercise and
Physical activity
Inactivity
SES
Mother’s
Nutrition
Carcinogen
Exposures
Fetal
Growth
birth weight
susceptibility to Preventable
risk

21. Conclusions
 There is increasing evidence that early life exposures
are associated with cancer risk
 Need long term cohort follow up studies, including
randomized controlled interventions that confirm
putative associations
 Understanding the mechanisms that control cell biology
and influence the cancer process will help us to better
target cancer preventive strategies related to early life
 Need to identify optimal growth standards for cancer
prevention

22. For further information
Professor Ricardo Uauy
University of Chile
London School of Hygiene and Tropical Medicine
druauy@gmail.com
@wcrfint
facebook.com/wcrfint
www.wcrf.org