Download How Early Should we be Concerned with Cancer Prevention?

Life course approach is key in cancer prevention
•  Cancer process takes decades, there may be as much as
40 years between first assault and diagnosis
•  Cancer biology may be determined in very early life (eg
maternal hormones & vaginal cancer in offspring; early diet
and carcinogen exposure, birth weight, early growth, dietary
Diet, Nutrition
and theheight,
Life Courseobesity,
Approach tobreast
Cancer Prevention
preferences,
attained
feeding etc)
•  Adult diet and PA 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)
R. Uauy MD.PhD LSHTM/UK, INTA/UCHILE/IUNS/past President
Annual Cancer Rates 1970-1996 all races (rates per 100,000)
Males ———
Females — — —
P. Perera Science 1997 278:1068
polycyclic aromatic
Hydrocarbons PAH
Cancer
Environment
Susceptibility
Genes
P450, glutathione S-transferase
(GST) N-acetyltransferase (NAT)
Cancer prevention : a Life Course Approach
Development of Cancer
Infancy
and
Childhood
Adolescence
Adult Life
Older ages
Fetal
Life
Accumulated
risk
Genetic susceptibility to Cancer
Age
Diet, Nutrition and Life Course Approach to Cancer Prevention
•  Nutrients and toxicants from food and water constitute
important life time exposures that contribute to cancer risk
•  Diet as a determinant of growth & body composition affects risk
•  Directly by cumulative exposure to carcinogens in foods,
Indirectly by affecting rates of tissue growth and body
composition and by inducing hormonal/metabolic/
inflammatory responses that affect the cancer process.
•  Obesity and rapid weight gain as cancer risk factors; Enhanced
linear growth may also affect risk for some cancers.
•  Food preferences and activity patterns become set relatively
early in life; leading to adoption of healthy or unhealthy habits
Adenocarcinoma of the Vagina: Diethylstilbestrol (DES)
therapy with tumor appearance in female offspring
during adolescence
In the late 1940s, 1950s, and later, DES was used as Rx in
early pregnancy in the belief that it would decrease toxemia
of pregnancy and bleeding and help to reduce the incidence
of premature births and neonatal deaths
This was the first documented instance where a prenatal
drug exposure–induced cancer in humans
Herbst AL et al Adenocarcinoma of the vagina: association of maternal stilbestrol
therapy with tumor appearance in young women. N Engl J Med 284:878–881. 1971.
Umbilical cord blood from
newborns found an array
of industrial chemicals,
pesticides and pollutants.
Ten newborns averaged
200 contaminants, and
209 pollutants had never
before been detected in
cord blood.
Of the 287 chemicals found in newborn umbilical cord
blood, 180 cause cancer in humans or animals, 217 are
toxic to the brain and nervous system, and 208 cause
developmental problems. The dangers of exposure to
these chemicals in combination has never been studied.
Endocrine disruptors during breast development
Synthetic halogenated chemicals increase liver tumors after early
life-stage exposure.
TCDD a prototypical endocrine-disrupting compound, 2,3,7,8tetra chloro dibenzo-p-dioxin, has been shown to be a
developmental toxicant of the mammary gland in rodents.
Dioxin alters multiple endocrine systems, and its effects on the
developing breast involve delayed proliferation/differentiation of
the mammary gland, as well as an elongation of the window of
sensitivity to potential carcinogens.
Implications of these new findings suggest that causes of
endocrine-related cancers or susceptibility to cancer may be a
result of developmental exposures rather than exposures existing
at or near the time of tumor detection.
Birnbaum SL Environ Health Perspect 111:389–394 (2003).
Endocrine disruptors during breast development
Control
ATR 100mg/kg
atrazine
TCDD 1 µg/kg
dioxin
PND 4
PND 33
PND 68
Mammary gland tissue from LE rats exposed in late gestation to ATR is
atrazine ( a pesticide) and TCDD or 2,3,7,8-tetrachlorodibenzo-p dioxin.
Birnbaum SL Environ Health Perspect 111:389–394 (2003).
PRODUCE: Pesticides used on many crops also
act as endocrine-disruptors, increasing risks for
cancer as well as neurodevelopmental disorders
PERSONAL CARE PRODUCTS: Many lotions
and cosmetics contain phthalates and chemicals
that may be absorbed across the skin.
LANDSCAPING: Exposure to chemicals used
on lawns, gardens, playgrounds, and athletic
fields may increase risk for cancer
LONG-TERM EXPOSURE: Young children and teens may be particularly
susceptible to long-term effects of exposure to chemicals because of the
rapid changes their bodies are undergoing.
PLASTICS: Additives may leach out of the plastics when they are heated
or when children chew on some toys.
GRILLED MEATS: Grilled meats, cigarette smoke and automobile
exhaust, all contain polycyclic aromatic carbons (PAHs), which are
potential carcinogens.
The use of Bisphenol A (BPA) in bottles and other food packaging continues
to stir controversy, with calls from a UK-based pregnancy charity for
mandatory labelling of the chemical present in packs.
The National Childbirth Trust (NCT) says that a clear labelling system,
particularly on infant feeding bottles, should be introduced over fears that
the chemical can leak into beverages and food.
Some recent animal studies have indicated that high levels of BPA could be
carcinogenic. European Food Safety Authority (EFSA) policy permitting a
maximum daily intake of 0.05 milligram/kg body weight.
US NIH/ National Institute of
Environmental Health Sciences
recommends:
• Don't microwave polycarbonate plastic food containers. Poly
carbonate is strong and durable, but over time it may break
down from over use at high temperatures.
• Polycarbonate containers that contain BPA usually have a #7
on the bottom.
• Reduce your use of canned foods.
• When possible, opt for glass, porcelain or stainless steel
containers, particularly for hot food or liquids.
• Use baby bottles that are BPA free.
USA National Toxicology Program Brief on Bisphenol A [CAS No. 80-05-7]. Published April 14, 2008.
Diet, Nutrition and Life Course Approach to Cancer Prevention
•  Nutrients and toxicants from food and water constitute important life
time exposures that contribute to the risk of some cancers
•  Diet as a determinant of growth & body composition affects risk
Directly by the cumulative effect of exposure to carcinogens in
foods,
Indirectly by the hormonal/metabolic responses to growth or
the inflammatory response associated the metabolic
syndrome.
•  Obesity and rapid weight gain as cancer risk factors; enhanced linear
growth may also affect cancer risk
•  Food preferences and physical activity patterns become set relatively
early in life; leading to adoption of healthy or unhealthy habits
Birth Weight and Breast Cancer Risk
I dos Santos et al PLOS Med 5: e19308
Birth Weight Increment and Breast Cancer Risk
I dos Santos et al PLOS Med 5: e19308
Birth Length Increment and Breast Cancer Risk
I dos Santos et al PLOS Med 5: e19308
Health effects of breastfeeding I
•  Breastfeeding has positive health effects, the largest health gain are
realized through policies that encourages all mothers to breastfeed.
• The literature review shows that breastfeeding has both short
and the longer term beneficial health effects
• There is convincing evidence that the incidence
obesity is reduced in breastfed children.
• Probable evidence that breastfed children have enhanced intellectual
and motor development.
• Probable Breastfeeding is related to a reduction of type I diabetes
mellitus and leukaemia.
CTM van Rossum, et al Quantification of health effects of breastfeeding RIVM report 350040001/05
CTM van Rossum, et al Quantification of health effects of breastfeeding RIVM report 350040001/05
1. “How o(en does your baby drink all of his or her bo7le of formula?” 2. “How o(en does your baby drink all of his or her cup or bo7le of pumped milk?” 3. “How o(en is your baby encouraged to finish a bo7le if he or she stops drinking before the formula is all gone?” 4. “How o(en is your baby encouraged to finish a cup or bo7le if he or she stops drinking before the pumped breast milk is all gone?” “never,” “rarely,” “someEmes,” “most of the Eme,” or “always” Bivariate Analysis for AssociaEon Between Variables & Infants’ Risk of Having Excess Weight > 6 mo of age R Li, S Fein, L Grummer-­‐Strawn Pediatrics 2008;122:S77–S84 Infants’ risk for excess weight during late infancy was negaEvely associated with breasWeeding intensity but posiEvely associated with infant-­‐iniEated bo7le emptying during early infancy. These findings provide evidence for the potenEal risk of not breasWeeding or breasWeeding at a low intensity in development of childhood obesity, They also suggest that infant-­‐iniEated bo7le emptying may be an independent risk factor for obesity as well. R Li, S Fein, L Grummer-­‐Strawn Pediatrics 2008;122:S77–S84 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 Distaste expression before and after 8 days of home-exposure. Fed only green beans
Cumulative number per spoon offer
Fed green beans + mothers reported eaRng fruits during the previous week peaches
Peach consumption when first fed
P < 0.05, compared
with breastfed infants
Mothers eating
fruit prior week
P < 0.05, compared
with Lactating mothers
mothers reported eaRng fruits during the previous week Distaste expression when first fed
P < 0.05, compared
with breastfed infants
mothers reported eaRng fruits during the previous week BreasWeeding confers an advantage in iniEal acceptance of a food, but only if mothers eat the food regularly. Once weaned, infants repeatedly exposed to a food eat more of rieported t and may le
earn to like its flavor. the mothers aRng fruits during eek of distaste Because infants dprevious isplay facial w
expressions in response to certain flavors, caregivers may disconEnue offering these foods. Mothers should offer repeatedly fruits & vegetables www.pediatrics.org/cgi/doi/10.1542/peds.2007-­‐0858 focusing on willingness to conEnue feeding. Growth and Obesity Cohort Study (GOCS): 1200 Chilean children a<ending public nursery schools in the year 2006 2002 -­‐2003 0y 2006 3.5y 2007 4y GOCS I 2008 5.5y 2009 6.5y GOCS II 2500-­‐4500gr n= 14330 n= 313 n= 1196 n= 1196 n= 1050 2012 9.5y Timing of adiposity rebound in 805 Chilean children born in 2002, by BMI status at 7y BMI kg/m2 BAZ >2 Timing of AR %
<2y 52.7 2-­‐4y 48.1 4-­‐5y 1 <=BAZ <=2 5-­‐7y 38.7 27.7 BAZ <1 25.0 24.8 20.7 22.6 18.9 10.5 8.6 1.7 Age (months) BMI Z-­‐scores based on WHO 2007 Pre
Pregnancy
Pubertal
Sexual
maturation
BMI
Early
Adiposity
rebound
Maternal
Glucose
Insulin
Placental
Fetal blood
flow
Hormonal
responses
Fetal
growth
restriction
Fetal
Macrosomia
feeding
fast
Weight
gain
Central
Obesity
Metabolic syn
Hormonal
responses
High BMI
Obesity
Breast Cancer — Early Life Matters
Relation between
height at 12 yrs of
age among Japanese
girls and breast
cancer 30 yrs later in
women 40 to 44 yrs
Michels KB and Willett WC
NEJM 351;16 (2004)
% Cancer deaths attributable to environmental and
behavioural factors in developed country setting
Tobacco
Food+water
Infections
Hormonal
Natural radiation
Alcohol
Occupation
Ultraviolet light
Medical radiation
0
5
10
15
Percent
20
25
30
35
Doll and Peto, 1996
Peak exposure
started
stopped
G. Marshall et al J NCI 99: 920–8 2007
Lung Cancer As related adult mortality
according to timing of As exposure
AMR=observed/expected age adjusted death rate
Young adulthood
infancy
p < 0.001
p < 0.001
AMR
AMR
childhood
p < 0.001
Middle age adulthood
p < 0.001
G. Marshall et al J NCI 99: 920–8 2007
Conclusions
This review suggests that the combination of specific exposures
(environmental, nutritional or metabolic), hormonal responses related to
accelerated growth at critical periods, adrenarchy, puberty and menarchy
interacting with obesogenic diets may confer increased risk for some
types of cancer.
Therefore, modification in early life of diet, nutrition, growth, physical
activity patterns and body composition may help to reduce this risk.
Following-up biomarker profiles that predict cancer may increase the
effectiveness of nutritional intervention since epi- and genetic variability
affect timing of growth and endocrine responses related to cancer risk.
Such approach should be part of a strategy to enhance effectiveness of
interventions by focusing on reducing risk at critical time-windows in
order to achieve greatest impact on cancer incidence.
1035
5746
Survival by
Group
Surgery vs
Control
Christou et al Annals of Surgery 240:416–424, 2004
Weight Loss, Bariatric Surgery Cohort n=1035
Christou et al Annals of Surgery 240:416–424, 2004
Five-Year Morbidity & Mortality (Cohort Surgery vs Control)
Christou et al Annals of Surgery 240:416–424, 2004
L Sjöström et al,NEJM 357:741-52 2007.
NUTRITIONALLY INDUCED EPIGENETIC IMPRINTING
betaine
choline
folic
acid
vit B12.
Yellow!
Slightly
Mottled
Mottled
Heavily
Mottled
Pseudo
agouti
Isogenic Avy/a animals
representing 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
Avy hyper methylation
silences ectopic Agouti
expression in
Pseudo-agouti animals,
recapitulating the
agouti phenotype.
Waterland & Jirtle Nutrition20:1 2004
Difference in IGF2 DMR methylation between individuals
prenatally exposed to famine and their same-sex sibling.
Periconceptional exposure
Exposure late in gestation
Heijmansa BT et al PNAS 105:17046–17049 2008
Periconceptional exposure was defined as the mother’s last menstrual period before conceiving the exposed individual between
November 28, 1944 and May 15, 1945. This yielded 60 sibships. Exposure late in gestation was defined as a birth between
January 28 and May 30, 1945, so that the duration of the famine exposure was at least 10 weeks. This yielded 62 sibships.
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
Conclusion—Our results show that in a population with
a genetic tendency for obesity, effects of maternal
obesity accumulate over successive generations to shift
the population distribution toward increased adult body
weight, and suggest that epigenetic mechanisms are
involved in this process.
Developmental Plasticity
A single genotype can produce many !
phenotypes, depending on many contingencies!
encountered during development. That is, !
phenotype is an outcome of a complex series of!
developmental processes that are influenced by !
environmental factors as well as genes. !
H. F. Nijhout, 1999!
Towards a new developmental synthesis:adaptive
developmental plasticity and human disease
Gluckman P ..... Uauy R et al Lancet 2009; 373:1654-7
Cancer prevention : a Life Course Approach
Development of Cancer
Infancy
and
Childhood
Fetal
Life
SES
Mother’s
Nutrition
Carcinogen
Exposures
Fetal
Growth
birth weight
Breast Feeding
SES
Infections/PEM
Micronutrients
Contaminants
(air, food, water,)
Growth rate
Stature
Physical Activity
Food and Play
Behaviours
Adolescence
Smoking
Contaminants
(air, food, water,)
Time of Puberty
Obesity
Exercise and
Physical activity
Inactivity
Adult Life Older ages
Established adult risky behaviours
Diet/Physical activity, Tobacco,
Alcohol, Carcinogens
OBESITY
Biological risks
Socioeconomic status
Environmental conditions
Preventable
risk
Cumulative
incidence
Genetic susceptibility to Cancer
Age
Cancer prevention : a Life Course Approach
Development of Cancer
Infancy
and
Childhood
Adolescence
Adult Life
Older ages
Fetal
Life
Genetic susceptibility to Cancer
Age
Cancer prevention : a Life Course Approach
Development of Cancer
Infancy
and
Childhood
Adolescence
Adult Life
Older ages
Fetal
Life
IN THE IDEAL WORLD
Genetic susceptibility to Cancer
Age