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Why is body fatness important in cancer prevention? Lessons from
Mendelian Randomisation
Satellite meeting for the European Congress on Obesity, Dundee
27 April 2019
Richard Martin
@BrisCancerEpi @richard36418277 @mrc_ieu
Cancer research for cancer
prevention
DESCRIBE
OCCURRENCE
UNDERSTAND
THE CAUSES
PREVENTION
AND IMPLEMENTATION
Global burden of cancer • 18.1 million new
cancers in 2018 • 29.5 million by
2040
IARC Director • “…no country
can treat its way out of the cancer problem”.
Age-standardised incidence of renal, pancreatic & colorectal cancer 2-4 X higher in
central Europe than many parts of Asia
http://gco.iarc.fr/
Several cancers rising in successively younger birth cohorts, USA Incidence rate ratio by birth cohort from 1910-19 to 1980-89 for 12 cancers, 1995–2014
Lancet Public Health 2019;4:e137-47
• Sufficient evidence to conclude obesity/overweight causes cancer on 13 sites
• IARC Working Group: ˗ “absence of excess body
fatness lower risk of most cancers”
• Why? ˗ Conclusive mechanistic
evidence largely lacking
Kyrgiou M et al. BMJ. 2017 Lauby-Secretan B. et al. NEJM. 2016
% of UK cancers accounted for by smoking & overweight/obesity: • 2015, overweight & obesity: 6% of all UK
cancers; smoking: 15% • 2035, overweight & obesity: 8% of all UK
cancers; smoking: 11% • 2043, overweight & obesity > smoking in
women
Brown et al, BJC 2018;118:1130–1141 https://www.cancerresearchuk.org/about-us/cancer-news/press-release/2018-09-24-obesity-could-overtake-
smoking-as-biggest-preventable-cause-of-cancer-in-women-0
Obesity thought to cause 1/20 cancers (2nd only to tobacco smoke)
ADDRESSING THE PREVENTION OF CANCERS ATTRIBUTED TO EXCESS ADIPOSITY IS A GROWING & GLOBALLY IMPORTANT HEALTH PROBLEM
How can genetic approaches help improve the evidence-base for interventions?
• Confirm causal relevance & generate more precise estimates of effect vs single exposure measure (i.e. predict the effect of intervening)
• Identify molecular mechanisms
• Inform targeted public health interventions
• Inform potential drug repurposing (e.g. statins)
Mendelian randomization: Genetic information to improve causal
inference in observational epi
Adiposity
Traits inherited independent of each
other & future environmental factors
Modifiable exposure, X
Outcome, Y Instrumental variable, G
Confounders, U
Reverse causation
@BrisCancerEpi
Nature’s
RCT Free from
confounding &
reverse causation
Selecting genetically supported
targets doubles success at 25%
lower costs
23
24
25
26
27
28
29
30
31
32
Decile1 Decile2 Decile3 Decile4 Decile5 Decile6 Decile7 Decile8 Decile9 Decile10
Example: Deprivation & measured BMI
BM
I [kg
/m2]
in U
K b
iob
ank
Deciles of Townsend deprivation index
More deprived
UK Biobank
23
24
25
26
27
28
29
30
31
32
Decile1 Decile2 Decile3 Decile4 Decile5 Decile6 Decile7 Decile8 Decile9 Decile10
Genetic instrument for BMI: 73 SNPs (GIANT Consortium)
Genetic instrument for BMI in deciles
Mea
sure
d B
MI i
n U
K b
iob
ank
UK Biobank
1.65
1.7
1.75
1.8
1.85
1.9
1.95
2
Decile1 Decile2 Decile3 Decile4 Decile5 Decile6 Decile7 Decile8 Decile9 Decile10
Example: Deprivation & a genetic instrument for BMI
Deciles of Townsend deprivation index
Gen
etic
inst
rum
en
t o
f B
MI
More deprived
UK Biobank
CONFIRM CAUSAL RELEVANCE & GENERATE MORE PRECISE ESTIMATES OF EFFECT VS SINGLE EXPOSURE MEASURE (I.E. PREDICT THE EFFECT OF INTERVENING)
Relative risks for 5-unit BMI increment – Classical cohort studies
Cancer Sites
Colorectum
Kidney
Pancreas
Endometrium
Ovary
Esophagus (Adeno)
WCRF RR
1.05 [1.03;1.07]
1.30 [1.25;1.35]
1.10 [1.07;1.14]
1.50 [1.42;1.59]
1.06 [1.02;1.11]
1.48 [1.35;1.62]
MR RR
1.44 [1.22;1.70]
1.59 [1.45;1.74]
1.47 [1.31;1.66]
2.06 [1.89;2.21]
1.13 [1.06;1.21]
2.10 [1.05;4.16]
1 1.5 2
Relative Risk
Cancer Sites
Colorectum
Kidney
Pancreas
Endometrium
Ovary
Esophagus (Adeno)
WCRF RR
1.05 [1.03;1.07]
1.30 [1.25;1.35]
1.10 [1.07;1.14]
1.50 [1.42;1.59]
1.06 [1.02;1.11]
1.48 [1.35;1.62]
MR RR
1.44 [1.22;1.70]
1.59 [1.45;1.74]
1.47 [1.31;1.66]
2.06 [1.89;2.21]
1.13 [1.06;1.21]
2.10 [1.05;4.16]
1 1.5 2
Relative Risk
Relative risks for 5-unit BMI increment – Mendelian randomization
Mariosa et al. Submitted *Nead et al. JNCI 2015
IDENTIFY MOLECULAR MECHANISMS
• Reducing population adiposity & maintaining fat loss in individuals are difficult
• Could upstream factors or causal intermediates be intervened on to diminish the effects of adiposity?
Can genetics help untangle the causal pathway?
Obesity Hypertension
Dyslipidaemia
Hyperglycaemia
Insulin resistance Cancer
Metabolites, proteins
Pro-inflammatory factors
Microbiome, epigenome
Poor dietary pattern
Physical inactivity
Smoking
Causal effect estimates of obesity-related risk factors for RCC
Causal effect estimates of obesity-related risk factors for RCC
Causal effect estimates of obesity-related risk factors for RCC
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