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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

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Page 1: Why is body fatness important in cancer prevention ... · Cancer research for cancer prevention DESCRIBE OCCURRENCE UNDERSTAND THE CAUSES PREVENTION AND IMPLEMENTATION Global burden

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

Page 2: Why is body fatness important in cancer prevention ... · Cancer research for cancer prevention DESCRIBE OCCURRENCE UNDERSTAND THE CAUSES PREVENTION AND IMPLEMENTATION Global burden

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”.

Page 3: Why is body fatness important in cancer prevention ... · Cancer research for cancer prevention DESCRIBE OCCURRENCE UNDERSTAND THE CAUSES PREVENTION AND IMPLEMENTATION Global burden

Age-standardised incidence of renal, pancreatic & colorectal cancer 2-4 X higher in

central Europe than many parts of Asia

http://gco.iarc.fr/

Page 4: Why is body fatness important in cancer prevention ... · Cancer research for cancer prevention DESCRIBE OCCURRENCE UNDERSTAND THE CAUSES PREVENTION AND IMPLEMENTATION Global burden

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

Page 5: Why is body fatness important in cancer prevention ... · Cancer research for cancer prevention DESCRIBE OCCURRENCE UNDERSTAND THE CAUSES PREVENTION AND IMPLEMENTATION Global burden

• 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

Page 6: Why is body fatness important in cancer prevention ... · Cancer research for cancer prevention DESCRIBE OCCURRENCE UNDERSTAND THE CAUSES PREVENTION AND IMPLEMENTATION Global burden

% 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)

Page 7: Why is body fatness important in cancer prevention ... · Cancer research for cancer prevention DESCRIBE OCCURRENCE UNDERSTAND THE CAUSES PREVENTION AND IMPLEMENTATION Global burden

ADDRESSING THE PREVENTION OF CANCERS ATTRIBUTED TO EXCESS ADIPOSITY IS A GROWING & GLOBALLY IMPORTANT HEALTH PROBLEM

Page 8: Why is body fatness important in cancer prevention ... · Cancer research for cancer prevention DESCRIBE OCCURRENCE UNDERSTAND THE CAUSES PREVENTION AND IMPLEMENTATION Global burden

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)

Page 9: Why is body fatness important in cancer prevention ... · Cancer research for cancer prevention DESCRIBE OCCURRENCE UNDERSTAND THE CAUSES PREVENTION AND IMPLEMENTATION Global burden

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

Page 10: Why is body fatness important in cancer prevention ... · Cancer research for cancer prevention DESCRIBE OCCURRENCE UNDERSTAND THE CAUSES PREVENTION AND IMPLEMENTATION Global burden

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

Page 11: Why is body fatness important in cancer prevention ... · Cancer research for cancer prevention DESCRIBE OCCURRENCE UNDERSTAND THE CAUSES PREVENTION AND IMPLEMENTATION Global burden

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

Page 12: Why is body fatness important in cancer prevention ... · Cancer research for cancer prevention DESCRIBE OCCURRENCE UNDERSTAND THE CAUSES PREVENTION AND IMPLEMENTATION Global burden

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

Page 13: Why is body fatness important in cancer prevention ... · Cancer research for cancer prevention DESCRIBE OCCURRENCE UNDERSTAND THE CAUSES PREVENTION AND IMPLEMENTATION Global burden

CONFIRM CAUSAL RELEVANCE & GENERATE MORE PRECISE ESTIMATES OF EFFECT VS SINGLE EXPOSURE MEASURE (I.E. PREDICT THE EFFECT OF INTERVENING)

Page 14: Why is body fatness important in cancer prevention ... · Cancer research for cancer prevention DESCRIBE OCCURRENCE UNDERSTAND THE CAUSES PREVENTION AND IMPLEMENTATION Global burden

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

Page 15: Why is body fatness important in cancer prevention ... · Cancer research for cancer prevention DESCRIBE OCCURRENCE UNDERSTAND THE CAUSES PREVENTION AND IMPLEMENTATION Global burden

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

Page 16: Why is body fatness important in cancer prevention ... · Cancer research for cancer prevention DESCRIBE OCCURRENCE UNDERSTAND THE CAUSES PREVENTION AND IMPLEMENTATION Global burden

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?

Page 17: Why is body fatness important in cancer prevention ... · Cancer research for cancer prevention DESCRIBE OCCURRENCE UNDERSTAND THE CAUSES PREVENTION AND IMPLEMENTATION Global burden

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

Page 18: Why is body fatness important in cancer prevention ... · Cancer research for cancer prevention DESCRIBE OCCURRENCE UNDERSTAND THE CAUSES PREVENTION AND IMPLEMENTATION Global burden

Causal effect estimates of obesity-related risk factors for RCC

Page 19: Why is body fatness important in cancer prevention ... · Cancer research for cancer prevention DESCRIBE OCCURRENCE UNDERSTAND THE CAUSES PREVENTION AND IMPLEMENTATION Global burden

Causal effect estimates of obesity-related risk factors for RCC

Page 20: Why is body fatness important in cancer prevention ... · Cancer research for cancer prevention DESCRIBE OCCURRENCE UNDERSTAND THE CAUSES PREVENTION AND IMPLEMENTATION Global burden

Causal effect estimates of obesity-related risk factors for RCC