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Summary
Background High body-mass index (BMI) predisposes to several site-specic cancers, but a large-scale systematic and
detailed characterisation of patterns of risk across all common cancers adjusted for potential confounders has not
previously been undertaken. We aimed to investigate the links between BMI and the most common site-specic
cancers.
Methods With primary care data from individuals in the Clinical Practice Research Datalink with BMI data, we tted
Cox models to investigate associations between BMI and 22 of the most common cancers, adjusting for potential
confounders. We tted linear then non-linear (spline) models; investigated eect modication by sex, menopausal
status, smoking, and age; and calculated population eects.
Findings 524 million individuals were included; 166 955 developed cancers of interest. BMI was associated with 17 of
22 cancers, but eects varied substantially by site. Each 5 kg/m increase in BMI was roughly linearly associated with
cancers of the uterus (hazard ratio [HR] 162, 99% CI 156169; p<00001), gallbladder (131, 112152; p<00001),
kidney (125, 117133; p<00001), cervix (110, 103117; p=000035), thyroid (109, 100119; p=00088), and
leukaemia (109, 105113; p00001). BMI was positively associated with liver (119, 112127), colon (110,
107113), ovarian (109, 1.041.14), and postmenopausal breast cancers (105, 103107) overall (all p<00001), but
these eects varied by underlying BMI or individual-level characteristics. We estimated inverse associations with
prostate and premenopausal breast cancer risk, both overall (prostate 098, 095100; premenopausal breast cancer
089, 086092) and in never-smokers (prostate 096, 093099; premenopausal breast cancer 089, 085094).
By contrast, for lung and oral cavity cancer, we observed no association in never smokers (lung 099, 093105; oral
cavity 107, 091126): inverse associations overall were driven by current smokers and ex-smokers, probably
because of residual confounding by smoking amount. Assuming causality, 41% of uterine and 10% or more of
gallbladder, kidney, liver, and colon cancers could be attributable to excess weight. We estimated that a 1 kg/m
population-wide increase in BMI would result in 3790 additional annual UK patients developing one of the ten cancers
positively associated with BMI.
Published Online
August 14, 2014
http://dx.doi.org/10.1016/
S0140-6736(14)60892-8
See Online/Comment
http://dx.doi.org/10.1016/
S0140-6736(14)61172-7
Department of NonCommunicable Diseases
Epidemiology , London School
of Hygiene and Tropical
Medicine, London, UK
(K Bhaskaran PhD, I Douglas PhD,
H Forbes MSc,
Prof I dos-Santos-Silva PhD,
Prof D A Leon PhD,
Prof L Smeeth PhD); and Farr
Institute of Health Informatics
Research , London, UK
(Prof L Smeeth)
Correspondence to:
Dr Krishnan Bhaskaran,
Department of NonCommunicable Diseases
Epidemiology, London School of
Hygiene and Tropical Medicine,
London WC1E 7HT, UK
krishnan.bhaskaran@lshtm.
ac.uk
Interpretation BMI is associated with cancer risk, with substantial population-level eects. The heterogeneity in the
eects suggests that dierent mechanisms are associated with dierent cancer sites and dierent patient subgroups.
Funding National Institute for Health Research, Wellcome Trust, and Medical Research Council.
Copyright Bhaskaran et al. Open Access article distributed under the terms of CC BY.
Introduction
Understanding of the eects of adiposity on major
health outcomes has never been more urgent, given the
rapid rise in obesity worldwide in recent years.1 Research
has suggested that body-mass index (BMI) is an
important predictor of cancer risk:2 a Norwegian cohort
study reported associations with several cancer sites,
including the thyroid3 and ovaries;4 and the UK Million
Women Study showed associations between BMI and
ten of 17 sites investigated.5 Two large reviews brought
these and many smaller studies together.6,7 In a
meta-analysis of 221 datasets, strong associations were
recorded between BMI and cancers of the oesophagus,
thyroid, colon, kidneys, endometrium, and gallbladder,
and weaker associations were shown for several other
sites.7 Increased BMI was negatively associated with
lung cancer.
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Methods
Study design and setting
See Online for appendix
Assignment of BMI
Figure 1: Flow diagram showing the creation of the main dataset, reasons for exclusions, and assignment of
body-mass index (BMI) at study entry
CPRD= Clinical Practice Research Datalink. *When the rst available BMI was after start of CPRD follow-up, the
patient was late-entered into the risk set.
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Underweight
(BMI <185 kg/m)
Normal BMI
(18525 kg/m)
Overall
165 530
2 571 573
2 506 875
5 243 978
62 (48)
74 (54)
76 (52)
75 (53)
Median (IQR)
47 (2489)
59 (29111)
64 (32111)
60 (30110)
Range
10245
0869
10245
10246
10246
16451
16521
33841
334 (246484)
436 (315576)
379 (270537)
Age (years)
Median (IQR)
255 (195394)
Sex
Male
49 107 (297)
Never smoker
75 464 (456)
Current smoker
69 580 (420)
Ex-smoker
17 364 (105)
3122 (19)
25 024 (10)
21 060 (08)
49 206 (09)
Female
Smoking status
Missing
Alcohol use
Non-drinker
33 778 (204)
80 323 (485)
8133 (49)
4499 (27)
64 177 (25)
70 285 (28)
6414 (39)
96 109 (37)
98 992 (39)
Ex-drinker
10 043 (61)
Missing
22 340 (135)
1965 (12)
46 330 (18)
Previous diabetes
Index of multiple deprivation quintile
1 (least deprived)
20 526 (124)
42 175 (255)
46 881 (283)
35 950 (217)
5 (most deprived)
19 998 (121)
Calendar year
<1989
2139 (13)
42 548 (17)
36 460 (15)
81 147 (15)
32 163 (194)
199599
34 157 (206)
200004
40 390 (244)
200509
46 310 (280)
2010
10 371 (63)
199094
Data are n (%) unless otherwise stated. Time-varying characteristics are at date of rst eligible BMI measurement. *After excluding rst 12 months after registration, and any
time without a mature (12 months old) BMI measurement available. Light, moderate, or heavy current drinking were assigned when either the general practitioner had
recorded a Read code with one of these terms, or when the units per day were recorded as 12 (light), 36 (moderate), 7+ (heavy).
Table 1: Characteristics of individuals included in the study, overall and by body-mass index (BMI) category
Statistical analysis
People were followed-up from study entry until the
earliest of: rst cancer diagnosis (any site), death, transfer
out of CPRD, or last data collection date for the practice.
We censored 30 days after the rst record of hysterectomy
for uterine and cervical cancer, and after bilateral
oophorectomy for ovarian cancers (we allowed 30 days to
capture cancers related to, or detected at, the procedure).
To relate BMI to risk of each cancer, we tted Cox
models with attained age as the underlying timescale. We
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HR (99% CI)
p value
081 (074089)
107 (091126)
<00001
026
Oesophageal (C15)
(5213)
103 (099108)
116 (109124)
0056
<00001
Stomach (C16)
(3337)
103 (098109)
108 (100118)
016
0013
Colon (C18)
(13 465)
110 (107113)
111 (107115)
<00001
<00001
Rectum (C20)
(6123)
104 (100108)
105 (099112)
0017
0024
Liver (C22)
(1859)
119 (112127)
126 (114140)
<00001
<00001
Gallbladder (C23)
(303)
131 (112152)
150 (121185)
<00001
<00001
Pancreas (C25)
(3851)
105 (100110)
111 (103119)
Lung (C34)
(19 339)
082 (081084)
099 (093105)
<00001
055
099 (096102)
096 (092100)
039
0013
Breastpremenopausal (C50)
(6298)
089 (086092)
089 (085094)
<00001
<00001
Breastpostmenopausal (C50)
(28 409)
105 (103107)
105 (103108)
<00001
<00001
Cervix (C53)
(1389)
110 (103117)
114 (103126)
Uterus (C5455)
(2758)
162 (156169)
163 (155171)
<00001
<00001
Ovaries (C56)
(3684)
109 (104114)
108 (102115)
<00001
000036
Prostate (C61)
(24 901)
098 (095100)
096 (093099)
00042
00021
Kidney (C64)
(1906)
125 (117133)
125 (113138)
<00001
<00001
Bladder (C67)
(7976)
103 (099106)
105 (099112)
0062
0033
104 (099110)
102 (094110)
0053
056
Thyroid (C73)
(941)
109 (100119)
111 (099125)
00088
0017
103 (099106)
100 (095105)
0050
096
103 (098109)
103 (095111)
015
040
Leukaemia (C9195)
(5833)
109 (105113)
107 (102114)
<00001
00011
Overall
Never smokers only
08
1
12
14
16
Estimated HR per 5 kg/m2 increase in BMI (99% CI)
0012
000024
000035
00010
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Oesophagus (C15)
p-overall<00001
p-non-linear<00001
HR (99% Cl )
Rectum (C20)
p-overall<00001
p-non-linear=000014
Liver (C22)
p-overall=0022
p-non-linear=019
p-overall<00001
p-non-linear=00030
1
05
0
Gallbladder (C23)
Pancreas (C25)
p-overall<00001
p-non-linear=095
Lung (C34)
p-overall=00079
p-non-linear=0081
p-overall<00001
p-non-linear<00001
p-overall=00088
p-non-linear=00031
p-overall<00001
p-non-linear<00001
p-overall<00001
p-non-linear<00001
2
1
05
0
Cervix (C53)
3
HR (99% Cl )
Colon (C18)
p-overall=000012
p-non-linear<00001
Ovaries (C56)
Uterus (C5455)
p-overall=000091
p-non-linear=053
Prostate (C61)
p-overall<00001
p-non-linear=078
Kidney (C64)
p-overall<00001
p-non-linear<00001
Bladder (C67)
p-overall<00001
p-non-linear=085
p-overall=0023
p-non-linear=0049
2
p-overall<00001
p-non-linear=0025
1
05
0
0
Brain and CNS (C7172)
3
HR (99% Cl )
Stomach (C16)
p-overall<00001
p-non-linear<00001
Thyroid (C73)
p-overall=013
p-non-linear=064
p-overall=0010
p-non-linear=011
p-overall=0025
p-non-linear=0060
Leukaemia (C9195)
p-overall=028
p-non-linear=054
20
30
40
BMI (kg/m2)
50
p-overall<00001
p-non-linear=038
2
1
05
0
20
30
40
BMI (kg/m2)
50
20
30
40
BMI (kg/m2)
50
20
30
40
BMI (kg/m2)
50
20
30
40
BMI (kg/m2)
50
20
30
40
BMI (kg/m2)
50
Figure 3: Association between body-mass index (BMI) and specic cancers, allowing for non-linear eects, with 99% CIs
The reference BMI for these plots (with HR xed as 10) was 22 kg/m. Separate models were tted for each cancer type, each with a restricted cubic spline for BMI (knots placed at equal percentiles of
BMI), adjusted for age, calendar year, diabetes status, alcohol use, smoking (all at time of BMI recording), socioeconomic status (index of multiple deprivation), and stratied by sex. HR=hazard ratio.
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HR (99% CI)
Men
Women
Results
1
05
0
Estimated HR per 5 kg/m2 (99% CI)
<22 kg/m2
092 (069123)
2234 kg/m2
123 (117130)
>34 kg/m2
097 (081115)
Women
105 (101108)
(overall)
Men
HR (99% CI)
<22 kg/m2
>22 kg/m2
Women
(overall)
057 (033100)
130 (119143)
114 (104126)
Men
Women
Postmenopausal
Premenopausal
1
05
0
Estimated HR per 5 kg/m2 (99% CI)
<24 kg/m2
>24 kg/m2
Men
148 (117187)
099 (093106)
096 (092100)
Women
(overall)
HR (99% CI)
Premenopause
Postmenopause
<22 kg/m2
>22 kg/m2
<29 kg/m2
>29 kg/m2
120 (101143)
086 (082090)
111 (108114)
098 (095101)
Prostate (C61)
Postmenopausal
Premenopausal
1
05
0
20
30
BMI (kg/m2)
40
50
20
30
BMI (kg/m2)
40
50
Figure 4: Modelled associations between body-mass index (BMI) and colon, liver, breast, ovarian, and
prostate cancers and malignant melanoma, including detected non-linearities and eect modication
Curves for each cancer type estimated from models with BMI tted as a spline, adjusted for age, calendar year,
diabetes status, smoking, alcohol use, socioeconomic status (index of multiple deprivation). Stratied curves were
produced by adding interaction terms with the BMI spline basis. For estimated eect modication by sex,
smoking, menopausal status, and present age for all cancer types, see appendix pp 912. Estimated HRs per
5 kg/m derived from best tting piecewise linear or linear model (with Akaike information criterion used to select
optimal knots or thresholds). HR=hazard ratio.
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Discussion
In the largest single dataset assembled so far for this
purpose, we recorded associations between BMI and 17 of
22 cancers studied, but eects varied substantially by
cancer type, in both direction and size. Higher BMI was
roughly linearly related with increased risk of uterine,
gallbladder, kidney, cervical, thyroid cancers, and
leukaemia. Overall positive associations were recorded
HR (99% CI)
Current smoker
Ex-smoker
Never-smoker
2
Pinteraction (smoking)=000031
1
05
0
Stomach (C16)
HR (99% CI)
2
Pinteraction (smoking)=0075
1
05
0
Lung (C34)
3
HR (99% CI)
Pinteraction (smoking)<00001
1
05
0
0
20
30
40
50
BMI (kg/m2)
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Colon (C18)
26 725
2970 (111%)
559 (519598)
Liver (C22)
4241
661 (156%)
145 (135154)
660
134 (203%)
39 812
2035 (51%)
36 (3537)
1441 (14171465)
Cervix (C53)
2851
214 (75%)
51 (5053)
Uterus (C5455)
8288
3384 (408%)
806 (784829)
Ovaries (C56)
7011
512 (73%)
125 (118133)
Kidney (C64)
9639
1597 (166%)
428 (414442)
Thyroid (C73)
2654
51 (19%)
49 (4851)
Leukaemia (C9195)
8257
522 (63%)
150 (138163)
Attributable cases and percentage based on models for each cancer with a three-category BMI variable (underweight,
normal, or overweight and obese), adjusted for age, diabetes status, smoking, alcohol use, socioeconomic status,
calendar year, and stratied by sex; attributable cases were calculated separately for men and women and then
combined; we assumed the prevalence of overweight including obese to be 65% in men and 58% in women (Health
Survey for England 201016). Further details on our method for these calculations are given in appendix (p 2). Projected
extra cases calculated with tted Poisson models with non-linear BMI splines to predict proportion of extra cases in an
articial population sampled from the original cohort to replicate the age and sex structure of the UK population, with
all BMIs increased by 1 kg/m, and applying proportionate increase to the annual number of UK cases (*Cancer Research
UK cancer statistics11); 99% CIs are from a bootstrapping procedure.
Table 2: Estimated UK population eects for cancers with evidence of a net positive association with
body-mass index (BMI)
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Contributors
All authors were involved in the study design. KB did the statistical
analysis. HF did the systematic literature search for the Research in
Context section. KB wrote the rst draft. All authors contributed to
further drafts and approved the nal manuscript.
Declaration of interests
We declare no competing interests.
Acknowledgments
This report is independent research arising from a postdoctoral
fellowship (for KB) supported by the National Institute for Health
Research. LS is supported by a Wellcome Trust senior research
fellowship in clinical science. ID is supported by an MRC methodology
research fellowship. The views expressed in this publication are those of
the authors and not necessarily those of the NHS, the National Institute
for Health Research, or the Department of Health.
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Comment
Published Online
August 14, 2014
http://dx.doi.org/10.1016/
S0140-6736(14)61172-7
See Online/Articles
http://dx.doi.org/10.1016/
S0140-6736(14)60892-8
Comment
Peter T Campbell
Epidemiology Research Program, American Cancer Society,
Atlanta, GA 30303, USA
peter.campbell@cancer.org
I declare no competing interests.
Copyright Campbell. Open Access article distributed under the terms of CC BY.
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