Research

JAMA Oncology | Original Investigation

Association of Obesity With Risk of Early-Onset

Colorectal Cancer Among Women
Po-Hong Liu, MD, MPH; Kana Wu, MD, MPH, PhD; Kimmie Ng, MD, MPH; Ann G. Zauber, PhD;
Long H. Nguyen, MD, MS; Mingyang Song, MD, ScD; Xiaosheng He, MD; Charles S. Fuchs, MD, MPH;
Shuji Ogino, MD, PhD, MS; Walter C. Willett, MD, DrPH; Andrew T. Chan, MD, MPH;
Edward L. Giovannucci, MD, ScD; Yin Cao, MPH, ScD

Supplemental content
IMPORTANCE Colorectal cancer (CRC) incidence and mortality among individuals younger CME Quiz at
than 50 years (early-onset CRC) are increasing. The reasons for such increases are largely jamanetwork.com/learning
unknown, although the increasing prevalence of obesity may be partially responsible. and CME Questions page 125

OBJECTIVE To investigate prospectively the association between obesity and weight gain
since early adulthood with the risk of early-onset CRC.

DESIGN, SETTING, AND PARTICIPANTS The Nurses’ Health Study II is a prospective, ongoing
cohort study of US female nurses aged 25 to 42 years at study enrollment (1989). A total of
85 256 women free of cancer and inflammatory bowel disease at enrollment were included in
this analysis, with follow-up through December 31, 2011. Validated anthropomorphic
measures and lifestyle information were self-reported biennially. Statistical analysis was
performed from June 12, 2017, to June 28, 2018.

EXPOSURES Current body mass index (BMI) (calculated as weight in kilograms divided by
height in meters squared), BMI at 18 years of age, and weight gain since 18 years of age.

MAIN OUTCOMES AND MEASURES Relative risk (RR) for incident early-onset CRC.

RESULTS Among the 85 256 women studied, 114 cases of early-onset CRC were documented
(median age at diagnosis, 45 years; interquartile range, 41-47 years) during 1 196 452
person-years of follow-up. Compared with women with a BMI of 18.5 to 22.9, the
multivariable RR was 1.37 (95% CI, 0.81-2.30) for overweight women (BMI, 25.0-29.9) and
1.93 (95% CI, 1.15-3.25) for obese women (BMI, ⱖ30.0). The RR for each 5-unit increment in
BMI was 1.20 (95% CI, 1.05-1.38; P = .01 for trend). Similar associations were observed among
women without a family history of CRC and without lower endoscopy within the past 10
years. Both BMI at 18 years of age and weight gain since 18 years of age contributed to this
observation. Compared with women with a BMI of 18.5 to 20.9 at 18 years of age, the RR of
early-onset CRC was 1.32 (95% CI, 0.80-2.16) for women with a BMI of 21.0 to 22.9 and 1.63
(95% CI, 1.01-2.61) for women with a BMI of 23.0 or greater at 18 years of age (P = .66 for
trend). Compared with women who had gained less than 5.0 kg or had lost weight, the RR of
early-onset CRC was 1.65 (95% CI, 0.96-2.81) for women gaining 20.0 to 39.9 kg and 2.15
(95% CI, 1.01-4.55) for women gaining 40.0 kg or more (P = .007 for trend).

CONCLUSIONS AND RELEVANCE Obesity was associated with an increased risk of early-onset
CRC among women. Further investigations among men and to elucidate the underlying
biological mechanisms are warranted.

Author Affiliations: Author

affiliations are listed at the end of this
article.
Corresponding Author: Yin Cao,
MPH, ScD, Division of Public Health
Sciences, Department of Surgery,
Washington University School of
Medicine, 660 S Euclid Ave,
JAMA Oncol. 2019;5(1):37-44. doi:10.1001/jamaoncol.2018.4280 Campus Box 8100, St Louis, MO 63310
Published online October 11, 2018. Corrected on March 7, 2019. ([email protected]).

(Reprinted) 37
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 Research Original Investigation Association of Obesity With Risk of Early-Onset Colorectal Cancer Among Women

T
he overall colorectal cancer (CRC) incidence and mortal-
ity rates have decreased by more than 45% since the Key Points
1980s,1,2 in part owing to greater screening uptake among
Question Isobesityassociatedwithearly-onsetcolorectalcancer,which
average-risk adults typically starting at 50 years of age3,4 and may have etiologic differences from late-onset colorectal cancer?
favorable changes in some lifestyle risk factors.5,6 In contrast
Findings In a prospective cohort study of 85 256 women, those
to the decreasing trends in adults 50 years or older, incidence
with obesity (body mass index ⱖ30) had a nearly doubled risk of
and mortality of CRC have been increasing among all
early-onset colorectal cancer compared with women with a body
age groups between 20 and 49 years.7-9 According to population- mass index of 18.5 to 22.9.
based projections, by 2030, colon cancer will increase by 90%
Meaning The findings suggest that obesity is associated with an
among individuals aged 20 to 34 years and by 28% among those
increased risk of early-onset colorectal cancer; further investigations
aged 35 to 49 years, and rectal cancer will increase by 124%
are needed to identify whether this association is causal.
among individuals aged 20 to 34 years and by 46% among those
aged 35 to 49 years.10 Although the incidence of early-onset CRC
remains low at approximately 8 per 100 000 population,11 it 90%,35 and 98% of deaths are documented.36 We excluded
represents at least 10% of total CRC that have not been women who reported implausible energy intake (<500 or
prevented or detected through screening.12 >3500 kcal/d, n = 2193) and women with a prior diagnosis of
The drivers for the increases in incidence of early-onset CRC cancer or inflammatory bowel disease at baseline (n = 415). Par-
have not been elucidated.13 Increasing prevalence of estab- ticipants who did not report baseline weight or weight at 18
lished CRC risk factors, such as obesity,14 sedentary lifestyle,15-17 years of age were also excluded (n = 1117). We additionally ex-
Western diet,18-20 and diabetes,21 may contribute. However, cluded participants whose baseline body mass index (BMI) (cal-
these factors were identified in studies that captured CRC pre- culated as weight in kilograms divided by height in meters
dominantly among older individuals. With the emerging evi- squared) was less than 18.5 (n = 2964). Participants with a BMI
dence that sporadic early-onset CRC may have distinct molecu- less than 18.5 in subsequent cycles were skipped (n = 4146).
lar features22-26 compared with cancers that arise in older Participants provided written informed consent. Data were
individuals and that these cases are often detected at a more deidentified. This study was approved by the institutional
advanced stage9 with greater years of life lost,27 there is an review board of the Brigham and Women’s Hospital.
urgent and unmet public health and clinical need to identify risk
factors of early-onset CRC to develop targeted preventive and Ascertainment of CRC
detection strategies for younger adults with higher risk.8,28 We requested written permission to acquire medical records and
Thus far, few studies29,30 have prospectively evaluated pathology reports from participants who reported having CRC
the association between obesity and risk of early-onset CRC. on biennial questionnaires. We also identified unreported, lethal
Because of the parallel increase in obesity31,32 and early-onset CRC cases through family members, the postal system, and the
CRC, a thorough examination of the role of current and early-life National Death Index. For all deaths due to CRC, we requested
obesity is among the first steps in our understanding of the medical records from next of kin. An NHSII study physician
increasing burden of early-onset CRC.7,33,34 We used data from masked to exposure information reviewed medical records to
the Nurses’ Health Study II (NHSII), a US-based prospective verify CRC diagnosis and extracted information on histopatho-
cohort of young women with detailed assessments of body logic findings and anatomical location. Our primary end point
weight, family and endoscopy histories, lifestyle factors, and was incident CRC diagnosed before 50 years of age.
other potential CRC risk factors to comprehensively examine the
association of obesity with CRC diagnosed before 50 years of age. Assessment of Anthropomorphic Measures
In the NHSII, height and weight were reported at baseline, and
weight was updated biennially. In the NHS, the predecessor
to the NHSII, self-reported body weight correlated well with
Methods measured weight (correlation coefficient, 0.97).37 We catego-
Study Population rized current BMI (BMI according to the immediately preced-
This prospective cohort study included 85 256 women aged 25 ing questionnaire) based on accepted standards using 18.5 to
to 42 years from the NHSII who were free of cancer and in- 20.9, 21.0 to 22.9, 23.0 to 24.9, 25.0 to 29.9, and 30.0 or
flammatory bowel disease at enrollment and were followed up greater.38,39 At baseline, participants were asked to recall their
from 1989 to December 31, 2011. The NHSII is an ongoing pro- body weight at early adulthood (18 years of age). In a prior vali-
spective cohort study that began in 1989, when 116 430 dation study, we observed a correlation coefficient of 0.87 be-
female nurses aged 25 to 42 years living in 14 US states pro- tween recalled weight and weight obtained from school rec-
vided detailed information on lifestyle and medical history. Par- ords at 18 years of age.40 Because participants were generally
ticipants were followed up every 2 years since inception by self- leaner at 18 years of age, we categorized early adulthood BMI
administered questionnaires on demographics, lifestyle using less than 18.5, 18.5 to 20.9, 21.0 to 22.9, and 23.0 or
factors, and medical and other health-related information, greater.39 We calculated weight change as the difference be-
which were complemented by quadrennial assessments of di- tween current weight and weight at 18 years of age. At base-
etary intake using semiquantitative food frequency question- line, we also asked participants to recall their body shapes at
naires. The overall active follow-up rate was approximately 5, 10, and 20 years of age using a validated 9-level pictogram.

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 Association of Obesity With Risk of Early-Onset Colorectal Cancer Among Women Original Investigation Research

Pictograms are graphic representations of body shape, rang- We performed sensitivity analyses using cumulative-
ing from 1 (most lean) to 9 (most overweight).35 Body shape average BMI. To minimize the possibility that undiagnosed CRC
reported retrospectively was used as a measurement of body may have contributed to weight change, we introduced a 4-year
fat and correlated well with measured BMI.35,41 lag analysis. We also performed subgroup analyses based on
tumor site (colon or rectum), year of diagnosis (before or
Assessment of Covariates after 2001), smoking status (never or ever), and physical
Biennially, we asked participants to report lower gastrointesti- activity (fourth to fifth quintiles or first to third quintiles). We
nal tract endoscopies. The indication for endoscopy, including also conducted joint analysis of BMI at 18 years of age and
symptoms (eg, bleeding or abdominal pain), family history of weight change since 18 years of age.
CRC, or routine screening without symptoms, was collected. We Finally, we examined whether the association between BMI
assessed total caloric, red meat, fiber, calcium, folate, and alco- and risk of CRC differed according to age of diagnosis using
hol consumption using semiquantitative food frequency ques- duplication-method Cox proportional hazards regression
tionnaires every 4 years since 1991.42 Diet quality was assessed modeling.56 In brief, we followed up women for all incident
using the Alternative Healthy Eating Index 2010, for which a CRC through 2011 and examined the association of BMI with
higher score has been consistently associated with reduced risk early-onset CRC and late-onset CRC (CRC diagnosed at 50 years
of cancer, diabetes, and cardiovascular disease.43,44 Physical ac- or older). For the analysis of late-onset CRC, early-onset CRC
tivity was self-reported with validated questionnaires every 2 to cases were censored at diagnosis. P for heterogeneity was
4 years.45 A metabolic equivalent of tasks (MET) score based on calculated assuming a linear association between current BMI
energy expenditure was assigned to each type of physical activ- vs early-onset or late-onset CRC using a likelihood ratio test.
ity, and the amount of total physical activity was calculated by Statistical significance was set as P ≤ .05 in 2-tailed tests. Analy-
multiplying the MET score by the mean time spent in each ac- ses were conducted with SAS statistical software, version 9.4
tivity. Smoking status was updated every 2 years,46 and pack- (SAS Institute Inc). Statistical analysis was performed from June
years among smokers were derived by multiplying the number 12, 2017, to June 28, 2018.
of packs smoked daily by the number of years during which that
amount was smoked.46 Participants also updated information
on family history of CRC among first-degree relatives, regular use
of aspirin, nonaspirin nonsteroidal anti-inflammatory drug use,
Results
multivitamin use, diabetes, menopausal status, and use of meno- Among the 85 256 women studied, 114 cases of early-onset CRC
pausal hormone therapy regularly.47-50 were documented (median age at diagnosis, 45 years; interquartile
range, 41-47 years) during 1 196 452 person-years of follow-up. The
Statistical Analysis median follow-up duration was 13.9 years. The age-standardized
We evaluated the association between current BMI and risk of characteristics of person-years according to current BMI are given
early-onset CRC as the primary analysis. We also examined the in Table 1. Baseline characteristics in 1989 are given in eTable 1
contribution of BMI at 18 years of age, weight gain since 18 years in the Supplement. Women with higher current BMI were older
of age, and early-life body shape. Person-time accrued from the and more likely to have diabetes. They engaged in less physical
return of the baseline questionnaire until the date of CRC activityandconsumedmoreredmeat.CurrentBMIwascorrelated
diagnosis, death from any cause, 50th birthday, or the end of with BMI at 18 years of age (Pearson correlation coefficient, 0.55).
follow-up, whichever came first. Obesity was independently associated with an increased risk
We used Cox proportional hazards regression models strati- of early-onset CRC. Compared with women with a BMI of 18.5 to
fied by age (months) and study period (2-year intervals) to esti- 22.9, women with a BMI of 23.0 to 24.9 had a multivariable RR
mate multivariable-adjusted hazard ratios and 95% CIs to ap- of 1.33 (95% CI, 0.75-2.36), overweight women (BMI, 25.0-29.9)
proximate relative risks (RRs). Covariates were chosen a priori had an RR of 1.37 (95% CI, 0.81-2.30), and obese women (BMI,
based on established risk factors of CRC and were included in the ≥30.0) had an RR of 1.93 (95% CI, 1.15-3.25) for early-onset CRC
model on a time-varying basis, including height (continuous), (Table 2). This association appears to be linear (Table 2 and the
family history of CRC (yes/no), personal history of diabetes (yes/ eFigure in the Supplement). Each 5-unit increase in BMI was as-
no), screening lower endoscopy within 10 years (yes/no), lower sociated with an RR of 1.20 (95% CI, 1.05-1.38; P = .01 for trend).
endoscopy for other indications within 10 years (yes/no), smok- The association between current BMI and risk of early-onset CRC
ing pack-years (continuous), physical activity (continuous), al- was similar when we restricted the analysis to women with no
cohol use (continuous), regular use of aspirin (yes/no), nonste- family history of CRC or to those without lower endoscopy within
roidal anti-inflammatory drug use (yes/no), multivitamin use the past 10 years. When we assessed the cumulative average and
(yes/no), menopausal status (premenopausal or postmeno- 4-year lagged BMI, the association was attenuated but the over-
pausal), menopausal hormone use (never, past, or current), and all findings were similar (eTable 2 in the Supplement). Although
dietary intake (total calories, red meat, fiber, folate, calcium, and we had limited case numbers, we observed slightly stronger as-
Alternate Healthy Eating Index 2010, all continuous). For dietary sociations for rectal cancer and among women who were past or
factors, we calculated the cumulative average to represent long- current smokers (eTable 3 and eTable 4 in the Supplement).
term consumption.51,52 Tests for linear trend were performed Both BMI at early adulthood and change in weight since early
using variables of interest as continuous variables. We examined adulthood were associated with risk of early-onset CRC (Table 3
possible nonlinear associations using restricted cubic splines.53-55 and the eFigure in the Supplement). Compared with participants

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 Research Original Investigation Association of Obesity With Risk of Early-Onset Colorectal Cancer Among Women

Table 1. Characteristics of Person-Years According to Current BMI Among Women Younger Than 50 Years
in the Nurses' Health Study IIa

Current BMI
Characteristic 18.5-22.9 23.0-24.9 25.0-29.9 ≥30.0
Age, mean (SD), y 39.7 (5.8) 40.9 (5.6) 41.7 (5.5) 42.4 (5.2)
Person-years, No. 455 250 217 271 296 763 230 169
BMI at 18 y of age, mean (SD) 19.8 (1.9) 20.8 (2.3) 21.8 (2.8) 24.7 (4.5)
Weight change since 18 y of age, mean (SD), kgb 3.7 (5.5) 8.4 (6.5) 14.6 (8.3) 29.6 (14.5)
Height, mean (SD), cm 165 (7) 164 (6) 165 (7) 164 (7)
Postmenopausal women 6.1 6.9 7.7 8.8
Current menopausal hormone therapy among 68.8 71.0 68.8 64.7
postmenopausal women
Family history of colorectal cancer 5.5 5.4 5.5 5.6 Abbreviations: BMI, body mass index
Screening lower endoscopy within past 10 y 3.1 3.1 3.1 3.2 (calculated as weight in kilograms
divided by height in meters squared);
Lower endoscopy for other indications 6.1 6.1 6.8 7.9
within past 10 yc MET, metabolic equivalent of tasks;
NSAID, nonsteroidal
History of diabetes 0.7 0.9 1.4 4.6
anti-inflammatory drugs.
Ever smokers 32.5 33.6 33.4 33.5 a
Data are presented as mean
Pack-years among ever smokers, mean (SD) 11.4 (9.2) 12.0 (9.2) 12.6 (9.4) 13.1 (9.7)
(percentage) of person-years unless
Alcohol intake, mean (SD), g/d 4.3 (7.4) 4.0 (7.1) 3.5 (6.9) 2.3 (5.8) otherwise indicated. All values other
Physical activity, mean (SD), MET h/wk 25.0 (30.9) 22.1 (27.8) 19.4 (25.4) 14.7 (21.1) than age have been directly
Regular aspirin use 10.0 10.3 10.8 12.0 standardized to age distribution
(in 5-year age group) of all the
Regular NSAID use 20.8 24.0 27.8 34.6
participants.
Current use of multivitamin 47.5 46.1 44.7 41.0 b
Weight loss was calculated as a
Total energy intake, mean (SD), kcal/d 1789 (537) 1790 (539) 1813 (556) 1862 (582) negative value.
Red meat intake, mean (SD), servings per week 5.6 (4.4) 6.1 (4.5) 6.6 (4.8) 7.5 (5.3) c
Lower endoscopy for indications
Fiber intake, mean (SD), g/d 19.4 (6.2) 19.1 (5.9) 18.8 (5.6) 18.0 (5.4) other than screening (eg, having
Folate intake, mean (SD), μg/d 537 (300) 530 (302) 524 (301) 494 (294) symptoms, family history of
Calcium intake, mean (SD), mg/d 1114 (520) 1102 (511) 1094 (507) 1052 (498) colorectal cancer, follow-up
endoscopy, or positive fecal occult
Alternate Healthy Eating Index 2010, mean (SD) 46.6 (11.2) 45.9 (10.8) 45.3 (10.7) 43.4 (10.6)
blood test result).

Table 2. Current BMI and Risk of Early-Onset Colorectal Cancer

Abbreviations: BMI, body mass index
Multivariable- (calculated as weight in kilograms
No. of No. of Age-Adjusted RR Adjusted RR divided by height in meters squared);
Variable Cases Person-Years (95% CI) (95% CI)a NA, not applicable; RR, relative risk.
All Participants a
All multivariable-adjusted RRs were
Current BMI adjusted for height (continuous),
18.5-22.9 29 455 250 1 [Reference] 1 [Reference] history of diabetes (yes/no),
23.0-24.9 20 217 271 1.27 (0.71-2.24) 1.33 (0.75-2.36) smoking pack-years (continuous),
physical activity (continuous),
25.0-29.9 30 296 763 1.32 (0.79-2.22) 1.37 (0.81-2.30)
alcohol intake (continuous), regular
≥30 35 230 169 1.86 (1.13-3.06) 1.93 (1.15-3.25) use of aspirin (yes/no), nonsteroidal
Each 5-unit increase NA NA 1.18 (1.04-1.35) 1.20 (1.05-1.38) anti-inflammatory drug use
P for trendb NA NA .01 .01 (yes/no), multivitamin use (yes/no),
menopausal status (premenopausal
Participants Without Family History of Colorectal Cancer
or postmenopausal), menopausal
Current BMI hormone use (never, past, and
18.5-22.9 25 429 876 1 [Reference] 1 [Reference] current), and dietary intake (total
23.0-24.9 17 205 824 1.22 (0.66-2.27) 1.27 (0.68-2.36) calories, red meat, fiber, folate,
25.0-29.9 27 280 184 1.36 (0.79-2.36) 1.40 (0.81-2.44) calcium, and Alternate Healthy
Eating Index 2010, continuous).
≥30 30 216 759 1.82 (1.06-3.11) 1.88 (1.07-3.30)
Analyses among all participants and
Each 5-unit increase NA NA 1.17 (1.01-1.35) 1.18 (1.02-1.38) participants without family history
P for trendb NA NA .03 .03 of colorectal cancer were also
Participants Without Endoscopy in Past 10 Years adjusted for lower endoscopy for
screening (yes/no) or for other
Current BMI
indications (yes/no) within the past
18.5-22.9 25 420 262 1 [Reference] 1 [Reference] 10 years. Analyses among all
23.0-24.9 17 200 095 1.23 (0.66-2.29) 1.28 (0.69-2.38) participants and participants
25.0-29.9 25 269 644 1.26 (0.72-2.20) 1.30 (0.74-2.29) without endoscopy in past 10 years
≥30 34 205 587 2.01 (1.19-3.40) 2.10 (1.22-3.63) were also adjusted for family history
of colorectal cancer (yes/no).
Each 5-unit increase NA NA 1.21 (1.06-1.38) 1.23 (1.07-1.42)
b
Calculated using the current BMI as
P for trendb NA NA .005 .004
a continuous variable.

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 Association of Obesity With Risk of Early-Onset Colorectal Cancer Among Women Original Investigation Research

Table 3. BMI at 18 Years of Age, Change in Body Weight Since 18 Years of Age, and Risk of Early-Onset Colorectal Cancer
No. of No. of Age-Adjusted RR Multivariable-Adjusted RR Multivariable-Adjusted RR
Variable Cases Person-Years (95% CI) (95% CI)a (95% CI)a,b
BMI at 18 Years of Age
BMI
<18.5 13 146 589 1.13 (0.60-2.11) 1.06 (0.56-2.00) 1.05 (0.56-1.97)
18.5-20.9 39 512 802 1 [Reference] 1 [Reference] 1 [Reference]
21.0-22.9 27 278 558 1.29 (0.79-2.11) 1.34 (0.82-2.20) 1.32 (0.80-2.16)
≥23 35 258 504 1.72 (1.09-2.72) 1.72 (1.08-2.74) 1.63 (1.01-2.61)
Each 5-point increase NA NA 1.09 (0.84-1.42) 1.08 (0.83-1.41) 1.06 (0.81-1.40)
P for trendc NA NA .51 .58 .66
Weight Change Since 18 Years of Aged
Loss or gain <5.0 kge 27 373 061 1 [Reference] 1 [Reference] 1 [Reference]
Gain of 5.0-19.9 kg 42 561 417 0.86 (0.53-1.41) 0.86 (0.52-1.42) 0.86 (0.52-1.43)
Gain of 20.0-39.9 kg 34 214 633 1.66 (0.99-2.77) 1.64 (0.96-2.81) 1.65 (0.96-2.81)
Gain ≥40.0 kg 11 47 342 2.25 (1.11-4.59) 2.15 (1.02-4.54) 2.15 (1.01-4.55)
Each 5-kg increase NA NA 1.09 (1.03-1.16) 1.09 (1.03-1.16) 1.09 (1.02-1.16)
P for trendc NA NA .002 .006 .007
b
Abbreviations: BMI, body mass index (calculated as weight in kilograms divided For the model for BMI at 18 years of age, we additionally adjusted for weight
by height in meters squared); NA, not applicable; RR, relative risk. change since 18 years of age. For the model for weight change since 18 years of
a
Additionally adjusted for height (continuous), family history of colorectal age, we additionally adjusted for BMI at 18 years of age.
c
cancer (yes/no), history of diabetes (yes/no), screening lower endoscopy Calculated using BMI at 18 years of age or weight change since 18 years of age
within the past 10 years (yes/no), lower endoscopy for other indications within as a continuous variable.
the past 10 years (yes/no), smoking pack-years (continuous), physical activity d
Weight change was calculated as current weight minus weight at 18 years of age.
(continuous), alcohol intake (continuous), regular use of aspirin (yes/no), e
Two patients with early-onset CRC had weight loss of 5.0 kg or more since 18
nonsteroidal anti-inflammatory use (yes/no), multivitamin use (yes/no),
years of age. The multivariable-adjusted RR was 0.59 (95% CI, 0.13-2.65)
menopausal status (premenopausal or postmenopausal), menopausal
compared with women with weight change within 5.0 kg. Because of the
hormone use (never, past, and current use of menopausal hormones), and
limited number of cases, we combined weight loss of 5.0 kg or more and
dietary intake (total calories, red meat, fiber, folate, calcium, and Alternate
weight change within 5.0 kg in the same category.
Healthy Eating Index 2010, continuous).

with a BMI of 18.5 to 20.9 at 18 years of age, the RR was 1.63 (95% adulthood were associated with increased risk of early-onset
CI, 1.01-2.61) for participants with a BMI of 23.0 or higher at 18 CRC. To our knowledge, this study is among the first to inves-
years of age (P = .66 for trend). Compared with women who had tigate prospectively the association between obesity and risk of
lost weight or gained less than 5.0 kg since 18 years of age, the CRC diagnosed at younger than 50 years. Our additional analy-
RR was 1.65 (95% CI, 0.96-2.81) for women gaining 20.0 to 39.9 ses by age at onset indicate that obesity may play a substantial
kg and 2.15 (95% CI, 1.01-4.55) for women gaining 40.0 kg or role in colorectal carcinogenesis among younger people and
more. The RR for every 5.0-kg increase in weight since 18 years may contribute to the age-specific differences in CRC trends.8,57
of age was 1.09 (95% CI, 1.02-1.16; P = .007 for trend). Women Our results may help in estimating the contribution of obesity
with a BMI of 23.0 or greater at 18 years of age and weight gain with early-onset CRC trends using simulation studies.6
of 20.0 kg or more had the highest risk of early-onset CRC The association between obesity and increased risk of
(eTable 5 in the Supplement). Body shape during childhood (5 overall CRC diagnosed at a median of over 63 years of age has
years of age) and adolescence (10 years of age) and change in body been well documented, with stronger and more consistent find-
shape during early life were not associated with risk of early-onset ings among men compared with women. 14,58,59 A recent
CRC (eTables 6 and 7 in the Supplement). Body shape during early meta-analysis60 found a higher risk of colon cancer for each
adulthood (20 years of age) appeared to correlate with the risk 5-unit increment in BMI of 30% among men and 12% among
of early-onset CRC. Compared with participants with a pictogram women. This analysis incorporated findings from the Health
of 1 or 2 (leaner) at 20 years of age, the RR was 1.71 (95% CI, 1.01- Professionals Follow-Up Study 61 and the NHS, 62 2 large
2.89) for participants with a pictogram of at least 4 (more obese). prospective cohorts similar to the NHSII but with participants
We observed that the association between current BMI and of older ages and a mean age at CRC diagnosis of 65 years. Early-
risk of CRC differed significantly according to age at onset life body fat, measured by weight or body shape during early
(P = .01 for heterogeneity). Current BMI was associated with adulthood, was also associated with increased risk of overall
risk of early-onset CRC but not CRC diagnosed at 50 years or CRC,63,64 including in analyses among women in the NHS.63
older (P = .38 for trend) (eTable 8 in the Supplement). However, these studies63,64 did not examine the associations spe-
cifically for early-onset CRC. Little work has been performed to
directly evaluate the association between obesity and risk of
early-onset colorectal neoplasia in a prospective fashion.30 A
Discussion case-control study29 based in Switzerland and Italy found that
In this large prospective study of women, we found that higher BMI at 30 years of age was not associated with risk of CRC at
current BMI, BMI at 18 years of age, and weight gain since early younger than 45 years. In another study,30 obesity was associated

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 Research Original Investigation Association of Obesity With Risk of Early-Onset Colorectal Cancer Among Women

with increased risk of advanced early-onset colorectal Of note, we also observed slightly stronger associations be-
adenoma. Our analyses in a large prospective cohort found that tween obesity and rectal cancer compared with cancers of the
each 5-unit increase in BMI was associated with a 20% increase colon. Rectal cancer incidence rates have been increasing to a
in risk of early-onset CRC driven by sporadic early-onset CRC. greater degree than colon cancer among individuals younger
Both BMI at 18 years of age and weight gain since 18 years of age than 50 years.7 Although the number of patients was limited,
contributed to this association. Moreover, the association be- our findings suggest that obesity may partially contribute to
tween obesity and CRC was stronger for early-onset CRC com- the comparatively faster increase in early-onset rectal
pared with CRC diagnosed at 50 years or older. Although the cancer.7,81 Moreover, our results indicate that the obesity and
study may have been underpowered to fully detect, if any, a weak early-onset CRC association may be stronger among younger
association between BMI and CRC at 50 years or older,58 our find- women with a history of smoking.
ing that obesity may be associated with early-onset CRC is in line
with a previous meta-analysis59 in which the association be- Strengths and Limitations
tween BMI and CRC was stronger for premenopausal com- The strengths of this investigation include the use of a large, well-
pared with postmenopausal women. Taken together, our find- characterized cohort of younger women. Prospectively col-
ings demonstrate the importance of obesity control during early lected and validated assessments of weight and other risk fac-
adulthood as a way to prevent early-onset CRC. tors minimized the influence of residual confounding, recall bias,
The biological mechanisms underlying the association be- and measurement errors. Although we could not distinguish
tween obesity and CRC remain unclear.14 Metabolic syndrome, whether the findings are the same across all genetic predispo-
insulin resistance,65,66 systemic inflammation, and immunity67 sition types, such as familial adenomatous polyposis or Lynch
are important mediators. 68 Microbial dysbiosis may also syndrome, our results are generalizable to all persons with early-
contribute.69,70 In addition, obesity can induce mucosal meta- onset CRC as a group, and the findings were robust when we ex-
bolic abnormalities in glycolytic and lipogenic pathways and al- cluded individuals with family or screening history. Moreover,
ter adenosine monophosphate–activated protein kinase and sir- most early-onset CRC is sporadic; only approximately 7% of cases
tuin function.71 The positive association observed only with have confirmed hereditary cancer syndromes.82 Our robust find-
early-onset CRC underscores the need for mechanistic investi- ings among participants without a family history of CRC and
gations into the interactions among obesity, estrogen, and CRC without a lower endoscopy within the past 10 years reassured
carcinogenesis in the context of molecular histopathologic the role of obesity in sporadic early-onset CRC. We were not able
profiles.72 Emerging evidence seems to support the unique- to capture visceral adiposity directly or indirectly because our
ness of early-onset CRC. For instance, patients with early-onset data on waist and hip measurements were limited. Our study
CRC have a higher rate of long interspersed element 1 hypometh- comprised mainly white women. Validations in men and other
ylation and lower frequencies of BRAF (OMIM 164757) and KRAS races/ethnicities are warranted.8,12
(OMIM 190070) mutations, CpG island methylator phenotype,
and poorly differentiated foci.22-26 Elucidating the mediating role
of these molecular profiles in obesity-induced colorectal carci-
nogenesis may provide mechanistic and therapeutic insights.
Conclusions
Apart from direct contributions to colorectal tumorigenesis, Obesity and weight gain since early adulthood were associ-
obesity could be a surrogate for other established risk factors ated with increased risk of early-onset CRC in a large, pro-
for CRC.73 For example, dietary red meat intake and prolonged spective cohort of US women. Given that most of these
sedentary time are associated with weight gain74,75 and risk of younger cases are diagnosed symptomatically with more
CRC.17,76-78 Metabolic syndrome and diabetes are also correlated advanced tumors83 and with a significant influence on years
with BMI79 and risk of CRC.80 Of importance, all these factors of life lost,27 our findings reinforce the benefits of maintain-
have been increasing at the population scale. Taken together, ing a healthy weight throughout life. Our findings suggest
unhealthy diet, sedentary behavior, and resultant excess body the promise of using body weight to personalize and
weight complicated by metabolic syndrome may independently complement early cancer screening strategies among adults
and collectively increase the risk of early-onset CRC.33 younger than 50 years.84

ARTICLE INFORMATION Institute, Harvard Medical School, Boston, Harvard Medical School, Boston, Massachusetts
Accepted for Publication: July 13, 2018. Massachusetts (Ng); Department of Epidemiology and (Ogino); Broad Institute of MIT and Harvard,
Biostatistics, Memorial Sloan Kettering Cancer Center, Cambridge, Massachusetts (Ogino, Chan); Channing
Published Online: October 11, 2018. New York, New York (Zauber); Division of Division of Network Medicine, Department of
doi:10.1001/jamaoncol.2018.4280 Gastroenterology, Massachusetts General Hospital and Medicine, Brigham and Women’s Hospital and Harvard
Correction: This article was corrected on March 7, Harvard Medical School, Boston (Nguyen, Chan); Yale Medical School, Boston, Massachusetts (Willett, Chan);
2019, to correct omissions in the Conflict of Interest Cancer Center, New Haven, Connecticut (Fuchs); Department of Immunology and Infectious Diseases,
Disclosures. Department of Epidemiology, Harvard T.H. Chan Harvard T.H. Chan School of Public Health, Boston,
Author Affiliations: Clinical and Translational School of Public Health, Boston, Massachusetts (Ogino, Massachusetts (Chan); Division of Public Health
EpidemiologyUnit,MassachusettsGeneralHospitaland Giovannucci); Program in MPE Molecular Pathological Sciences, Department of Surgery, Washington
HarvardMedicalSchool,Boston(Liu,Nguyen,Song,He, Epidemiology, Department of Pathology, Brigham and University School of Medicine, St Louis, Missouri (Cao);
Chan,Cao);DepartmentofNutrition,HarvardT.H.Chan Women’s Hospital and Harvard Medical School, Siteman Cancer Center, Washington University School
School of Public Health, Boston, Massachusetts (Wu, Boston, Massachusetts (Ogino); Department of of Medicine, St Louis, Missouri (Cao).
Song, Willett, Giovannucci); Dana-Farber Cancer Oncologic Pathology, Dana-Farber Cancer Institute and

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 Association of Obesity With Risk of Early-Onset Colorectal Cancer Among Women Original Investigation Research

Author Contributions: Drs Chan, Giovannucci, and 5. Ezzati M, Riboli E. Behavioral and dietary risk 21. Tsilidis KK, Kasimis JC, Lopez DS, Ntzani EE,
Cao contributed equally to this work. Drs Liu and factors for noncommunicable diseases. N Engl J Med. Ioannidis JP. Type 2 diabetes and cancer: umbrella
Cao had full access to all the data in the study and 2013;369(10):954-964. doi:10.1056/ review of meta-analyses of observational studies.
take responsibility for the integrity of the data and NEJMra1203528 BMJ. 2015;350:g7607. doi:10.1136/bmj.g7607
the accuracy of the data analysis. 6. Edwards BK, Ward E, Kohler BA, et al. Annual 22. Kothari N, Teer JK, Abbott AM, et al. Increased
Concept and design: Liu, Chan, Giovannucci, Cao. report to the nation on the status of cancer, incidence of FBXW7 and POLE proofreading
Acquisition,analysis,orinterpretationofdata:Allauthors. 1975-2006, featuring colorectal cancer trends and domain mutations in young adult colorectal
Drafting of the manuscript: Liu, Cao. impact of interventions (risk factors, screening, and cancers. Cancer. 2016;122(18):2828-2835. doi:10.
Critical revision of the manuscript for important treatment) to reduce future rates. Cancer. 2010; 1002/cncr.30082
intellectual content: All authors. 116(3):544-573. doi:10.1002/cncr.24760 23. Pearlman R, Frankel WL, Swanson B, et al; Ohio
Statistical analysis: Liu, Cao. 7. Siegel RL, Fedewa SA, Anderson WF, et al. Colorectal Cancer Prevention Initiative Study
Obtained funding: Fuchs, Ogino, Willett, Chan, Colorectal cancer incidence patterns in the United Group. Prevalence and spectrum of germline cancer
Giovannucci, Cao. States, 1974-2013. J Natl Cancer Inst. 2017;109 susceptibility gene mutations among patients with
Administrative, technical, or material support: Chan, (8):djw322. doi:10.1093/jnci/djw322 early-onset colorectal cancer. JAMA Oncol. 2017;3
Giovannucci, Cao. 8. Siegel RL, Miller KD, Jemal A. Colorectal cancer (4):464-471. doi:10.1001/jamaoncol.2016.5194
Supervision: Chan, Giovannucci, Cao. mortality rates in adults aged 20 to 54 years in the 24. Kirzin S, Marisa L, Guimbaud R, et al. Sporadic
Conflict of Interest Disclosures: Dr Chan reported United States, 1970-2014. JAMA. 2017;318(6): early-onset colorectal cancer is a specific sub-type
receiving consulting fees from Janssen, Pfizer Inc, 572-574. doi:10.1001/jama.2017.7630 of cancer: a morphological, molecular and genetics
and Bayer Pharma A.G. Dr Fuchs has been a 9. Davis DM, Marcet JE, Frattini JC, Prather AD, study. PLoS One. 2014;9(8):e103159. doi:10.1371/
consultant and/or a scientific advisor for Eli Lilly, Mateka JJ, Nfonsam VN. Is it time to lower the journal.pone.0103159
Entrinsic Health, Pfizer, Merck, Sanofi, Roche, recommended screening age for colorectal cancer? 25. Cavestro GM, Mannucci A, Zuppardo RA, Di Leo
Genentech, Merrimack Pharmaceuticals, Dicerna, J Am Coll Surg. 2011;213(3):352-361. doi:10.1016/j. M, Stoffel E, Tonon G. Early onset sporadic
Bayer, Celgene, Agios, Gilead Sciences, Five Prime jamcollsurg.2011.04.033 colorectal cancer: worrisome trends and oncogenic
Therapeutics, Taiho, and KEW. No other disclosures 10. Bailey CE, Hu CY, You YN, et al. Increasing features. Dig Liver Dis. 2018;50(6):521-532. doi:10.
were reported. disparities in the age-related incidences of colon 1016/j.dld.2018.02.009

Funding/Support: This work was supported by and rectal cancers in the United States, 1975-2010. 26. Connell LC, Mota JM, Braghiroli MI, Hoff PM.
JAMA Surg. 2015;150(1):17-22. doi:10.1001/ The rising incidence of younger patients with
grants UM1 CA176726 (Willett), R01 CA205406 (Ng),
jamasurg.2014.1756 colorectal cancer: questions about screening,
R35 CA197735 (Ogino), R01 CA137178 (Chan), K24
11. National Cancer Institute. Surveillance, biology, and treatment. Curr Treat Options Oncol.
DK098311 (Chan), and K07 CA218377 (Cao) from the
Epidemiology, and End Results (SEER) Program 2017;18(4):23. doi:10.1007/s11864-017-0463-3
National Institutes of Health. Dr Chan is also
supported by a Crohn’s and Colitis Foundation Senior Research Data (1973-2015). Bethesda, MD: National 27. Lortet-Tieulent J, Soerjomataram I, Lin CC,
Investigator Award and a Stuart and Suzanne Steele Cancer Institute, DCCPS, Surveillance Research Coebergh JWW, Jemal A. U.S. burden of cancer by
Program; April 2018. race and ethnicity according to disability-adjusted
Massachusetts General Hospital Research Scholars
12. Siegel RL, Miller KD, Fedewa SA, et al. life years. Am J Prev Med. 2016;51(5):673-681. doi:
Award. Dr Cao is supported by the Raymond P.
Colorectal cancer statistics, 2017. CA Cancer J Clin. 10.1016/j.amepre.2016.07.039
Lavietes Foundation and a National Comprehensive
Cancer Network Young Investigator Award. 2017;67(3):177-193. doi:10.3322/caac.21395 28. Ahnen DJ, Wade SW, Jones WF, et al. The
13. Murphy CC, Lund JL, Sandler RS. Young-onset increasing incidence of young-onset colorectal
Role of the Funder/Sponsor: The funding sources had cancer: a call to action. Mayo Clin Proc. 2014;89(2):
noroleinthedesignandconductofthestudy;collection, colorectal cancer: earlier diagnoses or increasing
disease burden? Gastroenterology. 2017;152(8): 216-224. doi:10.1016/j.mayocp.2013.09.006
management, analysis, and interpretation of the data;
1809-1812.e1803. 29. Rosato V, Bosetti C, Levi F, et al. Risk factors for
preparation, review, or approval of the manuscript; and
14. Bardou M, Barkun AN, Martel M. Obesity and young-onset colorectal cancer. Cancer Causes Control.
the decision to submit the manuscript for publication.
colorectal cancer. Gut. 2013;62(6):933-947. doi:10. 2013;24(2):335-341. doi:10.1007/s10552-012-0119-3
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