Abstract
Background
Despite the increasing incidence in colorectal cancer (CRC) among the young population, the involvement of modifiable early-life exposures is understudied.
Methods
We prospectively investigated the association of lifestyle score, which measures adherence to the 2018 World Cancer Research Fund/American Institute for Cancer Research (WCRF/AICR) cancer prevention recommendations, in adolescence and adulthood with risk of CRC precursors in 34,509 women enrolled in the Nurses’ Health Study II. Participants reported adolescent diet in 1998 and subsequently underwent at least one lower gastrointestinal endoscopy between 1999 and 2015. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using multivariable logistic regression for clustered data.
Results
During follow-up (1998–2015), 3036 women had at least one adenoma, and 2660 had at least one serrated lesion. In multivariable analysis, per unit increase in adolescent WCRF/AICR lifestyle score was not associated with risk of total adenoma or serrated lesions, in contrast to adult WCRF/AICR lifestyle score (OR = 0.92, 95% CI: 0.87–0.97, Ptrend = 0.002 for total adenoma; and OR = 0.86, 95% CI: 0.81–0.92, Ptrend < 0.001 for total serrated lesions).
Conclusion
Adherence to the 2018 WCRF/AICR recommendations during adulthood but not during adolescence was associated with a lower risk of CRC precursors.
Subject terms: Cancer epidemiology, Cancer prevention, Colorectal cancer
Introduction
Globally, colorectal cancer (CRC) accounted for over 1.9 million (10%) of all new cancer cases and 935,000 deaths in 2020 [1, 2]. The burden is projected to increase to more than 2.2 million new cases and 1.1 million cancer deaths by 2030 [3]. Despite rapid declines in CRC incidence among individuals older than age 65, incidence continues to rise in young and middle-aged adults, especially in high-income countries [4]. In the US, the CRC incidence among individuals under age 50 has been increasing since the mid-1990s [5] and has increased by approximately 2% annually from 2011 to 2016 [4, 6]. The declining CRC incidence in older people is likely largely a result of screening and removal of colorectal adenomas and serrated polyps [7], known CRC precursors, which share similar risk factors to CRC [8–12]. In turn, changes in dietary patterns, increasing sugar intake, and sedentary lifestyle prevalent in the younger generation may increase the risk of adenomas, and thus contribute to the rising incidence of CRC in the younger population [13–18]. From both mutational and epidemiologic perspectives, colorectal carcinogenesis is a long process that takes several decades, and the initial steps may occur at young ages [19]. A tumorigenesis timeline model has indicated the first mutation in a driver gene for an eventual CRC tends to occur approximately at age 14 [20]. Accumulating epidemiologic evidence has also suggested many lifetime risk factors may have lagged effects [21–23] and perhaps even opposing actions early and later in carcinogenesis [24]. Therefore, the aetiology of CRC should be elucidated from the life course perspective [25].
In 2018, the World Cancer Research Fund/American Institute for Cancer Research (WCRF/AICR) released the third expert report, “Diet, Nutrition, Physical Activity and Cancer: a Global Perspective”, aiming to provide recommendations to reduce total cancer risk [26]. The recommendations have been operationalized into a standardised composite lifestyle score [27], and higher lifestyle score was associated with lower risk of CRC in previous studies [28, 29]. To date, however, few studies have examined the comprehensive association of cancer risk factors, capturing diet and lifestyle across multiple life stages, including adolescence, with risk of CRC precursors. To address this evidence gap, we investigated whether a lifestyle score measuring adherence to the 2018 WCRF/AICR cancer prevention recommendations during adolescence or adulthood is independently associated with lower risk of CRC precursors, including those diagnosed before age 50.
Methods
Study population
We leveraged data from the Nurses’ Health Study II (NHSII), a large, prospective ongoing US cohort of 116,429 female registered nurses aged 25–42 years at enrolment in 1989. The participants returned a mailed questionnaire about demographics, lifestyle factors, diet and medical history every 2 years [30]. We included 47,355 participants who had returned a High School Food Frequency Questionnaire (HS-FFQ) [31] inquiring about adolescent diet in 1998 and subsequently underwent at least one lower gastrointestinal endoscopy between 1999 and 2015. We excluded 12,520 women who had no lower bowel endoscopy during follow-up, because colorectal polyps are generally asymptomatic but detectable during an endoscopy, and who had a history of any cancer (other than nonmelanoma skin cancer), colorectal polyps, Crohn’s disease or ulcerative colitis before the return of the HS-FFQ. Individuals with missing lifestyle or dietary scores were further excluded from analyses (n = 326), leaving a total of 34,509 women for the current analyses. The study protocol was approved by the institutional review boards of the Brigham and Women’s Hospital and Harvard T.H. Chan School of Public Health, and those participating registries as required.
Assessment of high school and adult dietary intakes
Adolescent diet was assessed in 1998 using a self-administered HS-FFQ, specifically designed to include 124 food or beverage items commonly consumed between 1960 and 1982 when participants were aged 13–18 [31]. Participants were asked how often, on average, they had consumed a standard portion size of each food or beverage when they were in high school, with nine possible responses ranging from “never or less than once per month” to “6 or more times per day”. The reproducibility and validity of the HS-FFQ have been previously described in detail [31], which demonstrated moderate-to-good reproducibility and adequate validity. Adult diet was assessed every 4 years since 1991, using a validated FFQ on which participants reported how often they consumed ~130 food items during the previous year [32].
Assessment of anthropometry
We asked participants to report their adult height and weight at age 18 on the 1989 baseline questionnaire. Body mass index (BMI, kg/m2) at age 18 was calculated as weight (kg) divided by reported adult height squared (m2) in 1989. Adult BMI was calculated using current weight and baseline height. As a measure of central adiposity, tape-measured waist circumference (WC, inches) was reported in 1993 and 2005.
Assessment of physical activity
Physical activity during adolescence and early adulthood was assessed in 1997. Participants reported average hours a week (none, 1, 2–5, 6–10, 11–20, 21–40, 41–60, 61–90, >90 h/week) of walking to and from school or work and moderate (e.g., hiking, casual cycling, yard work) and strenuous recreational activities (e.g., running, aerobics, lap swimming) during grades 7–8 (at age 12–13) and 9–12 (at age 14–17) and at age 18–22, 23–29 and 30–34. Recreational physical activity in adulthood was assessed in 1989, 1991, 1997, 2001, 2005, 2009 and 2013. Participants also reported average weekly hours spent watching TV. Each activity was assigned a metabolic equivalent task (MET) score. Total MET-hours/week were calculated by summing values from the individual activities. We used hours/week spent watching TV as our measure of sedentary behaviour. The self-reported physical activity questionnaire provided reasonable validity [33].
Construction of the 2018 WCRF/AICR lifestyle score
We created the WCRF/AICR lifestyle score for both adolescence and adulthood based on the 2018 WCRF/AICR cancer prevention recommendations [26, 27]. The overall WCRF/AICR lifestyle score comprised three components (Supplementary Table 1): (i) the WCRF/AICR dietary score, (ii) adiposity score, and (iii) physical activity score. The WCRF/AICR dietary score included five subcomponents: (i) fruits, vegetables, dietary fibre, whole grains and legumes, (ii) refined grains and processed foods high in fat and sugar, (iii) red and processed meat, (iv) sugar-sweetened beverages and (v) alcohol. Each subcomponent was assigned a score of 0 (non-adherence), 0.5 (partial adherence) or 1 (adherence) then averaged to construct the final WCRF/AICR dietary score (ranging from 0 to 5). The adiposity score consisted of two subcomponents: BMI and WC. Because there was no measure of adolescent WC, we used BMI as the only subcomponent for adolescent adiposity score. The physical activity score consisted of two subcomponents: energy expenditure and sedentary activity. We averaged the participants’ physical activity score during grades 7–8 and 9–12 to represent their adolescent physical activity. For both adiposity and physical activity scores, subcomponents were assigned a score of 0, 0.5 or 1, which were averaged to form the final scores ranging from 0 to 1. We evaluated the WCRF/AICR lifestyle score (ranging from 0 to 7) that weighted each individual dietary factor, adiposity and physical activity equally for adolescence and each questionnaire cycle (Supplementary Table 2). The correlation between adolescent and adult lifestyle scores was 0.25 and that for dietary scores was 0.29.
Outcome ascertainment
On each biennial questionnaire, participants were asked whether they underwent a lower bowel endoscopy, the reasons why (screening or symptoms) and whether CRC or polyps were diagnosed. Self-reported negative endoscopy was reliably reported in our cohorts [34, 35]. Participants who reported a diagnosis of polyps were asked for permission to access medical and pathologic records. Physicians masked to participant exposure information reviewed the records to verify the diagnosis and extract information on polyp size, number, subtype (adenoma, serrated lesion), subsite (proximal, distal, rectal) and histology (tubular, tubulovillous, villous; with or without high-grade dysplasia). Total adenomas were subdivided into high (≥1 cm, any villous histology, high-grade dysplasia or 3 adenomas) versus low risk (1–2 tubular adenomas <1 cm in size) [36]. Serrated lesions included hyperplastic polyps, sessile serrated adenoma/polyp and traditional serrated adenoma [37], and were subdivided by size (small, <1 cm; large, ≥1 cm) as a predictor for the malignant potential [35].
Assessment of other covariates
From the biennial questionnaires during follow-up, we collected and updated information on smoking status, family history of CRC, personal history of diabetes, menopausal status and current use of aspirin and non-steroidal anti-inflammatory drugs (NSAIDs). Total intake of folate, vitamin D and calcium was also measured for both adolescence and adulthood using the FFQs.
Statistical analysis
Adolescent and adult lifestyle and dietary scores were categorised into quintiles. Missing values in covariates were carried forward from the previous questionnaire cycles. We generated a new dataset for each questionnaire cycle when participants reported an endoscopy. Thus, participants with multiple endoscopies during follow-up could provide multiple records. Once polyp(s) were diagnosed, the participant was censored. In addition, to best represent long-term adult risk factors, we calculated cumulatively updated WCRF/AICR scores and other nutrient intakes by averaging the available variables up to the start of the 2-year interval prior to the most recent endoscopy. To handle individuals with multiple endoscopies and time-varying variables efficiently, the Andersen-Gill data structure was used [38].
Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using logistic regression for clustered data (SAS PROC GENMOD with REPEATED statement), where each participant represented a cluster. To assess the association of adolescent WCRF/AICR lifestyle score with CRC precursor risk, we constructed three multivariable models with adjustment for various potential confounders during both adolescence and adulthood [26]. Model 1 included age, time period of endoscopy, time since the most recent endoscopy, number of endoscopies and reason for endoscopy. Model 2 was additionally adjusted for family history of CRC, personal history of diabetes, ever smoking before age 20, current smoking, menopausal status, current aspirin use, current NSAIDs use, adult height, total intake of folate, vitamin D and calcium in adolescence. Model 3 was additionally adjusted for covariates in adulthood, including cumulative total intake of folate, vitamin D and calcium and adult WCRF/AICR lifestyle score. We also examined the associations of adolescent WCRF/AICR dietary score with polyps, for which Models 2 and 3 were additionally adjusted for adolescent WCRF/AICR adiposity and physical activity scores. To further investigate the different associations of lifetime risk factors between early and later life, similar analysis for adult WCRF/AICR lifestyle and dietary scores was conducted with adjustment for potential confounders during both adolescence and adulthood.
Tests for trend were performed, using a median of each quintile of scores as a continuous variable with the Wald test to assess statistical significance. Stratified analyses were performed to examine whether associations varied across strata of known risk factors for CRC precursors, including age (<50/≥50), family history of CRC (yes/no) [9, 39] and reason for endoscopy (screening/symptoms). In addition, considering that adiposity may be on the causal pathway between diet, physical activity and CRC precursors, we also conducted sensitivity analysis without adjusting for adult adiposity score.
We further categorised the adolescent and adult WCRF/AICR scores into high- versus low-score group, using the corresponding medians, and examined the joint associations of adolescent and adult scores with the risk of CRC precursors. Within the same population, another joint analysis was conducted for early-onset cases, which were defined as CRC precursors diagnosed before age 50. All tests were two-sided with P < 0.005 considered statistically significant and with 0.005 ≤ P < 0.05 considered suggestively significant [40]. All analyses were performed using SAS 9.4 (SAS Institute).
Results
During follow-up (1998–2015), 4985 women were diagnosed with at least one colorectal polyp, of whom 3036 had at least one adenoma (544 high-risk adenomas, and 2328 proximal, 2264 distal, 1331 rectal), and 2660 at least one serrated lesion (337 large, serrated lesions). The mean age at diagnosis was 51.9 ± 5.2 years, with 35.7% of cases diagnosed before age 50. Participant characteristics by quintiles of adolescent and adult WCRF/AICR lifestyle scores were shown in Table 1. Compared to participants in the lowest quintile of adolescent and adult WCRF/AICR scores, those in the highest quintile were less likely to be current smokers, have diabetes, use aspirin and NSAIDs and have undergone endoscopy for symptoms. For the same comparison, they tended to have a higher intake of folate, vitamin D and calcium during both adolescence and adulthood and were more likely to be current multivitamin users. The distribution of family history of CRC and menopausal status was comparable across the quintiles.
Table 1.
Baseline characteristics of participants according to WCRF/AICR lifestyle scores during adolescence and adulthood in the Nurses’ Health Study II, 1998–2015a.
| Adolescent lifestyle score | Adult lifestyle score | |||||
|---|---|---|---|---|---|---|
| Q1 (N = 16,732) | Q3 (N = 13,525) | Q5 (N = 15,432) | Q1 (N = 15,654) | Q3 (N = 16,334) | Q5 (N = 15,709) | |
| Score, range | <3.58 | 3.83–<4.17 | 4.58–7.00 | <3.20 | 3.75–<4.15 | 4.65–7.00 |
| Age at 1998 questionnaire return (years)b | 44 (4.5) | 45.1 (4.3) | 45.4 (4.4) | 44.7 (4.5) | 44.7 (4.4) | 45.3 (4.3) |
| 34–39, % | 17.8 | 11.7 | 11.7 | 14.5 | 14.1 | 11.3 |
| 40–44, % | 35.0 | 30.5 | 27.8 | 31.6 | 32.0 | 28.7 |
| 45–49, % | 34.0 | 38.5 | 39.1 | 36.5 | 36.8 | 39.7 |
| ≥50, % | 13.1 | 19.4 | 21.4 | 17.5 | 17.1 | 20.2 |
| Adult height (cm) | 165.2 (7) | 164.9 (6.3) | 164.6 (6.6) | 164.9 (6.7) | 164.8 (6.6) | 165 (6.5) |
| Ever smoking before age 20, % | 32.8 | 19.7 | 16.5 | 24.2 | 22.7 | 22.5 |
| Current smoker, % | 42.8 | 30.6 | 28.0 | 35.4 | 34.4 | 32.4 |
| Personal history of diabetes, % | 6.9 | 5.4 | 4.5 | 10.2 | 4.5 | 2.4 |
| Family history of colorectal cancer, % | 15.4 | 15.9 | 14.4 | 14.7 | 15.3 | 15.4 |
| Current aspirin use, % | 33.0 | 32.5 | 30.4 | 34.5 | 32.3 | 29.4 |
| Current NSAIDs use, % | 51.0 | 48.9 | 43.8 | 52.3 | 49.3 | 41.6 |
| Current multivitamins use, % | 58.8 | 59.1 | 59.2 | 53.6 | 59.9 | 64.6 |
| Premenopausal, % | 35.9 | 36.0 | 36.2 | 35.6 | 36.9 | 36.0 |
| Number of endoscopies during the study period | 2.3 (1.5) | 2.3 (1.5) | 2.3 (1.5) | 2.3 (1.5) | 2.2 (1.5) | 2.4 (1.6) |
| Time since the most recent lower endoscopy (years) | 2.3 (3.4) | 2.3 (3.4) | 2.3 (3.4) | 2.3 (3.4) | 2.3 (3.4) | 2.4 (3.4) |
| Endoscopy for symptoms or signs, % | 25.8 | 23.3 | 21.8 | 27.6 | 23.6 | 20.5 |
| WCRF/AICR lifestyle score, adolescent | 3.2 (0.3) | 4.0 (0.1) | 4.9 (0.4) | 3.8 (0.6) | 4.0 (0.6) | 4.3 (0.7) |
| WCRF/AICR dietary score, adolescent | 1.8 (0.4) | 2.3 (0.2) | 3.1 (0.4) | 2.2 (0.5) | 2.3 (0.5) | 2.5 (0.6) |
| WCRF/AICR adiposity score, adolescent | 0.7 (0.3) | 0.9 (0.2) | 1.0 (0.1) | 0.8 (0.3) | 0.9 (0.2) | 0.9 (0.2) |
| WCRF/AICR physical activity score, adolescent | 0.7 (0.2) | 0.8 (0.2) | 0.9 (0.1) | 0.8 (0.2) | 0.8 (0.2) | 0.8 (0.2) |
| Nutrient intake during adolescence | ||||||
| Folate (g/d) | 294 (82) | 319 (93) | 362 (120) | 291 (80) | 321 (94) | 355 (111) |
| Vitamin D (IU/d) | 314 (161) | 344 (184) | 404 (234) | 318 (162) | 350 (187) | 378 (210) |
| Calcium (mg/d) | 999 (297) | 1068 (320) | 1209 (411) | 1022 (327) | 1078 (344) | 1142 (355) |
| WCRF/AICR lifestyle score, adult cumulative average | 3.7 (0.8) | 3.9 (0.8) | 4.2 (0.8) | 2.7 (0.4) | 3.9 (0.1) | 5.1 (0.4) |
| WCRF/AICR dietary score, adult cumulative average | 2.4 (0.6) | 2.5 (0.6) | 2.8 (0.6) | 1.9 (0.4) | 2.5 (0.4) | 3.3 (0.4) |
| WCRF/AICR adiposity score, adult cumulative average | 0.6 (0.4) | 0.7 (0.3) | 0.7 (0.3) | 0.4 (0.4) | 0.7 (0.3) | 0.9 (0.2) |
| WCRF/AICR physical activity score, adult cumulative average | 0.7 (0.3) | 0.7 (0.3) | 0.8 (0.3) | 0.4 (0.3) | 0.8 (0.3) | 0.9 (0.1) |
| Nutrient intake during adulthood | ||||||
| Folate (g/d) | 575 (208) | 590 (204) | 622 (215) | 499 (182) | 590 (190) | 694 (220) |
| Vitamin D (IU/d) | 446 (222) | 461 (222) | 491 (236) | 382 (199) | 459 (212) | 545 (247) |
| Calcium (mg/d) | 1213 (401) | 1256 (405) | 1328 (441) | 1068 (353) | 1247 (384) | 1463 (439) |
IU international unit, N number of endoscopies, NSAIDs non-steroidal anti-inflammatory drugs, Q quintile, WCRF/AICR World Cancer Research Fund/American Institute for Cancer Research.
aValues are means (standard deviations) or percentages and are standardised to the age distribution of the study population. Values of polychotomous variables may not sum to 100% due to rounding.
bValue is not age-adjusted.
Adolescent WCRF/AICR scores and CRC precursor risk
After adjusting for both adolescent and adult confounders, no significant association was observed between per unit increase in adolescent lifestyle score and risk of total adenoma (OR = 0.98, 95% CI: 0.91–1.05, Ptrend = 0.57) (Table 2). We did not find associations of per unit increase in adolescent WCRF/AICR lifestyle score with high-risk adenoma (OR = 0.95, 95% CI: 0.80–1.13, Ptrend = 0.57), total serrated lesions (OR = 1.02, 95% CI: 0.95–1.11, Ptrend = 0.56) and large serrated lesions (OR = 1.06, 95% CI: 0.85–1.32, Ptrend = 0.61). In addition, there was no association between adolescent WCRF/AICR dietary score and risk of total adenoma and serrated lesion. Detailed results by subsites and subtypes of CRC precursors are presented in Supplementary Tables 3 and 4. Models 1 and 2 showed similar results to fully adjusted Model 3, indicating that the null results for adolescent exposures were apparent before adjusting for adult exposures.
Table 2.
WCRF/AICR lifestyle and dietary scores during adolescence and risk of colorectal cancer precursors in the Nurses’ Health Study II, 1998–2015.
| Outcome | Q1 (<3.58) | Q2 (3.58–<3.83) | Q3 (3.83–<4.17) | Q4 (4.17–<4.58) | Q5 (4.58–7.00) | Ptrend | Per unit increase |
|---|---|---|---|---|---|---|---|
| Adolescent WCRF/AICR lifestyle score | |||||||
| Total adenoma | |||||||
| Cases/controls (N) | 664/16,068 | 651/15,939 | 534/12,991 | 608/15,829 | 579/14,853 | ||
| Fully adjusted model | 1 (ref) | 0.99 (0.88–1.11) | 1.01 (0.89–1.13) | 0.95 (0.85–1.07) | 0.98 (0.87–1.11) | 0.566 | 0.98 (0.91–1.05) |
| High-risk adenoma | |||||||
| Cases/controls (N) | 119/15,635 | 126/15,523 | 93/12,660 | 98/15,447 | 108/14,466 | ||
| Fully adjusted model | 1 (ref) | 1.05 (0.82–1.36) | 0.96 (0.73–1.26) | 0.84 (0.64–1.10) | 1.00 (0.76–1.32) | 0.568 | 0.95 (0.80–1.13) |
| Total serrated lesion | |||||||
| Cases/controls (N) | 596/15,635 | 562/15,523 | 450/12,660 | 531/15,447 | 521/14,466 | ||
| Fully adjusted model | 1 (ref) | 0.98 (0.87–1.11) | 1.00 (0.88–1.13) | 0.98 (0.86–1.10) | 1.05 (0.92–1.19) | 0.564 | 1.02 (0.95–1.11) |
| Large serrated lesion | |||||||
| Cases/controls (N) | 81/15,635 | 71/15,523 | 54/12,660 | 64/15,447 | 67/14,466 | ||
| Fully adjusted model | 1 (ref) | 0.95 (0.68–1.31) | 0.95 (0.67–1.35) | 0.94 (0.67–1.32) | 1.12 (0.79–1.59) | 0.610 | 1.06 (0.85–1.32) |
| Adolescent WCRF/AICR dietary score | |||||||
| Total adenoma | |||||||
| Cases/controls (N) | 583/14,510 | 684/16,597 | 649/15,488 | 564/15,055 | 556/14,030 | ||
| Fully adjusted model | 1 (ref) | 1.01 (0.90–1.13) | 1.04 (0.93–1.17) | 0.95 (0.84–1.08) | 1.01 (0.89–1.15) | 0.944 | 1.00 (0.91–1.09) |
| High-risk adenoma | |||||||
| Cases/controls (N) | 100/14,126 | 130/16,153 | 116/15,083 | 99/14,717 | 99/13,652 | ||
| Fully adjusted model | 1 (ref) | 1.10 (0.84–1.43) | 1.07 (0.82–1.40) | 0.96 (0.72–1.28) | 1.03 (0.77–1.39) | 0.900 | 0.99 (0.81–1.20) |
| Total serrated lesion | |||||||
| Cases/controls (N) | 528/14,126 | 616/16,153 | 545/15,083 | 470/14,717 | 501/13,652 | ||
| Fully adjusted model | 1 (ref) | 1.05 (0.93–1.18) | 1.02 (0.90–1.16) | 0.92 (0.81–1.05) | 1.07 (0.93–1.22) | 0.766 | 1.01 (0.92–1.11) |
| Large serrated lesion | |||||||
| Cases/controls (N) | 63/14,126 | 86/16,153 | 61/15,083 | 62/14,717 | 65/13,652 | ||
| Fully adjusted model | 1 (ref) | 1.31 (0.94–1.83) | 1.06 (0.74–1.53) | 1.16 (0.81–1.67) | 1.35 (0.93–1.96) | 0.214 | 1.17 (0.91–1.49) |
N number of endoscopies, Q quintile, WCRF/AICR World Cancer Research Fund/American Institute for Cancer Research.
Fully adjusted model for adolescent lifestyle score: adjusted for age (continuous), time period of endoscopy (continuous), time since the most recent endoscopy (continuous), number of endoscopies (continuous), reason for endoscopy (screening/symptoms), family history of CRC (yes/no), history of diabetes (yes/no), ever smoking before 20 years of age (yes/no), current smoking (yes/no), menopausal status (premenopausal/postmenopausal), current aspirin use (yes/no), current NSAIDs use (yes/no), adult height (cm), adolescent folate intake (g/d), calcium intake (mg/d) and vitamin D intake (IU/d), adult cumulative average folate intake (g/d), calcium intake (mg/d) and vitamin D intake (IU/d) and adult cumulative average WCRF/AICR lifestyle score.
Fully adjusted model for adolescent dietary score: adjusted for age (continuous), time period of endoscopy (continuous), time since the most recent endoscopy (continuous), number of endoscopies (continuous), reason for endoscopy (screening/symptoms), family history of CRC (yes/no), history of diabetes (yes/no), ever smoking before 20 years of age (yes/no), current smoking (yes/no), menopausal status (premenopausal/postmenopausal), current aspirin use (yes/no), current NSAIDs use (yes/no), adult height (cm), adolescent folate intake (g/d), calcium intake (mg/d) and vitamin D intake (IU/d), adolescent WCRF/AICR adiposity score and physical activity score, adult cumulative average folate intake (g/d), calcium intake (mg/d) and vitamin D intake (IU/d) and adult cumulative average WCRF/AICR dietary score.
High-risk adenoma: large (≥1 cm), any villous histology, high-grade dysplasia or more than 3 adenomas.
Large serrated lesion: large (≥1 cm).
P < 0.005 is considered statistically significant and 0.005 ≤ P < 0.05 is considered suggestively significant.
Subgroup analysis in participants with or without CRC family history, and participants undergoing endoscopy for screening versus symptoms also yielded nonsignificant estimates (Supplementary Table 5). As a sensitivity analysis, we modeled the adolescent lifestyle WCRF/AICR score without adjusting for adult adiposity score, and the results were similar to the primary, nonsignificant findings (Supplementary Table 6).
Adult WCRF/AICR scores and CRC precursor risk
We observed statistically significant inverse associations between adult WCRF/AICR lifestyle score and risk of CRC precursors. For total adenoma, the multivariable OR was 0.92 (95% CI: 0.87–0.97, Ptrend = 0.002) per unit increase in adult lifestyle score, while the association was not significant in high-risk adenoma (OR = 0.96, 95% CI: 0.84–1.09, Ptrend = 0.51) (Table 3). The multivariable OR was 0.86 (95% CI: 0.81–0.92, Ptrend < 0.001) for total serrated lesion. The association was stronger for large serrated lesion (OR = 0.75, 95% CI: 0.63–0.88, Ptrend = 0.001). We did not find significant associations between adult dietary score and risk of CRC precursors. Results by subsites and subtypes of CRC precursors are presented in Supplementary Tables 7 and 8. Similarly, results from Models 1 and 2 were largely comparable to those from fully adjusted Model 3.
Table 3.
WCRF/AICR lifestyle and dietary scores during adulthood and risk of colorectal cancer precursors in the Nurses’ Health Study II, 1998–2015.
| Outcome | Q1 (<3.58) | Q2 (3.58–<3.83) | Q3 (3.83–<4.17) | Q4 (4.17–<4.58) | Q5 (4.58–7.00) | Ptrend | Per unit increase |
|---|---|---|---|---|---|---|---|
| Adult WCRF/AICR lifestyle score | |||||||
| Total adenoma | |||||||
| Cases/controls (N) | 730/15,189 | 602/14,819 | 553/15,059 | 586/15,469 | 565/15,144 | ||
| Fully adjusted model | 1 (ref) | 0.85 (0.76–0.96) | 0.78 (0.69–0.87) | 0.82 (0.73–0.92) | 0.83 (0.74–0.95) | 0.002 | 0.92 (0.87–0.97) |
| High-risk adenoma | |||||||
| Cases/controls (N) | 127/14,741 | 118/14,388 | 95/14,715 | 98/15,095 | 106/14,792 | ||
| Fully adjusted model | 1 (ref) | 0.99 (0.77–1.28) | 0.79 (0.60–1.04) | 0.83 (0.63–1.10) | 0.98 (0.74–1.30) | 0.511 | 0.96 (0.84–1.09) |
| Total serrated lesion | |||||||
| Cases/controls (N) | 640/14,741 | 554/14,388 | 473/14,715 | 512/15,095 | 481/14,792 | ||
| Fully adjusted model | 1 (ref) | 0.88 (0.78–0.99) | 0.72 (0.64–0.82) | 0.77 (0.68–0.88) | 0.74 (0.65–0.85) | <0.001 | 0.86 (0.81–0.92) |
| Large serrated lesion | |||||||
| Cases/controls (N) | 92/14,741 | 76/14,388 | 56/14,715 | 55/15,095 | 58/14,792 | ||
| Fully adjusted model | 1 (ref) | 0.82 (0.60–1.11) | 0.57 (0.41–0.81) | 0.55 (0.39–0.78) | 0.59 (0.41–0.85) | 0.001 | 0.75 (0.63–0.88) |
| Adult WCRF/AICR dietary score | |||||||
| Total adenoma | |||||||
| Cases/controls (N) | 662/14,720 | 653/15,448 | 592/15,277 | 570/15,231 | 559/15,004 | ||
| Fully adjusted model | 1 (ref) | 0.96 (0.86–1.08) | 0.89 (0.79–1.01) | 0.89 (0.79–1.01) | 0.93 (0.82–1.06) | 0.161 | 0.95 (0.87–1.02) |
| High-risk adenoma | |||||||
| Cases/controls (N) | 132/14,312 | 100/15,038 | 109/14,889 | 99/14,841 | 104/14,651 | ||
| Fully adjusted model | 1 (ref) | 0.75 (0.58–0.99) | 0.86 (0.66–1.12) | 0.82 (0.62–1.09) | 0.94 (0.70–1.26) | 0.815 | 0.98 (0.81–1.18) |
| Total serrated lesion | |||||||
| Cases/controls (N) | 576/14,312 | 552/15,038 | 520/14,889 | 534/14,841 | 478/14,651 | ||
| Fully adjusted model | 1 (ref) | 0.91 (0.81–1.03) | 0.87 (0.77–0.99) | 0.92 (0.81–1.05) | 0.86 (0.74–0.98) | 0.057 | 0.92 (0.85–1.00) |
| Large serrated lesion | |||||||
| Cases/controls (N) | 86/14,312 | 67/15,038 | 58/14,889 | 69/14,841 | 57/14,651 | ||
| Fully adjusted model | 1 (ref) | 0.74 (0.54–1.02) | 0.65 (0.46–0.91) | 0.79 (0.56–1.11) | 0.67 (0.46–0.97) | 0.072 | 0.81 (0.64–1.02) |
N number of endoscopies, Q quintile, WCRF/AICR World Cancer Research Fund/American Institute for Cancer Research.
Fully adjusted model for adult lifestyle score: adjusted for age, time period of endoscopy, time since the most recent endoscopy, number of endoscopies, reason for endoscopy, family history of CRC, history of diabetes, ever smoking before 20 years of age, current smoking, menopausal status, current aspirin use, current NSAIDs use, adult height, adolescent folate intake, calcium intake and vitamin D intake, adolescent WCRF/AICR lifestyle score and adult cumulative average folate intake, calcium intake and vitamin D intake.
Fully adjusted model for adult dietary score: adjusted for age, time period of endoscopy, time since the most recent endoscopy, number of endoscopies, reason for endoscopy, family history of CRC, history of diabetes, ever smoking before 20 years of age, current smoking, menopausal status, current aspirin use, current NSAIDs use, adult height, adolescent folate intake, calcium intake and vitamin D intake, adolescent WCRF/AICR dietary score and adult cumulative average folate intake, calcium intake and vitamin D intake.
High-risk adenoma: large (≥1 cm), any villous histology, high-grade dysplasia or more than 3 adenomas.
Large serrated lesion: large (≥1 cm).
P < 0.005 is considered statistically significant, and 0.005 ≤ P < 0.05 is considered suggestively significant.
Joint analysis of adolescent and adult WCRF/AICR scores
Compared with women who had a low WCRF/AICR lifestyle score in both life stages, women with a high lifestyle score during adolescence but a low lifestyle score during adulthood had a lower risk of total adenoma (multivariable OR = 0.89, 95% CI: 0.81–0.99) (Table 4 and Figs. 1 and 2). Women with a high lifestyle score in both life stages had a lower risk of total adenoma (OR = 0.87, 95% CI: 0.79–0.97), total serrated lesion (OR = 0.83, 95% CI: 0.74–0.93) and large serrated lesion (OR = 0.68, 95% CI: 0.50–0.92). Women with a low lifestyle score during adolescence but a high lifestyle score during adulthood also had a lower risk of total adenoma (OR = 0.82, 95% CI: 0.73–0.92), total serrated lesion (OR = 0.79, 95% CI: 0.70–0.89) and large serrated lesion (OR = 0.61, 95% CI: 0.43–0.85). Detailed results of joint analysis for the WCRF/AICR lifestyle and dietary scores are presented in Supplementary Tables 9 and 10.
Table 4.
Joint analysis of WCRF/AICR lifestyle and dietary scores during adolescence and adulthood with risk of colorectal cancer precursors in the Nurses’ Health Study II, 1998–2015.
| Adolescent/adult WCRF/AICR lifestyle score | ||||
|---|---|---|---|---|
| Outcome | Low/low | High/low | Low/high | High/high |
| Total adenoma | 918/20,250 | 701/17,334 | 515/14,443 | 902/23,653 |
| 1 (ref) | 0.89 (0.81-0.99) | 0.82 (0.73–0.92) | 0.87 (0.79–0.97) | |
| High-risk adenoma | 166/19,678 | 125/16,850 | 96/14,102 | 157/23,101 |
| 1 (ref) | 0.88 (0.70–1.12) | 0.89 (0.69–1.15) | 0.87 (0.69–1.10) | |
| Proximal adenoma | 688/19,678 | 533/16,850 | 401/14,102 | 706/23,101 |
| 1 (ref) | 0.89 (0.79–1.00) | 0.80 (0.71–0.91) | 0.85 (0.76–0.95) | |
| Distal adenoma | 737/19,678 | 533/16,850 | 371/14,102 | 623/23,101 |
| 1 (ref) | 0.86 (0.77–0.97) | 0.72 (0.63–0.82) | 0.76 (0.67–0.85) | |
| Rectal adenoma | 369/19,678 | 357/16,850 | 227/14,102 | 378/23,101 |
| 1 (ref) | 1.20 (1.03–1.40) | 0.91 (0.76–1.08) | 0.98 (0.84–1.15) | |
| Total serrated lesion | 794/19,678 | 654/16,850 | 454/14,102 | 758/23,101 |
| 1 (ref) | 0.99 (0.89–1.11) | 0.79 (0.70–0.89) | 0.83 (0.74–0.93) | |
| Large serrated lesion | 112/19,678 | 87/16,850 | 51/14,102 | 87/23,101 |
| 1 (ref) | 0.97 (0.73–1.30) | 0.61 (0.43–0.85) | 0.68 (0.50–0.92) | |
| Adolescent/adult WCRF/AICR dietary score | ||||
|---|---|---|---|---|
| Outcome | Low/low | High/low | Low/high | High/high |
| Total adenoma | 906/20,664 | 639/14,937 | 596/16,049 | 895/24,030 |
| 1 (ref) | 0.97 (0.88–1.08) | 0.92 (0.82–1.02) | 0.92 (0.83–1.01) | |
| High-risk adenoma | 161/20,082 | 113/14,548 | 109/15,659 | 161/23,442 |
| 1 (ref) | 0.96 (0.75–1.22) | 0.99 (0.77–1.27) | 0.96 (0.76–1.22) | |
| Proximal adenoma | 683/20,082 | 473/14,548 | 457/15,659 | 715/23,442 |
| 1 (ref) | 0.95 (0.84–1.07) | 0.89 (0.78–1.01) | 0.92 (0.82–1.03) | |
| Distal adenoma | 713/20,082 | 452/14,548 | 458/15,659 | 641/23,442 |
| 1 (ref) | 0.89 (0.79–1.01) | 0.90 (0.79–1.02) | 0.86 (0.76–0.96) | |
| Rectal adenoma | 385/20,082 | 305/14,548 | 247/15,659 | 394/23,442 |
| 1 (ref) | 1.14 (0.98–1.33) | 0.91 (0.76–1.07) | 1.02 (0.88–1.19) | |
| Total serrated lesion | 796/20,082 | 537/14,548 | 540/15,659 | 787/23,442 |
| 1 (ref) | 0.95 (0.85–1.07) | 0.91 (0.81–1.02) | 0.91 (0.82–1.02) | |
| Large serrated lesion | 102/20,082 | 70/14,548 | 68/15,659 | 97/23,442 |
| 1 (ref) | 1.02 (0.75–1.39) | 0.93 (0.67–1.28) | 0.95 (0.70–1.27) | |
WCRF/AICR World Cancer Research Fund/American Institute for Cancer Research.
Odds ratios are based on multivariable models adjusting for covariates listed in the footnote of Figs. 1 and 2.
High-risk adenoma: large (≥1 cm), any villous histology, high-grade dysplasia or more than 3 adenomas.
Large serrated lesion: large (≥1 cm).
The median for adolescent lifestyle score is 4.00, and adult lifestyle score is 3.95.
The median for adolescent dietary score is 2.33, and adult dietary score is 2.
Fig. 1. Joint analysis of WCRF/AICR lifestyle scores during adolescence and adulthood with risk of colorectal cancer precursors in the Nurses’ Health Study II, 1998–2015.
Medians were used to define high versus low WCRF/AICR lifestyle scores in adolescence and adulthood. Data were adjusted for age, time period of endoscopy, time since the most recent endoscopy, number of endoscopies, reason for endoscopy, family history of CRC, history of diabetes, ever smoking before 20 years of age, current smoking, menopausal status, current aspirin use, current NSAIDs use, adult height, adolescent folate intake, calcium intake and vitamin D intake and adult cumulative average folate intake, calcium intake and vitamin D intake.
Fig. 2. Joint analysis of WCRF/AICR dietary scores during adolescent and adulthood with risk of colorectal cancer precursors in the Nurses’ Health Study II, 1998–2015.
Medians were used to define high versus low WCRF/AICR dietary scores in adolescence and adulthood. Data were adjusted for age, time period of endoscopy, time since the most recent endoscopy, number of endoscopies, reason for endoscopy, family history of CRC, history of diabetes, ever smoking before 20 years of age, current smoking, menopausal status, current aspirin use, current NSAIDs use, adult height, adolescent folate intake, calcium intake and vitamin D intake, adult cumulative average folate intake, calcium intake and vitamin D intake, adolescent adiposity score and physical activity score and adult cumulative average WCRF/AICR adiposity score and physical activity score.
Adolescent and adult WCRF/AICR scores and early-onset polyps
We further stratified colorectal polyp cases into two groups by age at diagnosis: <50 versus ≥50. The results showed nonsignificant associations between adolescent WCRF/AICR lifestyle score and risk of CRC precursors in both age groups (Supplementary Table 5). A suggestively lower risk of high-risk adenoma was observed for the WCRF/AICR lifestyle score in those aged <50 (multivariable OR = 0.71; 95% CI: 0.52–0.98, Ptrend = 0.035). We also investigated joint associations of WCRF/AICR lifestyle scores in adolescence and adulthood with risk of early-onset CRC precursors (Supplementary Table 11). Compared to women who had a low WCRF/AICR lifestyle score in both life stages, high lifestyle scores in both life stages were associated with a lower risk of early-onset CRC precursors, such as distal adenoma and large serrated lesion. Detailed results of joint analyses for the WCRF/AICR dietary score and early-onset polyps are presented in Supplementary Table 12. Overall, there were no or very weak associations between WCRF/AICR dietary score and early-onset polyps.
Discussion
In this large cohort of women with an average age of 45 at baseline, a lifestyle score based on the 2018 WCRF/AICR cancer prevention recommendations during adulthood was associated with a significantly lower risk of CRC precursors, while a higher score during adolescence was not. Women who had a high WCRF/AICR lifestyle score in both life stages had a lower risk of CRC precursors, mainly driven by the adult lifestyle score. Our findings indicate that the WCRF/AICR operation scores might not capture emerging adolescent lifestyle factors relevant to CRC development [14, 15, 41–43]. The current recommendations and corresponding scoring approaches are based on overall cancer risk factors established from the adult populations [28, 44] and thus possibly are less suited for adolescent populations.
The WCRF/AICR dietary score has the following limitations for examining adolescent diet and polyp risk. First, high consumption of red or processed meat during adolescence, an established CRC risk factor in adults, may be not similarly associated with risk of CRC precursors. In a large prospective study that used a 37-item FFQ to ascertain dietary intake at age 12–13, no significant associations were observed between red or processed meat intake during adolescence and risk of colon or rectal cancer, but a significantly higher risk was observed in participants who had high intakes during both adolescence and adulthood [45]. In the NHSII, no significant association between total red meat intake during high school and the risk of colorectal adenomas was observed, but poultry intake (not accounted for in the WCRF/AICR dietary score) was associated with a lower risk of total colorectal adenomas [41]. Moreover, the WCRF/AICR dietary score did not consider dairy and calcium intake, which have been associated with lower risk of colorectal adenoma or CRC in some studies [42, 46]. Usually, adolescent girls do not consume much alcohol [47, 48], so alcohol intake may not contribute importantly to the WCRF/AICR scores. In addition, consumption of sugar-sweetened beverages and sugar, which tends to be high in adolescence [49, 50], may be a more important risk factor for CRC precursors [14] than is adult intake.
To estimate the WCRF/AICR adiposity score, we mainly used BMI and two waist circumference measures following the same criteria for adolescence and adulthood. However, the high-school period of our study population was mostly before 1975 when the global prevalence of childhood and adolescent obesity was much lower [51]. The BMI cutoff for adolescent obesity should be lower than 30 kg/m2, which is the common cutoff for defining adult obesity. Future studies should consider more tailored measures and criteria when deriving the adolescent adiposity score. For instance, a study using a 9-level pictogram (1: most lean body shape, 9: most overweight body shape) found that greater body fatness during childhood was associated with increased risk of distal colon adenoma later in life, but overweight at age 20 was not associated with colorectal adenoma risk [52].
A previous study in this cohort [15] suggested that higher physical activity in adolescence may lower the risk of colorectal adenoma later in life, but the estimates were modest and mainly restricted to proximal adenomas, whereas being physically active during both adolescence and adulthood was more robustly associated with lower risk of adenoma. This finding suggested consistent physical activity throughout the life course may prevent colorectal polyps more effectively than physical activity in early life only. Levels of physical activity were relatively high in this cohort and the standard WCRF/AICR cut points may not have optimally captured this extent in our population.
We were able to examine CRC precursors diagnosed before the age of 50. Although the results were not entirely consistent across all precursors and some may have been driven by chance, there was some suggestion that adherence to the adolescent lifestyle score may have been associated with early-onset high-risk adenomas. These findings need to be confirmed, but a potential explanation is that the timing of these early-onset polyps may be closer to adolescent exposures, whereas later-onset polyps are more closely associated with later exposures. Possibly, adenomas that progressed to high-risk stage before age 50 may have been initiated relatively early in life.
This study has several strengths. To our knowledge, this study is the first prospective investigation of the association of adherence to the 2018 WCRF/AICR recommendations across different life stages with risk of colorectal polyps. The large sample size of polyp cases enabled assessment by subtypes and subsites, and stratified analyses including by age with sufficient power. The age range of the NHSII participants overlapped with the birth cohorts that have experienced recent increases in early-onset colorectal cancer. Participant information was validated and obtained throughout different life stages, enabling us to examine both independent and joint associations of the WCRF/AICR lifestyle and dietary scores in adolescence and adulthood with risk of CRC precursors.
There are some limitations that deserve further attention. First, there could be substantial measurement error in exposure assessment, since adolescent risk factors were recalled in 1998, years or decades after high school. However, the reasonable reproducibility and validity of the HS-FFQ supported the ability to rank individuals adequately; thus, any errors in exposure measurement should be nondifferential to case status, which generally attenuates risk estimates toward the null [31, 53]. Notably, the HS-FFQ shows robust associations with breast cancer, for which adolescent exposures are likely to be important [54–56]. Second, although our analyses considered both the established and potential lifestyle and dietary confounders across multiple life stages, unmeasured or residual confounding due to imperfect adjustment cannot be ruled out. Third, we had insufficient information to distinguish hyperplastic polyps from sessile serrated adenoma/polyp and traditional serrated adenoma, because diagnostic criteria for serrated lesions have changed over time. Endoscopies in this study were performed over a time period when standardised diagnostic criteria for serrated lesions were generally not routinely applied by pathologists [37]. Finally, the study population was limited to US female nurses, and thus the results may not be generalisable to other populations, especially males. However, the cumulative lifetime risk of CRC is similar between men and women, and CRC incidence rates in men and women younger than age 45 are very comparable [57].
Our study has several implications for cancer prevention and relevant research. First, more studies in the future are justified to investigate the long-term association of early-life exposures with CRC development and elucidate the causes of increasing CRC incidence in the young population [4]. Second, adolescent-specific, tailored cancer prevention recommendations and scoring methods should be developed. More research is needed to serve its evidence base. Third, the adult population is still recommended to maintain a healthy lifestyle consistent with the recommendations, which are beneficial for both CRC prevention [28] and survival [44]. Fourth, even if the aetiologically relevant period for some exposures is in adulthood, behaviours tend to track over the life course, so encouraging healthy lifestyles during early years is desirable.
In conclusion, higher WCRF/AICR lifestyle and dietary scores in adulthood, but not in adolescence, were associated with a lower risk of CRC precursors. Our findings suggest the 2018 WCRF/AICR cancer prevention recommendations mainly target the adult population but may not be specific enough for exposures relevant for adolescents. Future prospective studies focusing on early-life exposures and the development of valid scoring approaches for adolescence are warranted to address the increasing CRC rates among the young population.
Supplementary information
Acknowledgements
The authors would like to acknowledge the contribution to this study from central cancer registries supported through the Centers for Disease Control and Prevention’s National Program of Cancer Registries (NPCR) and/or the National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) Program. Central registries may also be supported by state agencies, universities, and cancer centres. Participating central cancer registries include the following: Alabama, Alaska, Arizona, Arkansas, California, Colorado, Connecticut, Delaware, Florida, Georgia, Hawaii, Idaho, Indiana, Iowa, Kentucky, Louisiana, Massachusetts, Maine, Maryland, Michigan, Mississippi, Montana, Nebraska, Nevada, New Hampshire, New Jersey, New Mexico, New York, North Carolina, North Dakota, Ohio, Oklahoma, Oregon, Pennsylvania, Puerto Rico, Rhode Island, Seattle SEER Registry, South Carolina, Tennessee, Texas, Utah, Virginia, West Virginia, Wyoming.
Author contributions
SZ, RS and PW had full access to all the data and take responsibility for the integrity of the data and accuracy of the data analysis. Study concept and design: EG, JH, YC and KW. Acquisition, analysis or interpretation of the data: SZ, JH and EG. Drafting of the manuscript: SZ, JH and EG. Critical revision of the manuscript for important intellectual content: all authors. Statistical analysis: SZ.
Funding
This work was supported by the National Institutes of Health (NHSII infrastructure grant of U01 CA176726 and R37 CA246175 to Yin Cao). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. JH was supported by a research grant from the Ottogi Ham Taiho Foundation.
Data availability
Further information including the procedures to obtain and access data from the Nurses’ Health Study is described at https://www.nurseshealthstudy.org/researchers (e-mail: nhsaccess@channing.harvard.edu).
Competing interests
The authors declare no competing interests.
Ethics approval and consent to participate
The study protocol was approved by the institutional review boards of the Brigham and Women’s Hospital and Harvard T.H. Chan School of Public Health, and those of participating registries as required. Completion of the questionnaire was considered to imply informed consent.
Consent for publication
Not applicable.
Footnotes
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary information
The online version contains supplementary material available at 10.1038/s41416-023-02255-5.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Data Availability Statement
Further information including the procedures to obtain and access data from the Nurses’ Health Study is described at https://www.nurseshealthstudy.org/researchers (e-mail: nhsaccess@channing.harvard.edu).