Hanyuda a Et Al. BMI and Risk of Colorectal Cancer by Tumor Differentiation. Page1

Hanyuda A et al. BMI and risk of colorectal cancer by tumor differentiation. Page1

Supplementary tables

Submission toEuropean Journal of Epidemiology

Article title

Body mass index and risk of colorectal carcinoma subtypes classified by tumor differentiation status

Co-corresponding authors:

Shuji Ogino, MD, PhD, MS

Program in MPE Molecular Pathological Epidemiology

Department of Pathology, Brigham and Women's Hospital

450 Brookline Ave., Room M422, Boston, MA 02215 USA

Telephone: +1-617-632-1972; Fax: +1-617-582-8558

Email:

Reiko Nishihara, PhD

Program in MPE Molecular Pathological Epidemiology

Department of Pathology, Brigham and Women's Hospital

450 Brookline Ave., Room M422, Boston, MA 02215 USA

Telephone: +1-617-432-1838; Fax: +1-617-432-2435

E-mail:

Supplementary tables

Table S1. Age-standardized characteristics of participants with and without tissue data in the Nurses' Health Study (NHS) and the Health Professionals Follow-up Study (HPFS)*
Characteristics / Women (NHS) / Men (HPFS)
Cases with tissue data / Cases without tissue data / Cases with tissue data / Cases without tissue data
Cases, No. / 860 / 885 / 668 / 561
Age, year / 67.4 (8.5) / 66.5 (9.9) / 71.3 (9.1) / 70.2 (9.6)
Family history of colorectal cancer, % / 20.2 / 19.0 / 18.4 / 16.9
History of diabetes, % / 9.8 / 10.5 / 10.6 / 12.6
Body mass index, kg/m² / 26.2 (4.7) / 26.1 (5.1) / 26.2 (3.2) / 26.3 (3.4)
Postmenopause, % / 91.6 / 91.9 / - / -
Current hormone therapy use, % / 23.1 / 17.8 / - / -
History of colonoscopy/sigmoidoscopy, % / 36.4 / 32.6 / 45.5 / 44.6
Current use of multivitamin, % / 51.9 / 48.8 / 49.3 / 45.2
Regular use of nonsteroidal anti-inflammatory drugs(NSAIDs), % / 20.0 / 13.1 / 14.9 / 11.8
Regular use of aspirins, % / 30.7 / 33.2 / 44.8 / 45.2
Pack-year among ever smokers / 29.1 (22.9) / 30.2 (23.8) / 28.3 (20.1) / 28.6 (22.1)
Total calorie, kcal/day / 1694 (425) / 1659 (449) / 1972 (535) / 1951 (580)
Alcohol intake, g/day / 6.4 (9.7) / 6.7 (10.4) / 14.2 (16.7) / 12.1 (14.2)
Physical activity, metabolic equivalent task score (METS)-hours/week / 15.9 (17.1) / 15.4 (16.2) / 29.3 (25.2) / 26.1 (25.2)
Red and processed meat, servings/week / 6.2 (3.1) / 6.6 (4.0) / 6.7 (4.3) / 6.5 (4.3)
Calcium, mg/day / 931 (346) / 900 (342) / 925 (383) / 921 (415)
Folate, μg/day / 424 (180) / 414 (197) / 525 (232) / 530 (244)
Alternate Healthy Eating Index (AHEI)-2010† / 46.5 (8.8) / 47.1 (9.4) / 48.2 (10.4) / 48.0 (10.0)
Disease stage, %
I / 24 / 24 / 28 / 25
II / 35 / 25 / 28 / 16
III / 27 / 25 / 29 / 21
IV / 14 / 26 / 15 / 37
Tumor location, %
Rectum / 22 / 22 / 24 / 27
Distal colon / 28 / 31 / 32 / 39
Proximal colon / 50 / 47 / 45 / 34
*Updated information throughout follow-up was used to calculate the mean (standard deviation [SD]) for continuous variables and percentage for categorical variables. All values other than age have been directly standardized to age distribution (in 5-year age group) of all the participants.
†Without alcohol intake.
AHEI, Alternate Healthy Eating Index; HPFS, Health Professionals Follow-up Study; METS, metabolic equivalent task score;NHS, Nurses’ Health Study; NSAIDs, nonsteroidal anti-inflammatory drugs.

Hanyuda A et al. BMI and risk of colorectal cancer by tumor differentiation. Page1

Table S2. The interrelationship between the subtypes based on each of the four morphological features (poorly-differentiated foci, overall tumor differentiation, mucinous differentiation, or signet ring cell component ) in the pooled cohorts, the Nurses’ Health Study (NHS) and the Health Professionals Follow-up Study (HPFS)
Poorly-differentiated foci / Overall tumor differentiation / Mucinous component / Signet ring cell component
Absent / Present / Well/moderate / Poor / Absent (0%) / 1% to 49% / ≥50% / Absent / Present
Pooled
Poorly-differentiated foci
Absent / - / - / 1069 (100%) / 0 (0%) / 650 (65%) / 269 (27%) / 79 (8%) / 1041 (97%) / 28 (3%)
Present / - / - / 288 (66%) / 149 (34%) / 215 (50%) / 131 (30%) / 84 (20%) / 290 (66%) / 147 (34%)
Overall tumor differentiation
Well/moderate / 1069 (79%) / 288 (21%) / - / - / 792 (62%) / 356 (28%) / 134 (10%) / 1250 (92%) / 116 (8%)
Poor / 0 (0%) / 149 (100%) / - / - / 74 (50%) / 44 (30%) / 29 (20%) / 90 (60%) / 59 (40%)
Mucinous component
Absent (0%) / 650 (75%) / 215 (25%) / 792 (91%) / 74 (9%) / - / - / - / 859 (98%) / 16 (2%)
1% to 49% / 269 (67%) / 131 (33%) / 356 (89%) / 44 (11%) / - / - / - / 329 (82%) / 71 (18%)
≥50% / 79 (48%) / 84 (52%) / 134 (82%) / 29 (18%) / - / - / - / 76 (46%) / 88 (54%)
Signet ring cell component
Absent / 1041 (78%) / 290 (22%) / 1250 (93%) / 90 (7%) / 859 (68%) / 329 (26%) / 76 (6%) / - / -
Present / 28 (16%) / 147 (84%) / 116 (66%) / 59 (34%) / 16 (9%) / 71 (41%) / 88 (50%) / - / -
NHS
Poorly-differentiated foci
Absent / - / - / 592 (100%) / 0 (0%) / 363 (65%) / 139 (25%) / 57 (10%) / 572 (78%) / 20 (22%)
Present / - / - / 155 (60%) / 104 (40%) / 125 (49%) / 86 (33%) / 46 (18%) / 169 (65%) / 90 (35%)
Overall tumor differentiation
Well/moderate / 592 (79%) / 155 (21%) / - / - / 437 (61%) / 189 (27%) / 87 (12%) / 681 (92%) / 69 (8%)
Poor / 0 (0%) / 104 (100%) / - / - / 51 (50%) / 36 (35%) / 16 (15%) / 63 (61%) / 41 (39%)
Mucinous component
Absent (0%) / 363 (74%) / 125 (26%) / 437 (90%) / 51 (10%) / - / - / - / 480 (98%) / 11 (2%)
1% to 49% / 139 (62%) / 86 (38%) / 189 (84%) / 36 (16%) / - / - / - / 176 (78%) / 49 (22%)
≥50% / 57 (55%) / 46 (45%) / 87 (84%) / 16 (16%) / - / - / - / 54 (52%) / 50 (48%)
Signet ring cell component
Absent / 572 (97%) / 20 (3%) / 681 (92%) / 63 (8%) / 480 (68%) / 176 (25%) / 54 (7%) / - / -
Present / 169 (65%) / 90 (35%) / 69 (63%) / 41 (37%) / 11 (10) / 49 (45%) / 50 (45%) / - / -
HPFS
Poorly-differentiated foci
Absent / - / - / 477 (100%) / 0 (0%) / 287 (65%) / 130 (30%) / 22 (5%) / 469 (98%) / 8 (2%)
Present / - / - / 133 (75%) / 45 (25%) / 90 (52%) / 45 (26%) / 38 (22%) / 121 (68%) / 57 (32%)
Overall tumor differentiation
Well/moderate / 477 (78%) / 133 (22%) / - / - / 355 (62%) / 167 (29%) / 47 (9%) / 569 (92%) / 47 (8%)
Poor / 0 (0%) / 45 (100%) / - / - / 23 (52%) / 8 (18%) / 13 (30%) / 27 (60%) / 18 (40%)
Mucinous component
Absent (0%) / 287 (76%) / 90 (24%) / 355 (94%) / 23 (6%) / - / - / - / 379 (99%) / 5 (1%)
1% to 49% / 130 (74%) / 45 (36%) / 167 (96%) / 8 (5%) / - / - / - / 153 (87%) / 22 (23%)
≥50% / 22 (37%) / 38 (64%) / 47 (78%) / 13 (22%) / - / - / - / 22 (37%) / 38 (63%)
Signet ring cell component
Absent / 469 (79%) / 121 (21%) / 569 (95%) / 27 (5%) / 379 (68%) / 153 (28%) / 22 (4%) / - / -
Present / 8 (12%) / 57 (88%) / 47 (72%) / 18 (28%) / 5 (8%) / 22 (34%) / 38 (58%) / - / -

HPFS, Health Professionals Follow-up Study;NHS, Nurses’ Health Study.

Hanyuda A et al. BMI and risk of colorectal cancer by tumor differentiation. Page1

Table S3. Body mass index and risk of colorectal cancer according to microsatellite instability (MSI)and the presence of poorly-differentiated foci stratified byMSIin the pooled cohorts
Body mass index (kg/m2) / Ptrend / Pheterogeneity‡
18.5-22.4 / 22.5-24.9 / 25.0-27.4 / 27.5-29.9 / ≥30
Microsatellite stable (MSS)
Cases, No. (n=1093) / 161 / 314 / 298 / 165 / 155
Age-adjusted HR (95% CI) / 1 [Reference] / 1.30 (1.07, 1.58) / 1.47 (1.21, 1.79) / 1.55 (1.24, 1.93) / 1.58 (1.27, 1.98) / <0.001 / 0.70
Multivariable HR (95% CI)† / 1 [Reference] / 1.30 (1.07, 1.57) / 1.45 (1.19, 1.77) / 1.51 (1.20, 1.88) / 1.55 (1.23, 1.95) / <0.001 / 0.72
MSI-high
Cases, No. (n=210) / 39 / 55 / 52 / 28 / 36
Age-adjusted HR (95% CI) / 1 [Reference] / 1.02 (0.67, 1.55) / 1.12 (0.74, 1.71) / 1.08 (0.66, 1.76) / 1.43 (0.91, 2.26) / 0.12
Multivariable HR (95% CI)† / 1 [Reference] / 1.02 (0.67, 1.54) / 1.12 (0.73, 1.71) / 1.06 (0.65, 1.73) / 1.40 (0.88, 2.22) / 0.15
MSS
Poorly-differentiated foci
Absent
Cases, No. (n=823) / 117 / 227 / 227 / 127 / 125
Age-adjusted HR (95% CI) / 1 [Reference] / 1.33 (1.06, 1.66) / 1.56 (1.24, 1.96) / 1.66 (1.29, 2.15) / 1.77 (1.38, 2.29) / <0.001
Multivariable HR (95% CI)† / 1 [Reference] / 1.32 (1.05, 1.66) / 1.54 (1.22, 1.94) / 1.62 (1.25, 2.09) / 1.73 (1.34, 2.25) / <0.001
Present
Cases, No. (n=262) / 43 / 84 / 69 / 37 / 29
Age-adjusted HR (95% CI) / 1 [Reference] / 1.22 (0.84, 1.78) / 1.25 (0.85, 1.84) / 1.25 (0.80, 1.95) / 1.08 (0.67, 1.74) / 0.77
Multivariable HR (95% CI)† / 1 [Reference] / 1.21 (0.84, 1.77) / 1.21 (0.82, 1.79) / 1.21 (0.77, 1.89) / 1.06 (0.66, 1.71) / 0.88
MSI-high
Poorly-differentiated foci
Absent
Cases, No. (n=85) / 11 / 17 / 27 / 14 / 16
Age-adjusted HR (95% CI) / 1 [Reference] / 1.05 (0.49, 2.26) / 2.09 (1.02, 4.26) / 1.90 (0.86, 4.21) / 2.27 (1.05, 4.91) / 0.008
Multivariable HR (95% CI)† / 1 [Reference] / 1.05 (0.49, 2.26) / 2.05 (1.01, 4.19) / 1.84 (0.83, 4.09) / 2.20 (1.01, 4.77) / 0.01
Present
Cases, No. (n=125) / 28 / 38 / 25 / 14 / 20
Age-adjusted HR (95% CI) / 1 [Reference] / 1.03 (0.63, 1.68) / 0.75 (0.43, 1.29) / 0.75 (0.39, 1.44) / 1.10 (0.62, 1.96) / 0.87
Multivariable HR (95% CI)† / 1 [Reference] / 1.02 (0.62, 1.67) / 0.75 (0.43, 1.30) / 0.74 (0.39, 1.42) / 1.09 (0.61, 1.95) / 0.83

†Adjusted for family history of colorectal cancer (yes/no), history of colonoscopy/sigmoidoscopy (yes/no), smoking in pack-years (never, <5,5-19, 20-39, 40+ pack-years), physical activity (quintiles of metabolic equivalent task score [METS]-hours per week), red and processed meat intake (quintiles of servings per day), alcohol consumption (0, <5, 5-<15, 15-<30, 30+ gram per day), current multivitamin use (yes/no), regular use of aspirin (yes/no), regular use of non-steroidal anti-inflammatory drugs (NSAIDs [yes/no]), total energy intake (quintiles of calories per day), folate intake (quintiles of μg per day), calcium intake (quintiles of mg per day), and Alternate Healthy Eating Index (AHEI)-2010 (quintiles of the overall AHEI-2010 score without alcohol intake). For women, we additionally adjusted for menopause/postmenopausal hormone use status (premenopausal, postmenopausal never use, postmenopausal past use, or postmenopausal current hormone use).
‡We assessed whether the magnitude of the subtype-specific associations had an increasing or decreasing ordinal trend according to the subtyping marker, using a likelihood ratio test with one degree of freedom, and the statistical significance of this trend was presented as Pheterogeneity.
CI, confidence interval; HR, hazard ratio; MSI, microsatellite instability; MSS, microsatellite stable.

Table S4. Body mass index and risk of colorectal cancer according to fatty acid synthase(FASN)and the presence of poorly-differentiated foci stratified byFASNin the pooled cohorts
Body mass index (kg/m2) / Ptrend / Pheterogeneity‡
18.5-22.4 / 22.5-24.9 / 25.0-27.4 / 27.5-29.9 / ≥30
FASN-negative
Cases, No. (n=399) / 62 / 90 / 108 / 66 / 73
Age-adjusted HR (95% CI) / 1 [Reference] / 1.06 (0.76, 1.47) / 1.54 (1.12, 2.12) / 1.71 (1.20, 2.43) / 2.03 (1.45, 2.86) / <0.001 / 0.008
Multivariable HR (95% CI)† / 1 [Reference] / 1.05 (0.76, 1.46) / 1.52 (1.10, 2.09) / 1.67 (1.17, 2.38) / 1.99 (1.40, 2.81) / <0.001 / 0.008
FASN-positive
Cases, No. (n=607) / 98 / 186 / 157 / 84 / 82
Age-adjusted HR (95% CI) / 1 [Reference] / 1.36 (1.06, 1.74) / 1.36 (1.05, 1.76) / 1.39 (1.03, 1.87) / 1.40 (1.04, 1.88) / 0.05
Multivariable HR (95% CI)† / 1 [Reference] / 1.36 (1.06, 1.75) / 1.35 (1.04, 1.75) / 1.36 (1.01, 1.83) / 1.37 (1.01, 1.85) / 0.08
FASN-negative
Poorly-differentiated foci
Absent
Cases, No. (n=441) / 63 / 135 / 125 / 59 / 59
Age-adjusted HR (95% CI) / 1 [Reference] / 1.05 (0.71, 1.54) / 1.56 (1.07, 2.27) / 1.74 (1.15, 2.64) / 2.46 (1.67, 3.63) / <0.001
Multivariable HR (95% CI)† / 1 [Reference] / 1.05 (0.71, 1.54) / 1.53 (1.05, 2.23) / 1.70 (1.12, 2.58) / 2.40 (1.62, 3.56) / <0.001
Present
Cases, No. (n=155) / 34 / 46 / 29 / 23 / 23
Age-adjusted HR (95% CI) / 1 [Reference] / 1.14 (0.62, 2.13) / 1.55 (0.84, 2.88) / 1.62 (0.81, 3.23) / 0.98 (0.45, 2.15) / 0.60
Multivariable HR (95% CI)† / 1 [Reference] / 1.13 (0.61, 2.10) / 1.54 (0.83, 2.86) / 1.58 (0.79, 3.16) / 0.98 (0.44, 2.15) / 0.62
FASN-positive
Poorly-differentiated foci
Absent
Cases, No. (n=300) / 44 / 65 / 80 / 49 / 62
Age-adjusted HR (95% CI) / 1 [Reference] / 1.57 (1.16, 2.12) / 1.73 (1.27, 2.36) / 1.57 (1.10, 2.25) / 1.58 (1.10, 2.26) / 0.03
Multivariable HR (95% CI)† / 1 [Reference] / 1.57 (1.16, 2.13) / 1.72 (1.26, 2.35) / 1.54 (1.07, 2.21) / 1.56 (1.08, 2.24) / 0.04
Present
Cases, No. (n=95) / 17 / 25 / 27 / 16 / 10
Age-adjusted HR (95% CI) / 1 [Reference] / 0.92 (0.58, 1.44) / 0.68 (0.41, 1.13) / 1.01 (0.59, 1.72) / 1.11 (0.65, 1.89) / 0.72
Multivariable HR (95% CI)† / 1 [Reference] / 0.93 (0.59, 1.46) / 0.68 (0.41, 1.12) / 0.99 (0.58, 1.70) / 1.09 (0.64, 1.87) / 0.80

†Adjusted for the same set of covariates in Table S3.
‡We assessed whether the magnitude of the subtype-specific associations had an increasing or decreasing ordinal trend according to the subtyping marker, using a likelihood ratio test with one degree of freedom, and the statistical significance of this trend was presented as Pheterogeneity.
CI, confidence interval; FASN, fatty acid synthase; HR, hazard ratio.

Table S5. Body mass index and risk of colorectal cancer according to signet ring cell component in the pooled cohorts and the Nurses’ Health Study (NHS)*
Signet ring cell component / Body mass index (kg/m2) / Ptrend / Pheterogeneity‡
18.5-22.5 / 22.5-24.9 / 25-27.5 / 27.5-29.9 / ≥30
Pooled
Absent (0%)
Cases, No. (n=1254) / 197 / 349 / 333 / 184 / 191
Age-adjusted HR (95% CI) / 1 [Reference] / 1.22 (1.02, 1.45) / 1.38 (1.15, 1.65) / 1.44 (1.17, 1.76) / 1.62 (1.33, 1.98) / <0.001 / 0.36
Multivariable HR (95% CI)† / 1 [Reference] / 1.22 (1.02, 1.46) / 1.37 (1.14, 1.64) / 1.41 (1.15, 1.73) / 1.61 (1.31, 1.98) / <0.001 / 0.36
1% to 49%
Cases, No. (n=149) / 24 / 40 / 37 / 22 / 26
Age-adjusted HR (95% CI) / 1 [Reference] / 1.13 (0.68, 1.89) / 1.23 (0.73, 2.08) / 1.30 (0.72, 2.34) / 1.54 (0.88, 2.70) / 0.13
Multivariable HR (95% CI)† / 1 [Reference] / 1.11 (0.66, 1.85) / 1.21 (0.71, 2.04) / 1.26 (0.70, 2.27) / 1.50 (0.86, 2.64) / 0.15
≥50%
Cases, No. (n=26) / 3 / 10 / 7 / 2 / 4
Age-adjusted HR (95% CI) / 1 [Reference] / 2.21 (0.60, 8.11) / 1.85(0.47, 7.26) / 0.91 (0.15, 5.52) / 2.08 (0.46, 9.35) / 0.78
Multivariable HR (95% CI)† / 1 [Reference] / 2.25 (0.61, 8.29) / 1.87 (0.48, 7.35) / 0.93 (0.15, 5.67) / 2.12 (0.47, 9.59) / 0.76
NHS
Absent (0%)
Cases, No. (n=708) / 150 / 175 / 152 / 91 / 140
Age-adjusted HR (95% CI) / 1 [Reference] / 1.13 (0.90, 1.40) / 1.30 (1.04, 1.63) / 1.28 (0.98, 1.66) / 1.64 (1.30, 2.07) / <0.001 / 0.62
Multivariable HR (95% CI)† / 1 [Reference] / 1.12 (0.90, 1.40) / 1.28 (1.02, 1.61) / 1.26 (0.96, 1.64) / 1.61 (1.27, 2.05) / <0.001 / 0.61
1% to 49%
Cases, No. (n=94) / 19 / 26 / 20 / 13 / 16
Age-adjusted HR (95% CI) / 1 [Reference] / 1.21 (0.67, 2.18) / 1.21 (0.64, 2.27) / 1.22 (0.60, 2.47) / 1.23 (0.63, 2.41) / 0.59
Multivariable HR (95% CI)† / 1 [Reference] / 1.18 (0.65, 2.14) / 1.20 (0.64, 2.25) / 1.18 (0.58, 2.40) / 1.20 (0.61, 2.35) / 0.65
≥50%
Cases, No. (n=16) / 3 / 5 / 3 / 2 / 3
Age-adjusted HR (95% CI) / 1 [Reference] / 1.40 (0.33, 5.89) / 1.10 (0.22, 5.49) / 1.16 (0.19, 7.00) / 1.60 (0.32, 2.41) / 0.67
Multivariable HR (95% CI)† / 1 [Reference] / 1.40 (0.33, 5.90) / 1.10 (0.22, 5.49) / 1.15 (0.19, 6.96) / 1.61 (1.27, 2.05) / 0.68

*Due to the limited sample size in the Health Professionals Follow-up Study (HPFS), we could not assess separately in the male cohort.