Table 3.
Empirical Dietary Inflammatory Pattern Scores and Risk of Colorectal Cancer by Microsatellite Instability, CpG Island Methylator Phenotype, BRAF Mutation, PTGS2 Expression and Peritumoral Lymphocytic Reaction
| Tumor Characteristic | Peritumoral Lymphocytic Reaction |
Quintiles of the Empirical Dietary Inflammatory Pattern (EDIP) Scores | Ptrenda | ||||
|---|---|---|---|---|---|---|---|
|
| |||||||
| Q1 (Lowest) | Q2 | Q3 | Q4 | Q5 (Highest) | |||
| Microsatellite instability | |||||||
| Non-MSI-high | Absent/low | ||||||
| N of cases (n=142) | 23 | 26 | 23 | 32 | 38 | ||
| Age-adjusted HR (95% CI)b | 1 (referent) | 1.18 (0.66–2.11) | 0.96 (0.52–1.74) | 1.47 (0.84–2.58) | 2.19 (1.29–3.74) | .003 | |
| Multivariable HR (95% CI)c | 1 (referent) | 1.24 (0.69–2.22) | 1.03 (0.56–1.88) | 1.60 (0.91–2.80) | 2.40 (1.40–4.10) | <.001 | |
| Intermediate | |||||||
| N of cases (n=705) | 159 | 138 | 136 | 135 | 137 | ||
| Age-adjusted HR (95% CI)b | 1 (referent) | 0.78 (0.61–0.98) | 0.79 (0.62–1.00) | 0.86 (0.68–1.09) | 0.96 (0.76–1.22) | .99 | |
| Multivariable HR (95% CI)c | 1 (referent) | 0.81 (0.64–1.03) | 0.85 (0.67–1.08) | 0.94 (0.74–1.19) | 1.04 (0.82–1.32) | .48 | |
| High | |||||||
| N of cases (n=113) | 22 | 27 | 22 | 25 | 17 | ||
| Age-adjusted HR (95% CI)b | 1 (referent) | 1.14 (0.65–2.00) | 1.04 (0.57–1.89) | 1.05 (0.58–1.89) | 0.83 (0.42–1.62) | .57 | |
| Multivariable HR (95% CI)c | 1 (referent) | 1.17 (0.67–2.05) | 1.10 (0.61–2.00) | 1.12 (0.62–2.01) | 0.86 (0.45–1.67) | .70 | |
| MSI-high | |||||||
| Absent/low | |||||||
| N of cases (n=9) | 0 | 1 | 2 | 5 | 1 | ||
| Age-adjusted HR (95% CI)b | 1 (referent) | - | - | - | - | - | |
| Multivariable HR (95% CI)c | 1 (referent) | - | - | - | - | - | |
| Intermediate | |||||||
| N of cases (n=102) | 21 | 16 | 25 | 18 | 22 | ||
| Age-adjusted HR (95% CI)b | 1 (referent) | 0.68 (0.34–1.35) | 1.09 (0.60–1.98) | 0.77 (0.40–1.46) | 1.05 (0.56–1.95) | .78 | |
| Multivariable HR (95% CI)c | 1 (referent) | 0.72 (0.36–1.44) | 1.17 (0.65–2.12) | 0.83 (0.44–1.59) | 1.13 (0.60–2.11) | .61 | |
| High | |||||||
| N of cases (n=73) | 16 | 15 | 19 | 11 | 12 | ||
| Age-adjusted HR (95% CI)b | 1 (referent) | 0.83 (0.42–1.67) | 1.08 (0.55–2.10) | 0.74 (0.34–1.63) | 0.89 (0.42–1.88) | .68 | |
| Multivariable HR (95% CI)c | 1 (referent) | 0.88 (0.45–1.75) | 1.15 (0.59–2.25) | 0.79 (0.36–1.72) | 0.97 (0.46–2.07) | .86 | |
|
| |||||||
| CpG island methylator phenotype (CIMP) | |||||||
| CIMP-low/negative | Absent/low | ||||||
| N of cases (n=129) | 19 | 23 | 23 | 31 | 33 | ||
| Age-adjusted HR (95% CI)b | 1 (referent) | 1.33 (0.70–2.53) | 1.26 (0.67–2.38) | 1.70 (0.93–3.10) | 2.38 (1.33–4.27) | .002 | |
| Multivariable HR (95% CI)c | 1 (referent) | 1.41 (0.74–2.67) | 1.36 (0.72–2.57) | 1.84 (1.00–3.37) | 2.57 (1.44–4.61) | <.001 | |
| Intermediate | |||||||
| N of cases (n=681) | 156 | 137 | 128 | 124 | 136 | ||
| Age-adjusted HR (95% CI)b | 1 (referent) | 0.74 (0.59–0.94) | 0.77 (0.60–0.98) | 0.79 (0.62–1.01) | 0.89 (0.70–1.13) | .48 | |
| Multivariable HR (95% CI)c | 1 (referent) | 0.78 (0.61–0.99) | 0.83 (0.65–1.06) | 0.85 (0.66–1.09) | 0.95 (0.75–1.21) | .89 | |
| High | |||||||
| N of cases (n=105) | 20 | 25 | 21 | 23 | 16 | ||
| Age-adjusted HR (95% CI)b | 1 (referent) | 1.25 (0.69–2.26) | 1.03 (0.54–1.97) | 1.09 (0.59–2.01) | 0.92 (0.46–1.86) | .80 | |
| Multivariable HR (95% CI)c | 1 (referent) | 1.31 (0.73–2.36) | 1.09 (0.57–2.08) | 1.15 (0.62–2.13) | 0.97 (0.48–1.92) | .92 | |
| CIMP-high | |||||||
| Absent/low | |||||||
| N of cases (n=16) | 3 | 4 | 2 | 4 | 3 | ||
| Age-adjusted HR (95% CI)b | 1 (referent) | 1.66 (0.34–8.18) | 0.83 (0.14–4.92) | 1.64 (0.36–7.52) | 1.92 (0.38–9.60) | .44 | |
| Multivariable HR (95% CI)c | 1 (referent) | 1.67 (0.34–8.26) | 0.85 (0.14–5.05) | 1.78 (0.38–8.24) | 2.02 (0.40–10.16) | .39 | |
| Intermediate | |||||||
| N of cases (n=110) | 22 | 16 | 25 | 25 | 22 | ||
| Age-adjusted HR (95% CI)b | 1 (referent) | 0.70 (0.36–1.38) | 0.95 (0.53–1.72) | 1.08 (0.60–1.93) | 1.07 (0.58–1.98) | .59 | |
| Multivariable HR (95% CI)c | 1 (referent) | 0.75 (0.38–1.47) | 1.03 (0.58–1.85) | 1.19 (0.67–2.13) | 1.13 (0.61–2.08) | .44 | |
| High | |||||||
| N of cases (n=64) | 13 | 15 | 17 | 10 | 9 | ||
| Age-adjusted HR (95% CI)b | 1 (referent) | 0.83 (0.40–1.72) | 1.13 (0.55–2.33) | 0.75 (0.32–1.74) | 0.64 (0.27–1.51) | .26 | |
| Multivariable HR (95% CI)c | 1 (referent) | 0.87 (0.43–1.79) | 1.22 (0.60–2.49) | 0.78 (0.33–1.81) | 0.69 (0.29–1.62) | .34 | |
|
| |||||||
| BRAF | |||||||
| Wild-type | Absent/low | ||||||
| N of cases (n=130) | 20 | 22 | 21 | 30 | 37 | ||
| Age-adjusted HR (95% CI)b | 1 (referent) | 1.19 (0.64–2.24) | 1.13 (0.60–2.13) | 1.56 (0.86–2.82) | 2.61 (1.49–4.58) | <.001 | |
| Multivariable HR (95% CI)c | 1 (referent) | 1.27 (0.68–2.38) | 1.23 (0.65–2.31) | 1.71 (0.94–3.10) | 2.85 (1.63–4.99) | <.001 | |
| Intermediate | |||||||
| N of cases (n=717) | 155 | 141 | 143 | 135 | 143 | ||
| Age-adjusted HR (95% CI)b | 1 (referent) | 0.79 (0.62–1.00) | 0.87 (0.69–1.10) | 0.87 (0.69–1.11) | 1.00 (0.79–1.27) | .75 | |
| Multivariable HR (95% CI)c | 1 (referent) | 0.84 (0.66–1.06) | 0.94 (0.74–1.19) | 0.95 (0.75–1.22) | 1.08 (0.85–1.37) | .33 | |
| High | |||||||
| N of cases (n=139) | 27 | 31 | 32 | 29 | 20 | ||
| Age-adjusted HR (95% CI)b | 1 (referent) | 1.05 (0.63–1.77) | 1.14 (0.67–1.94) | 0.97 (0.57–1.66) | 0.79 (0.42–1.47) | .43 | |
| Multivariable HR (95% CI)c | 1 (referent) | 1.11 (0.67–1.87) | 1.22 (0.72–2.07) | 1.05 (0.61–1.79) | 0.83 (0.45–1.53) | .58 | |
| Mutant | |||||||
| Absent/low | |||||||
| N of cases (n=20) | 3 | 5 | 4 | 5 | 3 | ||
| Age-adjusted HR (95% CI)b | 1 (referent) | 1.42 (0.33–6.08) | 0.77 (0.17–3.38) | 1.25 (0.31–5.05) | 0.87 (0.18–4.10) | .87 | |
| Multivariable HR (95% CI)c | 1 (referent) | 1.47 (0.35–6.20) | 0.82 (0.19–3.65) | 1.34 (0.33–5.50) | 0.95 (0.20–4.54) | .99 | |
| Intermediate | |||||||
| N of cases (n=101) | 29 | 16 | 18 | 18 | 20 | ||
| Age-adjusted HR (95% CI)b | 1 (referent) | 0.50 (0.27–0.93) | 0.50 (0.27–0.91) | 0.57 (0.31–1.05) | 0.85 (0.48–1.52) | .60 | |
| Multivariable HR (95% CI)c | 1 (referent) | 0.53 (0.28–0.98) | 0.53 (0.29–0.97) | 0.62 (0.34–1.14) | 0.93 (0.52–1.65) | .78 | |
| High | |||||||
| N of cases (n=48) | 11 | 12 | 11 | 7 | 7 | ||
| Age-adjusted HR (95% CI)b | 1 (referent) | 0.87 (0.39–1.94) | 0.86 (0.38–1.98) | 0.73 (0.27–1.92) | 0.82 (0.32–2.11) | .56 | |
| Multivariable HR (95% CI)c | 1 (referent) | 0.89 (0.40–1.97) | 0.92 (0.40–2.10) | 0.77 (0.29–2.02) | 0.89 (0.34–2.29) | .69 | |
|
| |||||||
| PTGS2 expression | |||||||
| Negative | |||||||
| Absent/low | 8 | 16 | 11 | 8 | 13 | ||
| N of cases (n=56) | 1 (referent) | 2.42 (0.96–6.10) | 1.68 (0.63–4.43) | 1.45 (0.52–4.04) | 2.25 (0.87–5.81) | .32 | |
| Age-adjusted HR (95% CI)b | 1 (referent) | 2.62 (1.05–6.54) | 1.84 (0.70–4.87) | 1.63 (0.59–4.50) | 2.49 (0.97–6.40) | .20 | |
| Multivariable HR (95% CI)c | |||||||
| Intermediate | |||||||
| N of cases (n=281) | 65 | 44 | 66 | 51 | 55 | ||
| Age-adjusted HR (95% CI)b | 1 (referent) | 0.59 (0.39–0.88) | 0.85 (0.59–1.23) | 0.71 (0.48–1.03) | 0.87 (0.60–1.28) | .71 | |
| Multivariable HR (95% CI)c | 1 (referent) | 0.62 (0.41–0.93) | 0.92 (0.64–1.33) | 0.76 (0.52–1.11) | 0.95 (0.65–1.39) | .97 | |
| High | |||||||
| N of cases (n=73) | 15 | 20 | 17 | 11 | 10 | ||
| Age-adjusted HR (95% CI)b | 1 (referent) | 1.01 (0.52–1.95) | 1.05 (0.51–2.17) | 0.66 (0.29–1.51) | 0.75 (0.33–1.71) | .29 | |
| Multivariable HR (95% CI)c | 1 (referent) | 1.07 (0.56–2.04) | 1.14 (0.55–2.33) | 0.71 (0.31–1.61) | 0.80 (0.35–1.82) | .38 | |
| Positive | |||||||
| Absent/low | |||||||
| N of cases (n=80) | 14 | 7 | 13 | 22 | 24 | ||
| Age-adjusted HR (95% CI)b | 1 (referent) | 0.49 (0.19–1.29) | 0.88 (0.39–1.97) | 1.49 (0.73–3.08) | 2.28 (1.16–4.50) | .003 | |
| Multivariable HR (95% CI)c | 1 (referent) | 0.52 (0.20–1.35) | 0.95 (0.42–2.11) | 1.62 (0.78–3.35) | 2.46 (1.24–4.85) | .001 | |
| Intermediate | |||||||
| N of cases (n=501) | 105 | 105 | 94 | 91 | 106 | ||
| Age-adjusted HR (95% CI)b | 1 (referent) | 0.85 (0.64–1.12) | 0.88 (0.66–1.18) | 0.85 (0.63–1.14) | 1.01 (0.76–1.34) | .97 | |
| Multivariable HR (95% CI)c | 1 (referent) | 0.90 (0.67–1.19) | 0.95 (0.71–1.28) | 0.93 (0.69–1.25) | 1.08 (0.81–1.44) | .65 | |
| High | |||||||
| N of cases (n=82) | 12 | 16 | 22 | 16 | 16 | ||
| Age-adjusted HR (95% CI)b | 1 (referent) | 1.29 (0.59–2.82) | 1.58 (0.75–3.31) | 1.08 (0.50–2.37) | 1.09 (0.50–2.37) | .79 | |
| Multivariable HR (95% CI)c | 1 (referent) | 1.34 (0.61–2.92) | 1.67 (0.80–3.48) | 1.15 (0.52–2.51) | 1.14 (0.53–2.48) | .67 | |
Abbreviations: CI, confidence interval; CIMP, CpG island methylator phenotype; HR, hazard ratio; MSI, microsatellite instability.
a
Linear trend test using the median value of each EDIP score quintile.
b
Duplication-method Cox proportional cause-specific hazards regression weighted by inverse probabilities based on immune marker availability for competing risks data was used to compute HRs and 95% CIs. All analyses were stratified by age (in month), year of questionnaire return and sex.
c
Multivariable HR was further adjusted for time-varying pack-years of smoking (0 vs. 1–19 vs. 20–39 vs. ≥40 pack-years), family history of colorectal cancer, endoscopy status, physical activity level [quintiles of mean metabolic equivalent task score (METS) - hours per week], total energy intake (quintiles of kcal/day), total alcohol intake (0 vs. 1–5 vs. 6–15 vs. >15 g/day), current multivitamin use and regular aspirin use.