Table 6.
Cumulative Pack-years of Smoking and Incident Colorectal Cancer Risk by Combined Molecular Subtypesa in the Nurses' Health Study (1980–2008) and the Health Professionals Follow-up Study (1986–2008)
| Never Smoker |
Cumulative Pack-years of Smoking |
Ptrendb | |||||||
|---|---|---|---|---|---|---|---|---|---|
| 1–19 |
20–39 |
≥40 |
|||||||
| HR | 95% CI | HR | 95% CI | HR | 95% CI | HR | 95% CI | ||
| CIMP/MSI Subtyping | |||||||||
| CIMP-low/negative | |||||||||
| MSS | |||||||||
| No. | 340 | 227 | 161 | 137 | |||||
| Age-adjusted | 1.00 | Referent | 1.18 | 0.99, 1.40 | 1.20 | 0.99, 1.45 | 1.22 | 1.00, 1.49 | 0.05 |
| Multivariatec | 1.00 | Referent | 1.15 | 0.97, 1.37 | 1.16 | 0.96, 1.41 | 1.16 | 0.95, 1.43 | 0.15 |
| MSI-high | |||||||||
| No. | 19 | 10 | 8 | 6 | |||||
| Age-adjusted | 1.00 | Referent | 0.98 | 0.45, 2.11 | 1.14 | 0.49, 2.62 | 1.14 | 0.45, 2.88 | 0.72 |
| Multivariatec | 1.00 | Referent | 0.96 | 0.44, 2.07 | 1.08 | 0.47, 2.48 | 1.08 | 0.43, 2.75 | 0.82 |
| CIMP-high | |||||||||
| MSS | |||||||||
| No. | 29 | 11 | 7 | 14 | |||||
| Age-adjusted | 1.00 | Referent | 0.69 | 0.34, 1.39 | 0.60 | 0.26, 1.38 | 1.40 | 0.74, 2.67 | 0.42 |
| Multivariatec | 1.00 | Referent | 0.68 | 0.34, 1.37 | 0.58 | 0.25, 1.33 | 1.30 | 0.68, 2.48 | 0.56 |
| MSI-high | |||||||||
| No. | 41 | 22 | 28 | 42 | |||||
| Age-adjusted | 1.00 | Referent | 0.98 | 0.58, 1.65 | 1.90 | 1.17, 3.08 | 2.85 | 1.85, 4.40 | <0.0001 |
| Multivariatec | 1.00 | Referent | 0.97 | 0.57, 1.63 | 1.82 | 1.12, 2.96 | 2.75 | 1.78, 4.26 | <0.0001 |
| CIMP/BRAF Subtyping | |||||||||
| CIMP-low/negative | |||||||||
| BRAF-wildtype | |||||||||
| No. | 341 | 232 | 164 | 136 | |||||
| Age-adjusted | 1.00 | Referent | 1.20 | 1.02, 1.42 | 1.21 | 1.00, 1.46 | 1.23 | 1.00, 1.50 | 0.04 |
| Multivariatec | 1.00 | Referent | 1.17 | 0.99, 1.39 | 1.17 | 0.96, 1.41 | 1.17 | 0.95, 1.43 | 0.15 |
| BRAF-mutated | |||||||||
| No. | 22 | 8 | 6 | 10 | |||||
| Age-adjusted | 1.00 | Referent | 0.65 | 0.29, 1.48 | 0.81 | 0.33, 2.02 | 1.30 | 0.60, 2.81 | 0.49 |
| Multivariatec | 1.00 | Referent | 0.65 | 0.29, 1.47 | 0.81 | 0.32, 2.00 | 1.27 | 0.59, 2.75 | 0.53 |
| CIMP-high | |||||||||
| BRAF-wildtype | |||||||||
| No. | 28 | 12 | 13 | 20 | |||||
| Age-adjusted | 1.00 | Referent | 0.81 | 0.41, 1.60 | 1.14 | 0.59, 2.22 | 1.92 | 1.07, 3.42 | 0.02 |
| Multivariatec | 1.00 | Referent | 0.80 | 0.41, 1.59 | 1.10 | 0.56, 2.14 | 1.83 | 1.02, 3.27 | 0.03 |
| BRAF-mutated | |||||||||
| No. | 43 | 21 | 22 | 36 | |||||
| Age-adjusted | 1.00 | Referent | 0.87 | 0.52, 1.47 | 1.45 | 0.86, 2.43 | 2.44 | 1.56, 3.81 | <0.0001 |
| Multivariatec | 1.00 | Referent | 0.86 | 0.51, 1.45 | 1.39 | 0.82, 2.33 | 2.32 | 1.48, 3.63 | <0.0001 |
| MSI/BRAF Subtyping | |||||||||
| MSS | |||||||||
| BRAF-wildtype | |||||||||
| No. | 360 | 239 | 165 | 142 | |||||
| Age-adjusted | 1.00 | Referent | 1.16 | 0.99, 1.37 | 1.14 | 0.95, 1.38 | 1.20 | 0.99, 1.46 | 0.08 |
| Multivariatec | 1.00 | Referent | 1.13 | 0.96, 1.34 | 1.10 | 0.91, 1.33 | 1.14 | 0.93, 1.40 | 0.24 |
| BRAF-mutated | |||||||||
| No. | 36 | 14 | 9 | 17 | |||||
| Age-adjusted | 1.00 | Referent | 0.70 | 0.37, 1.30 | 0.70 | 0.34, 1.46 | 1.39 | 0.77, 2.50 | 0.35 |
| Multivariatec | 1.00 | Referent | 0.69 | 0.37, 1.28 | 0.68 | 0.33, 1.42 | 1.33 | 0.74, 2.40 | 0.42 |
| MSI-high | |||||||||
| BRAF-wildtype | |||||||||
| No. | 32 | 18 | 18 | 19 | |||||
| Age-adjusted | 1.00 | Referent | 1.04 | 0.58, 1.86 | 1.44 | 0.80, 2.57 | 1.86 | 1.04, 3.30 | 0.02 |
| Multivariatec | 1.00 | Referent | 1.03 | 0.57, 1.83 | 1.36 | 0.76, 2.44 | 1.79 | 1.01, 3.19 | 0.03 |
| BRAF-mutated | |||||||||
| No. | 30 | 16 | 19 | 31 | |||||
| Age-adjusted | 1.00 | Referent | 0.96 | 0.52, 1.76 | 1.82 | 1.02, 3.25 | 2.94 | 1.77, 4.87 | <0.0001 |
| Multivariatec | 1.00 | Referent | 0.94 | 0.51, 1.72 | 1.74 | 0.97, 3.11 | 2.81 | 1.69, 4.68 | <0.0001 |
Abbreviations: CI, confidence interval; CIMP, CpG island methylator phenotype; HR, hazard ratio; MSI, microsatellite instability; MSS, microsatellite stable.
a All models were stratified by calendar year of the questionnaire cycle, age, and sex.
b Based on the linear trend test by using the median value of each category.
c Models were adjusted for body mass index, family history of colorectal cancer in parent or sibling, regular use of aspirin, physical activity level, alcohol consumption, total caloric intake, and red meat intake.