Table 4.
Family history of colorectal cancer (CRC) and subsequent risk of developing CRC according to molecular subtypes in the combined cohorts*
| No. of first-degree relatives with CRC† | |||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|
| CRC molecular subtype | 0 | 1 | ≥2 | P trend | P heterogeneity‡ | ||||||
| Person-years | 2787643 | 370088 | 26684 | ||||||||
| All CRCs | |||||||||||
| No. of cancers | 976 | 216 | 32 | ||||||||
| Age-adjusted incidence rate§ | 37.2 | 54.6 | 100.4 | ||||||||
| Age-adjusted HR (95% CI) | 1 (referent) | 1.41 (1.22 to 1.64) | 2.70 (1.88 to 3.86) | <.001 | |||||||
| Multivariable HR (95% CI)|| | 1 (referent) | 1.40 (1.20 to 1.62) | 2.67 (1.86 to 3.82) | <.001 | |||||||
| LINE-1 methylation | .06 | ||||||||||
| Methylation-low, <55% (n = 240, 20%) | |||||||||||
| No. of cancers | 187 | 45 | 8 | ||||||||
| Age-adjusted incidence rate§ | 7.0 | 12.4 | 29.1 | ||||||||
| Age-adjusted HR (95% CI) | 1 (referent) | 1.66 (1.19 to 2.32) | 4.21 (2.08 to 8.56) | <.001 | |||||||
| Multivariable HR (95% CI)|| | 1 (referent) | 1.63 (1.16 to 2.28) | 4.32 (2.15 to 8.67) | <.001 | |||||||
| Methylation-intermediate, 55%–64.9% (n = 474, 39%) | |||||||||||
| No. of cancers | 376 | 84 | 14 | ||||||||
| Age-adjusted incidence rate§ | 14.7 | 21.3 | 42.6 | ||||||||
| Age-adjusted HR (95% CI) | 1 (referent) | 1.42 (1.12 to 1.81) | 2.90 (1.70 to 4.95) | <.001 | |||||||
| Multivariable HR (95% CI)|| | 1 (referent) | 1.42 (1.12 to 1.80) | 2.83 (1.66 to 4.83) | <.001 | |||||||
| Methylation-high, ≥65% (n = 510, 42%) | |||||||||||
| No. of cancers | 413 | 87 | 10 | ||||||||
| Age-adjusted incidence rate§ | 15.7 | 21.4 | 28.3 | ||||||||
| Age-adjusted HR (95% CI) | 1 (referent) | 1.30 (1.03 to 1.64) | 1.94 (1.03 to 3.66) | .005 | |||||||
| Multivariable HR (95% CI)|| | 1 (referent) | 1.28 (1.01 to 1.61) | 1.92 (1.02 to 3.63) | .007 | |||||||
| MSI status | .03 | ||||||||||
| MSS (n = 1002, 84%) | |||||||||||
| No. of cancers | 810 | 175 | 17 | ||||||||
| Age-adjusted incidence rate§ | 30.9 | 45.0 | 49.7 | ||||||||
| Age-adjusted HR (95% CI) | 1 (referent) | 1.40 (1.18 to 1.65) | 1.79 (1.11 to 2.89) | <.001 | |||||||
| Multivariable HR (95% CI)|| | 1 (referent) | 1.38 (1.17 to 1.63) | 1.79 (1.12 to 2.89) | <.001 | |||||||
| MSI-high (n = 188, 16%) | |||||||||||
| No. of cancers | 139 | 36 | 13 | ||||||||
| Age-adjusted incidence rate§ | 5.6 | 8.1 | 41.1 | ||||||||
| Age-adjusted HR (95% CI) | 1 (referent) | 1.50 (1.04 to 2.15) | 6.20 (3.43 to 11.2) | <.001 | |||||||
| Multivariable HR (95% CI)|| | 1 (referent) | 1.47 (1.02 to 2.10) | 5.86 (3.25 to 10.6) | <.001 | |||||||
| CIMP status | .40 | ||||||||||
| CIMP-low/negative (n = 963, 83%) | |||||||||||
| No. of cancers | 776 | 167 | 20 | ||||||||
| Age-adjusted incidence rate§ | 30.1 | 44.1 | 62.6 | ||||||||
| Age-adjusted HR (95% CI) | 1 (referent) | 1.40 (1.18 to 1.66) | 2.26 (1.45 to 3.52) | <.001 | |||||||
| Multivariable HR (95% CI)|| | 1 (referent) | 1.39 (1.17 to 1.64) | 2.27 (1.46 to 3.52) | <.001 | |||||||
| CIMP-high (n = 201, 17%) | |||||||||||
| No. of cancers | 152 | 40 | 9 | ||||||||
| Age-adjusted incidence rate§ | 5.6 | 8.8 | 26.7 | ||||||||
| Age-adjusted HR (95% CI) | 1 (referent) | 1.51 (1.07 to 2.13) | 3.45 (1.72 to 6.92) | <.001 | |||||||
| Multivariable HR (95% CI)|| | 1 (referent) | 1.48 (1.04 to 2.09) | 3.29 (1.64 to 6.59) | <.001 | |||||||
* CI = confidence interval; CIMP = CpG island methylator phenotype; HR = hazard ratio; LINE-1 = long interspersed nucleotide element 1; MSI = microsatellite instability; MSS = microsatellite stable.
† Not including offspring.
‡ P for heterogeneity for trends (0 vs 1 vs ≥2 affected first-degree relatives) between tumor molecular subtypes. A test for LINE-1 methylation subtypes assessed an ordinal linear trend for exposure (0 vs 1 vs ≥2 affected first-degree relatives) and for LINE-1 methylation-low to methylation-intermediate to methylation-high subtype.
§ Age-adjusted incidence rates (per 100000) were standardized to the age distribution of the population.
|| Adjusted for body mass index, cumulative mean physical activity, alcohol, folate, methionine, calcium, red meat intake, current smoking status, current multivitamin use, and regular aspirin use.