Table 2.
Family history of colorectal cancer (CRC) and subsequent risk of developing CRC according to molecular subtypes in the Nurses’ Health Study*
| No. of first-degree relatives with CRC† | |||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|
| CRC molecular subtype | 0 | 1 | ≥2 | P trend | P heterogeneity‡ | ||||||
| Person-years | 1967983 | 262761 | 22250 | ||||||||
| All CRCs | |||||||||||
| No. of cancers | 517 | 119 | 23 | ||||||||
| Age-adjusted incidence rate§ | 28.3 | 43.6 | 96.3 | ||||||||
| Age-adjusted HR (95% CI) | 1 (referent) | 1.41 (1.16 to 1.73) | 2.66 (1.74 to 4.06) | <.001 | |||||||
| Multivariable HR (95% CI)|| | 1 (referent) | 1.39 (1.13 to 1.70) | 2.60 (1.70 to 3.97) | <.001 | |||||||
| LINE-1 methylation | .25 | ||||||||||
| Methylation-low, <55% (n = 115, 17%) | |||||||||||
| No. of cancers | 86 | 24 | 5 | ||||||||
| Age-adjusted incidence rate§ | 4.6 | 9.9 | 28.9 | ||||||||
| Age-adjusted HR (95% CI) | 1 (referent) | 1.79 (1.12 to 2.86) | 3.98 (1.57 to 10.1) | .001 | |||||||
| Multivariable HR (95% CI)|| | 1 (referent) | 1.77 (1.11 to 2.82) | 3.96 (1.58 to 9.94) | .001 | |||||||
| Methylation-intermediate 55%–64.9% (n = 270, 41%) | |||||||||||
| No. of cancers | 216 | 44 | 10 | ||||||||
| Age-adjusted incidence rate§ | 12.4 | 16.2 | 38.7 | ||||||||
| Age-adjusted HR (95% CI) | 1 (referent) | 1.28 (0.92 to 1.77) | 2.76 (1.45 to 5.25) | .006 | |||||||
| Multivariable HR (95% CI)|| | 1 (referent) | 1.25 (0.90 to 1.74) | 2.69 (1.42 to 5.12) | .009 | |||||||
| Methylation-high, ≥65% (n = 274, 42%) | |||||||||||
| No. of cancers | 215 | 51 | 8 | ||||||||
| Age-adjusted incidence rate§ | 11.4 | 17.6 | 28.4 | ||||||||
| Age-adjusted HR (95% CI) | 1 (referent) | 1.40 (1.03 to 1.91) | 2.12 (1.04 to 4.32) | .005 | |||||||
| Multivariable HR (95% CI)|| | 1 (referent) | 1.37 (1.01 to 1.87) | 2.06 (1.01 to 4.20) | .008 | |||||||
| MSI status | .11 | ||||||||||
| MSS (n = 515, 80%) | |||||||||||
| No. of cancers | 411 | 93 | 11 | ||||||||
| Age-adjusted incidence rate§ | 23.0 | 36.3 | 47.4 | ||||||||
| Age-adjusted HR (95% CI) | 1 (referent) | 1.41 (1.12 to 1.77) | 1.68 (0.92 to 3.07) | .001 | |||||||
| Multivariable HR (95% CI)|| | 1 (referent) | 1.39 (1.10 to 1.75) | 1.66 (0.91 to 3.02) | .002 | |||||||
| MSI-high (n = 126, 20%) | |||||||||||
| No. of cancers | 93 | 23 | 10 | ||||||||
| Age-adjusted incidence rate‡ | 5.2 | 6.1 | 38.7 | ||||||||
| Age-adjusted HR (95% CI) | 1 (referent) | 1.40 (0.89 to 2.18) | 5.23 (2.66 to 10.3) | <.001 | |||||||
| Multivariable HR (95% CI)|| | 1 (referent) | 1.37 (0.87 to 2.14) | 4.98 (2.54 to 9.76) | <.001 | |||||||
| CIMP status | .87 | ||||||||||
| CIMP-low/negative (n = 516, 79%) | |||||||||||
| No. of cancers | 409 | 92 | 15 | ||||||||
| Age-adjusted incidence rate§ | 22.9 | 36.0 | 63.7 | ||||||||
| Age-adjusted HR (95% CI) | 1 (referent) | 1.42 (1.13 to 1.79) | 2.37 (1.41 to 4.00) | <.001 | |||||||
| Multivariable HR (95% CI)|| | 1 (referent) | 1.40 (1.11 to 1.76) | 2.34 (1.40 to 3.94) | <.001 | |||||||
| CIMP-high (n = 140, 21%) | |||||||||||
| No. of cancers | 107 | 26 | 7 | ||||||||
| Age-adjusted incidence rate§ | 5.4 | 7.3 | 23.6 | ||||||||
| Age-adjusted HR (95% CI) | 1 (referent) | 1.34 (0.88 to 2.04) | 3.01 (1.37 to 6.57) | .01 | |||||||
| Multivariable HR (95% CI)|| | 1 (referent) | 1.31 (0.86 to 2.00) | 2.87 (1.31 to 6.27) | .02 | |||||||
* 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.