Table 3.
Family history of colorectal cancer (CRC) and subsequent risk of developing CRC according to molecular subtypes in Health Professionals Follow-up Study*
| No. of first-degree relatives with CRC† | |||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|
| CRC molecular subtype | 0 | 1 | ≥2 | P trend | P heterogeneity‡ | ||||||
| Person-years | 819660 | 107327 | 4433 | ||||||||
| All CRCs | |||||||||||
| No. of cancers | 459 | 97 | 9 | ||||||||
| Age-adjusted incidence rate§ | 59.4 | 85.1 | 123.3 | ||||||||
| Age-adjusted HR (95% CI) | 1 (referent) | 1.41 (1.13 to 1.76) | 2.80 (1.43 to 5.50) | <.001 | |||||||
| Multivariable HR (95% CI)|| | 1 (referent) | 1.41 (1.12 to 1.75) | 2.88 (1.46 to 5.67) | <.001 | |||||||
| LINE-1 methylation | .12 | ||||||||||
| Methylation-low, <55% (n = 125, 22%) | |||||||||||
| No. of cancers | 101 | 21 | 3 | ||||||||
| Age-adjusted incidence rate§ | 13.5 | 19.3 | 38.1 | ||||||||
| Age-adjusted HR (95% CI) | 1 (referent) | 1.54 (0.95 to 2.49) | 4.75 (1.61 to 14.0) | .009 | |||||||
| Multivariable HR (95% CI)|| | 1 (referent) | 1.50 (0.93 to 2.44) | 5.18 (1.81 to 14.8) | .01 | |||||||
| Methylation-intermediate, 55%–64.9% (n = 204, 36%) | |||||||||||
| No. of cancers | 160 | 40 | 4 | ||||||||
| Age-adjusted incidence rate§ | 12.4 | 16.2 | 38.7 | ||||||||
| Age-adjusted HR (95% CI) | 1 (referent) | 1.63 (1.15 to 2.31) | 3.22 (1.23 to 8.43) | <.001 | |||||||
| Multivariable HR (95% CI)|| | 1 (referent) | 1.66 (1.17 to 2.35) | 3.22 (1.22 to 8.54) | <.001 | |||||||
| Methylation-high, ≥65% (n = 236, 42%) | |||||||||||
| No. of cancers | 198 | 36 | 2 | ||||||||
| Age-adjusted incidence rate§ | 25.6 | 32.1 | 25.5 | ||||||||
| Age-adjusted HR (95% CI) | 1 (referent) | 1.17 (0.82 to 1.68) | 1.51 (0.37 to 6.09) | .31 | |||||||
| Multivariable HR (95% CI)|| | 1 (referent) | 1.16 (0.81 to 1.66) | 1.55 (0.38 to 6.36) | .33 | |||||||
| MSI status | .10 | ||||||||||
| MSS (n = 487, 89%) | |||||||||||
| No. of cancers | 399 | 82 | 6 | ||||||||
| Age-adjusted incidence rate§ | 51.2 | 71.0 | 76.2 | ||||||||
| Age-adjusted HR (95% CI) | 1 (referent) | 1.38 (1.08 to 1.76) | 2.05 (0.95 to 4.45) | .002 | |||||||
| Multivariable HR (95% CI)|| | 1 (referent) | 1.38 (1.08 to 1.75) | 2.13 (0.99 to 4.59) | .002 | |||||||
| MSI-high (n = 62, 11%) | |||||||||||
| No. of cancers | 46 | 13 | 3 | ||||||||
| Age-adjusted incidence rate§ | 6.3 | 12.4 | 47.2 | ||||||||
| Age-adjusted HR (95% CI) | 1 (referent) | 1.72 (0.93 to 3.18) | 13.8 (4.18 to 45.7) | .002 | |||||||
| Multivariable HR (95% CI)|| | 1 (referent) | 1.69 (0.92 to 3.10) | 13.2 (3.87 to 44.8) | .003 | |||||||
| CIMP status | .17 | ||||||||||
| CIMP-low/negative (n = 447, 88%) | |||||||||||
| No. of cancers | 367 | 75 | 5 | ||||||||
| Age-adjusted incidence rate§ | 47.3 | 66.5 | 63.6 | ||||||||
| Age-adjusted HR (95% CI) | 1 (referent) | 1.37 (1.07 to 1.76) | 1.99 (0.86 to 4.59) | .004 | |||||||
| Multivariable HR (95% CI)|| | 1 (referent) | 1.37 (1.07 to 1.76) | 2.07 (0.90 to 4.77) | .004 | |||||||
| CIMP-high (n = 61, 12%) | |||||||||||
| No. of cancers | 45 | 14 | 2 | ||||||||
| Age-adjusted incidence rate§ | 5.5 | 12.0 | 34.3 | ||||||||
| Age-adjusted HR (95% CI) | 1 (referent) | 1.95 (1.05 to 3.60) | 6.22 (1.33 to 29.2) | .005 | |||||||
| Multivariable HR (95% CI)|| | 1 (referent) | 1.91 (1.03 to 3.54) | 5.89 (1.22 to 28.5) | .007 | |||||||
* 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.