Table 5.
Family history of colorectal cancer (CRC) and subsequent risk of developing microsatellite stable (MSS) CRC by long interspersed nucleotide element 1 (LINE-1) methylation level (censoring microsatellite instability-high cancers) in the combined cohorts*
| No. of first-degree relatives with CRC† | ||||||
|---|---|---|---|---|---|---|
| MSS CRC molecular subtype | 0 | 1 | ≥2 | P trend | P heterogeneity‡ | |
| Person-years | 2787643 | 370088 | 26684 | |||
| LINE-1 subtyping in MSS tumors | .02 | |||||
| Methylation-low, <55% | ||||||
| No. of cancers | 172 | 43 | 6 | |||
| Age-adjusted incidence rate§ | 6.8 | 11.8 | 17.4 | |||
| Age-adjusted HR (95% CI) | 1 (referent) | 1.71 (1.21 to 2.42) | 3.37 (1.52 to 7.50) | <.001 | ||
| Multivariable HR (95% CI)|| | 1 (referent) | 1.68 (1.19 to 2.38) | 3.48 (1.59 to 7.63) | <.001 | ||
| Methylation-intermediate, 55%–64.9% | ||||||
| No. of cancers | 330 | 77 | 6 | |||
| Age-adjusted incidence rate§ | 12.5 | 19.7 | 20.0 | |||
| Age-adjusted HR (95% CI) | 1 (referent) | 1.50 (1.17 to 1.93) | 1.42 (0.64 to 3.16) | .002 | ||
| Multivariable HR (95% CI)|| | 1 (referent) | 1.50 (1.17 to 1.93) | 1.42 (0.64 to 3.14) | .002 | ||
| Methylation-high, ≥65% | ||||||
| No. of cancers | 308 | 55 | 5 | |||
| Age-adjusted incidence rate§ | 11.6 | 14.1 | 12.4 | |||
| Age-adjusted HR (95% CI) | 1 (referent) | 1.12 (0.84 to 1.50) | 1.43 (0.59 to 3.48) | .31 | ||
| Multivariable HR (95% CI)|| | 1 (referent) | 1.11 (0.83 to 1.48) | 1.43 (0.59 to 3.49) | .35 | ||
* CI = confidence interval; HR = hazard ratio.
† Not including offspring.
‡ A heterogeneity test for LINE-1 methylation subtypes assessed an ordinal linear trend for exposure (0 vs 1 vs ≥2 affected first-degree relatives) as well as for LINE-1 methylation-high to methylation-intermediate to methylation-low 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, and red meat intake, current smoking status, current multivitamin use, and regular aspirin use.