Table 2. Associations with CIMP-high in colorectal cancer by univariate and multivariate analyses.
| Clinical, pathological, or molecular characteristics | Univariate OR (95% CI) | P value | OR adjusted for major confounder(s) | Major confounder(s) (in the order of strength of effect) | Multivariate OR (95% CI) | P value |
| Age (10-year increment) | 1.78 (1.40–2.27) | <0.0001 | 2.53 (1.69–3.78) | BRAF, MSI | 3.16 (1.93–5.18) | <0.0001 |
| Female (vs. male) | 1.79 (1.22–2.64) | 0.003 | - | - | 1.96 (0.95–4.08) | 0.071 |
| Proximal (vs. distal)∧ | 13.3 (7.64–23.3) | <0.0001 | 5.58 (2.80–11.1) | MSI, BRAF | 3.39 (1.57–7.34) | 0.002 |
| Tumor stage (vs. I) | tumor location, MSI, BRAF | |||||
| Stage II | 4.42 (2.44–8.00) | <0.0001 | 2.53 (1.06–6.08) | 1.83 (0.69–4.83) | 0.23 | |
| Stage III | 1.61 (0.83–3.12) | 0.16 | 1.91 (0.72–5.12) | 1.83 (0.63–5.28) | 0.26 | |
| Stage IV | 2.23 (1.06–4.71) | 0.04 | 2.28 (0.78–6.65) | 1.72 (0.53–5.62) | 0.37 | |
| Poor differentiation | 7.28 (4.50–11.8) | <0.0001 | 2.96 (1.42–6.19) | MSI, BRAF | 2.98 (1.15–7.69) | 0.024 |
| Mucinous feature (vs. 0%) | MSI, BRAF | |||||
| 1–49% | 2.31 (1.46–3.64) | 0.0003 | 1.72 (0.89–3.29) | 1.53 (0.71–3.32) | 0.28 | |
| ≥50% | 5.39 (3.37–8.63) | <0.0001 | 2.09 (1.03–4.24) | 2.06 (0.81–5.22) | 0.13 | |
| Signet ring cells, any | 3.82 (2.18–6.71) | <0.0001 | 0.68 (0.32–1.41) | mucin, differentiation | 0.98 (0.30–3.17) | 0.97 |
| MSI-high | 41.9 (25.5–68.9) | <0.0001 | 27.6 (16.2–47.1) | tumor location | 21.2 (9.79–45.8) | <0.0001 |
| BRAF mutation | 29.2 (18.0–47.6) | <0.0001 | 18.7 (11.0–31.7) | tumor location | 15.9 (6.60–38.4) | <0.0001 |
| KRAS mutation | 0.25 (0.15–0.41) | <0.0001 | 0.71 (0.36–1.40) | BRAF, MSI | 0.97 (0.44–2.10) | 0.93 |
| β-catenin activation* | 0.14 (0.07–0.28) | <0.0001 | 0.21 (0.10–0.44) | tumor location | 0.21 (0.070–0.62) | 0.005 |
| LINE-1 hypomethylation (30% decline) | 0.20 (0.10–0.39) | <0.0001 | 0.30 (0.13–0.69) | MSI | 0.27 (0.094–0.75) | 0.012 |
| p53 positivity | 0.34 (0.22–0.52) | <0.0001 | 0.66 (0.39–1.13) | MSI | 0.73 (0.35–1.51) | 0.39 |
Multivariate logistic regression model includes all of the above variables. Note that female, tumor stage, signet ring cells, mucinous feature, KRAS and p53 are not significantly related with CIMP-high after adjusting for other variables.
*
β-catenin activation is defined as β-catenin score ≥3. The β-catenin score is the sum of nuclear (0, 1+ or 2+), cytoplasmic (0, 1+ or 2+) and membrane (0 or 1+) scores as originally described by Jass et al.[35].
∧
Proximal colon includes cecum to transverse colon, and distal colon includes splenic flexure to rectum.
CI, confidence interval; CIMP, CpG island methylator phenotype; LINE-1, long interspersed nucleotide element-1; MSI, microsatellite instability; OR, odds ratio.