Table 2.
Molecular pathologic epidemiology studies to examine interactive prognostic effects of lifestyle or other etiologic factors and tumoral somatic changes in colorectal cancer.
| Ref. | First author | Year | Study design | Tissue specimens | Study cohort, sample sizes (N)* and notes | Tumoral feature | Hypothetical potential effect modifiers | Exploratory potential effect modifiers | Clinical outcome (number of events) | Findings |
|---|---|---|---|---|---|---|---|---|---|---|
| [18] | Baba | 2009 | PCS | CRC (stage I–IV) | NHS, HPFS. 598 CRC | CDX2 expression in CRC | Sex, age, BMI (prediagnosis), family history of CRC, tumor location, stage, grade, CIN, MSI, CIMP, LINE-1 methylation, KRAS, BRAF, PIK3CA mutation, expression of TP53, CDKN1A (p21), CCND1, CTNNB1, PTGS2 (COX-2) | CRC-specific survival (156 events), overall survival (255 events) | Loss of CDX2 expression is associated with poor prognosis among patients with family history of CRC, but not those without family history of CRC. | |
| [19] | Baba | 2009 | PCS | CRC (stage I–IV) | NHS, HPFS. 487 CRC | AURKA (Aurora-A) expression in CRC | Sex, age, BMI (prediagnosis), family history of CRC, tumor location, stage, grade, CIN, MSI, CIMP, LINE-1 methylation, KRAS, BRAF, PIK3CA mutation, expression of TP53, CDKN1A (p21), CCND1, CTNNB1, PTGS2 (COX-2), FASN | CRC-specific survival (124 events), overall survival (216 events) | AURKA expression in CRC is not associated with prognosis and there is no interaction between AURKA and any of the covariates. | |
| [20] | Baba | 2010 | PCS | CRC (stage I–IV) | NHS, HPFS. 731 CRC | HIF1A, EPAS1 (HIF-2A) expression in CRC | Sex, age, BMI (prediagnosis), family history of CRC, tumor location, stage, grade, MSI, CIMP, LINE-1 methylation, KRAS, BRAF, PIK3CA mutation, expression of TP53, PTGS2 (COX-2) | CRC-specific survival (221 events), overall survival (344 events) | HIF1A expression in CRC is associated with poor prognosis, and its prognostic effect is consistent across any stratum of the covariates. EPAS1 (HIF-2A) expression in CRC is not associated with prognosis and there is no interaction between EPAS1 and any of the covariates. | |
| [21] | Baba | 2010 | PCS | CRC (stage I–IV) | NHS, HPFS. 491 CRC | PTGER2 (prostaglandin EP2 receptor) expression in CRC | MSI, PTGS2 (COX-2) in CRC | Sex, age, BMI (prediagnosis), family history of CRC, tumor location, stage, grade, MSI, CIMP, LINE-1 methylation, KRAS, BRAF, PIK3CA mutation, expression of TP53, CTNNB1 | CRC-specific survival (139 events), overall survival (235 events) | PTGER2 expression in CRC is not associated with prognosis, and there is no interaction between PTGER2 and any of the covariates. |
| [23] | Baba | 2010 | PCS | CRC (stage I–IV) | NHS, HPFS. 1033 CRC | IGF2 DMR0 hypomethylation in CRC | Sex, age, BMI (prediagnosis), family history of CRC, tumor location, stage, grade, MSI, CIMP, LINE-1 methylation, KRAS, BRAF, PIK3CA mutation | CRC-specific survival (292 events), overall survival (494 events) | IGF2 DMR0 hypomethylation in CRC is associated with poor prognosis, and there is no interaction between IGF2 DMR0 hypomethylation and any of the covariates. | |
| [24] | Baba | 2010 | PCS | CRC (stage I–IV) | NHS, HPFS. 718 CRC | Phosphorylated PRKA (AMPK) expression in CRC | Phosphorylated MAPK3/1 (ERK) expression in CRC | Sex, age, BMI (prediagnosis), family history of CRC, tumor location, stage, grade, MSI, CIMP, LINE-1 methylation, KRAS, BRAF, PIK3CA mutation, expression of TP53, FASN | CRC-specific survival (194 events), overall survival (306 events) | There is a significant interactive prognostic effect between p-PRKA (p-AMPK) and p-MAPK3/1 in CRC. p-PRKA expression is associated with good prognosis in p-MAPK3/1-positive cases, but not in p-MAPK3/1-negative cases. |
| [25] | Baba | 2010 | PCS | CRC (stage I–IV) | NHS, HPFS. 717 CRC | Phosphorylated AKT expression in CRC | PIK3CA mutation in CRC | Sex, age, BMI (prediagnosis), family history of CRC, tumor location, stage, grade, MSI, CIMP, LINE-1 methylation, KRAS, BRAF mutation, expression of TP53, FASN | CRC-specific survival (210 events), overall survival (341 events) | p-AKT expression in CRC is associated with good prognosis, and there is no interaction between p-AKT and any of the covariates. |
| [173] | Chan | 2009 | PCS | CRC (stage I–III) | NHS, HPFS. 459 CRC | PTGS2 (COX-2) expression in CRC | Aspirin use (post-diagnosis) | CRC-specific survival (65 events), overall survival (167 events) | Aspirin decreases mortality of patients with PTGS2 (COX-2)-positive CRC, but not those with PTGS2-negative CRC. | |
| [57] | Fierstein | 2010 | PCS | CRC (stage I–IV) | NHS, HPFS. 452 CRC | CDK8 expression in CRC | CTNNB1 in CRC | Sex, age, BMI (prediagnosis), tumor location, stage, grade, MSI, CIMP, LINE-1 methylation, KRAS, BRAF, PIK3CA mutation, expression of TP53, CDKN1A (p21), CDKN1B (p27), CCND1, PTGS2 (COX-2), FASN | CRC-specific survival (116 events), overall survival (202 events) | CDK8 expression in CC is associated with poor prognosis and there is no interaction between CDK8 and any of the covariates. |
| [72] | Kure | 2009 | PCS | CRC (stage I–IV) | NHS, HPFS. 599 CRC | VDR expression in CRC | Sex, age, BMI (prediagnosis), family history of CRC, tumor location, stage, grade, MSI, CIMP, LINE-1 methylation, KRAS, BRAF, PIK3CA mutation, expression of TP53, CTNNB1, CDKN1A (p21), PTGS2 (COX-2) | CRC-specific survival (158 events), overall survival (260 events) | VDR expression in CRC is not associated with prognosis and there is no interaction between VDR and any of the covariates. | |
| [174] | Meyerhardt | 2009 | PCS | CC (stage I–III) | NHS, HPFS. 484 CRC | KRAS, PIK3CA mutation, expression of TP53, CDKN1A (p21), CDKN1B (p27), FASN | Physical activity (post-diagnosis) | CC-specific survival (50 events), overall survival (152 events) | Beneficial prognostic effect of physical activity may be limited to patients with CDKN1B (p27) nuclear+ CC. | |
| [92] | Nosho | 2009 | PCS | CRC (stage I–IV) | NHS, HPFS. 456 CRC | SIRT1 expression in CRC | BMI (pre-diagnosis) | Sex, age, family history of CRC, tumor location, stage, grade, MSI, CIMP, LINE-1 methylation, KRAS, BRAF, PIK3CA mutation, expression of TP53, CTNNB1, FASN, PTGS2 (COX-2) | CRC-specific survival (116 events), overall survival (200 events) | SIRT1 expression in CRC is not associated with prognosis and there is no interaction between SIRT1 and any of the covariates. |
| [93] | Nosho | 2009 | PCS | CRC (stage I–IV) | NHS, HPFS. 708 CRC | JC virus T antigen expression in CRC | Sex, age, BMI (prediagnosis), family history of CRC, tumor location, stage, grade, MSI, CIMP, LINE-1 methylation, KRAS, BRAF, PIK3CA mutation, expression of TP53, CTNNB1, FASN, PTGS2 (COX-2) | CRC-specific survival (182 events), overall survival (300 events) | JC virus T antigen expression in CRC is not associated with prognosis and there is no interaction between JC virus T antigen and any of the covariates. | |
| [175] | Nosho | 2009 | PCS | CRC (stage I–IV) | NHS, HPFS. 733 CRC | DNMT3B expression in CRC | CIMP in CRC | Sex, age, tumor location, stage, grade, MSI, CIMP, LINE-1 methylation, KRAS, BRAF, PIK3CA mutation, expression of TP53, CTNNB1 | CRC-specific survival (191 events), overall survival (313 events) | DNMT3B expression in CRC is not associated with prognosis and there is no interaction between DNMT3B and any of the covariates. |
| [2] | Ogino | 2008 | PCS | CC (stage I–IV) | NHS, HPFS. 647 CC | FASN expression in CC | BMI (pre-diagnosis) | Sex, age, tumor location, stage, grade, MSI, CIMP, KRAS, BRAF mutation, TP53 expression | CC-specific survival (160 events), overall survival (279 events) | High prediagnosis BMI increases mortality of patients with FASN+ CC, but not those with FASN-negative CC. Beneficial prognostic effect of FASN+ is limited to patients with non-obese prediagnosis BMI. |
| [176] | Ogino | 2008 | PCS | CC (stage I–IV) | NHS, HPFS. 662 CC | PTGS2 (COX-2) expression in CC | TP53 expression, MSI in CRC | Sex, age, tumor location, stage, grade, CIMP, KRAS, BRAF mutation | CC-specific survival (163 events), overall survival (283 events) | The adverse prognostic effect of PTGS2 (COX-2) is especially apparent in TP53-negative CC. |
| [177] | Ogino | 2008 | PCS | CC (stage I–IV) | NHS, HPFS. 643 CC | LINE-1 methylation in CC | Sex, age, tumor location, stage, grade, MSI, CIMP, TP53 expression, KRAS, BRAF mutation | CC-specific survival (160 events), overall survival (276 events) | The adverse prognostic effect of LINE-1 hypomethylation is consistent across any stratum of potential effect modifiers. | |
| [95] | Ogino | 2009 | PCS | CRC (stage I–IV) | NHS, HPFS. 470 CRC | PPARG expression in CRC | BMI (pre-diagnosis) | Sex, age, family history of CRC, tumor location, stage, grade, MSI, CIMP, LINE-1 methylation, KRAS, BRAF, PIK3CA mutation, expression of TP53, CDKN1A (p21), CDKN1B (p27), CCND1, FASN, PTGS2 (COX-2), CTNNB1 | CRC-specific survival (118 events), overall survival (199 events) | PPARG expression is associated with good prognosis, and its effect is not modified by any of the covariates. |
| [96] | Ogino | 2009 | PCS | CRC (stage I–IV) | NHS, HPFS. 546 CRC | STMN1 expression in CRC | BMI (pre-diagnosis) | Sex, age, family history of CRC, tumor location, stage, grade, MSI, CIMP, LINE-1 methylation, KRAS, BRAF, PIK3CA mutation, expression of TP53, CDKN1A (p21), CDKN1B (p27), CCND1, FASN, PTGS2 (COX-2) | CRC-specific survival (147 events), overall survival (236 events) | Obesity (prediagnosis) increases mortality of patients with STMN1+ CRC, but not those with STMN1-negative CRC. The beneficial prognostic effect of STMN1+ is limited to patients with non-obese prediagnosis BMI. |
| [97] | Ogino | 2009 | PCS | CC (stage I–III) | NHS, HPFS. 450 CC | PIK3CA mutation in CC | BMI (pre-diagnosis), KRAS mutation in CRC | Sex, age, tumor location, stage, grade, MSI, CIMP, LINE-1 methylation, BRAF, expression of TP53 | CC-specific survival (66 events), overall survival (152 events) | PIK3CA mutation in CC is associated with poor prognosis, and its adverse effect may be limited to patients with KRAS-WT tumors. |
| [178] | Ogino | 2009 | CC (stage III) | Inter-group trial CALGB 89803. 508 CC | KRAS mutation in CC | Sex, age, BMI, tumor location, stage, performance status, clinical bowel obstruction, bowel perforation, treatment arm, MSI in CC. | Disease-free survival (196 events), recurrence-free survival (180 events), overall survival (149 events) | KRAS mutation is not associated with clinical outcome. There is no interaction between KRAS and any of the covariates. | ||
| [98] | Ogino | 2009 | PCS | CC (stage I–IV) | NHS, HPFS. 630 CC | CDKN1B (p27) localization in CC | BMI (pre-diagnosis) | Sex, age, family history of CRC, tumor location, stage, grade, MSI, CIMP, KRAS, BRAF, PIK3CA mutation, expression of TP53, CDKN1A (p21), CCND1, CTNNB1 (β-catenin), FASN, PTGS2 (COX-2) | CC-specific survival (160 events), overall survival (272 events) | Obesity (prediagnosis) increases mortality of patients with CDKN1B (p27) nuclear+ CC, but not those with CDKN1B-altered CC. The beneficial prognostic effect of CDKN1B alteration is limited to obese patients (prediagnosis). |
| [99] | Ogino | 2009 | PCS | CC (stage I–IV) | NHS, HPFS. 647 CC | CDKN1A (p21) expression in CC | BMI (pre-diagnosis) | Sex, age, family history of CRC, tumor location, stage, grade, MSI, CIMP, LINE-1 methylation, KRAS, BRAF, PIK3CA mutation, expression of TP53, CCND1 | CC-specific survival (162 events), overall survival (279 events) | Obesity (prediagnosis) increases mortality of patients with CDKN1A (p21) expressing CC, but not those with CDKN1A-lost CC. CDKN1A loss is associated with good prognosis in patients 60 years old or older, but with poor prognosis in patients younger than 60 years. |
| [100] | Ogino | 2009 | PCS | CC (stage I–IV) | NHS, HPFS. 602 CC | CCND1 (cyclin D1) expression in CC | MSI in CRC | Sex, age, BMI (prediagnosis), family history of CRC, tumor location, stage, grade, CIMP, KRAS, BRAF, mutation, expression of TP53, CDKN1A, CDKN1B, PTGS2 (COX-2), FASN | CC-specific survival (153 events), overall survival (259 events) | The beneficial prognostic effect of CCND1 expression in CC may be limited to MSI-low/MSS CC. |
| [101] | Ogino | 2009 | PCS | CC (stage I–IV) | NHS, HPFS. 532 CRC | 18q LOH in CRC | Sex, age, BMI (prediagnosis), family history of CRC, tumor location, stage, grade, MSI, CIMP, LINE-1 methylation, KRAS, BRAF, PIK3CA, mutation, expression of TP53, CTNNB1, JC virus T antigen | CRC-specific survival (155 events), overall survival (239 events) | 18q LOH in CRC is not associated with prognosis. There is no interaction between 18q LOH and any of the covariates. | |
| [121] | Shima | 2010 | PCS | CRC (stage I–IV) | NHS, HPFS. 902 CRC | CDKN2A (p16) promoter methylation, loss of CDKN2A | Sex, age, BMI (prediagnosis), family history of CRC, tumor location, stage, grade, MSI, CIMP, LINE-1 methylation, KRAS, BRAF, PIK3CA, mutation, expression of TP53, CDKN1A, CDKN1B, CCND1, CTNNB1, PTGS2, FASN. | CRC-specific survival (235 events), overall survival (409 events) | CDKN2A promoter methylation (or loss of expression) in CRC is not associated with prognosis. There is no interaction between CDKN2A and any of the covariates. |
Only studies with >300 tumor cases (generally with >100 events) are listed. To examine interactions with adequate statistical power, a sample size of at least 300 cases is necessary.
Official gene and protein symbols are described in the HUGO-Gene Nomenclature Committee (HGNC) website (www.genenames.org).
*
Sample size is based on tumor tissue data available cases.
Abbreviations: BMI, body mass index; CALGB, Cancer and Leukemia Group B; CC, colon cancer; CIMP, CpG island methylator phenotype; CIN, chromosomal instability; COX-2, cyclooxygenase 2; CRC, colorectal cancer; DMR, differentially methylated region; HPFS, Health Professionals Follow-up Study; HR, hazard ratio; LOH, loss of heterozygosity; MSI, microsatellite instability; MSI-H, microsatellite instability-high; MSI-L, microsatellite instability-low; MSS, microsatellite stability; NHS, Nurses’ Health Study; NLCS, The Netherlands Cohort Study; PCS, prospective cohort study; PTGS2, prostaglandin endoperoxide synthase 2; WT, wild-type.