Table 1.
Molecular pathologic epidemiology studies on possible etiologic factors and molecular changes in colorectal neoplasia
| Ref. | First author | Year | Study design | Tissue specimens | Study cohort, sample sizes (N)* and notes | Exposure variables | Potential modifiable factors | Outcome variables | Main findings on modifiable (or genetic) factors and tumoral molecular changes |
|---|---|---|---|---|---|---|---|---|---|
| Case-case studies | |||||||||
| [17] | Arain | 2010 | Case-case | CC | 194 CC (63 interval CC), 0 non-cancer controls | Colonoscopy within 5 years prior to diagnosis of CC (interval cancer) | CIMP, MSI in CC | Colonoscopy within 5 years prior to diagnosis of CC is associated with CIMP and MSI in CC. | |
| [18] | Baba | 2009 | Case-case (in PCS) | CRC | NHS, HPFS. 621 CRC, 0 non-cancer controls | BMI (prediagnosis), family history of CRC | CDX2 expression in CRC | BMI or family history of CRC is not significantly associated with loss of CDX2 expression in CRC. | |
| [19] | Baba | 2009 | Case-case (in PCS) | CRC | NHS, HPFS. 517 CRC, 0 non-cancer controls | BMI (prediagnosis), family history of CRC | AURKA expression in CRC | BMI or family history of CRC is not significantly associated with AURKA expression in CRC. | |
| [20] | Baba | 2010 | Case-case (in PCS) | CRC | NHS, HPFS. 516 CRC, 0 non-cancer controls | BMI (prediagnosis), family history of CRC | HIF1A, EPAS1 (HIF-2A) expression in CRC | BMI or family history of CRC is not significantly associated with HIF1A or EPAS1 expression in CRC. | |
| [21] | Baba | 2010 | Case-case (in PCS) | CRC | NHS, HPFS. 731 CRC, 0 non-cancer controls | BMI (prediagnosis), family history of CRC | PTGER2 (prostaglandin EP2 receptor) expression in CRC | BMI or family history of CRC is not significantly associated with PTGER2 expression in CRC. | |
| [22] | Baba | 2010 | Case-case (in PCS) | CRC | NHS, HPFS. 869 CRC, 0 non-cancer controls | BMI (prediagnosis), family hisotry of CRC, smoking | LINE-1 methylation in CRC | Family history of CRC may be associated with LINE-1 hypomethylation in CRC. LINE-1 extreme hypomethylators are associated with young age of onset. | |
| [23] | Baba | 2010 | Case-case (in PCS) | CRC | NHS, HPFS. 1105 CRC, 0 non-cancer controls | BMI (prediagnosis), family history of CRC | IGF2 differentially methylated region-0 (DMR0) hypomethylation in CRC | Family history of CRC is associated with IGF2 DMR0 hypomethylation. | |
| [24] | Baba | 2010 | Case-case (in PCS) | CRC | NHS, HPFS. 718 CRC, 0 non-cancer controls | BMI (prediagnosis), family history of CRC | phospho-PRKA (AMPK) expression in CRC | Family history of CRC or BMI is not associated with phospho-PRKA (AMPK) expression in CRC. | |
| [25] | Baba | 2010 | Case-case (in PCS) | CRC | NHS, HPFS. 717 CRC, 0 non-cancer controls | BMI (prediagnosis), family history of CRC | phospho-AKT expression in CRC | Family history of CRC or BMI is not associated with phospho-AKT expression in CRC. | |
| [26] | Bapat | 2009 | Case-case | CRC | CCFR.3143 CRC | Family history of CRC and endometrial cancer | MSI in CRC | Family history of CRC and endometrial cancer is associated with MSI-high in CRC. Familial risk associated with MSI-high CRC is primarily driven by the Amsterdam criteria patients. | |
| [30] | Brink | 2003 | Case-case (in PCS) | CRC | NLCS.737 CRC, 0 non-cancer controls | Family history of CRC | KRAS mutation in CRC | Family history of CRC is not associtade with KRAS mutation in CRC | |
| [37] | Chang | 2007 | Case-case | CRC | 195 CRC | MTHFR codon 222 SNP, plasma folate | MSI, aneuploidy in CRC | MTHFR codon 222 variant is associated with MSI-H CRC. Plasma folate is lower in aneuploid MSS CRC than in diploid MSS CRC. | |
| [38] | Chen | 2007 | Case-case | CRC | 387 CRC | MLH1 SNPs | MLH1 methylation in CRC | MLH1 rs1800734 (−93G>A) SNP is associated with MLH1 methylation in CRC. | |
| [40] | Clarizia | 2006 | Case-case | CRC | 105 CRC, 0 non-cancer controls | MTHFR codon 222 SNP | MSI, methylation in MLH1, CDKN2A, MGMT, DAPK1, p14 in CRC | MTHFR codon 222 SNP variant is associated with MSI-H in CRC. | |
| [52] | Eaton | 2005 | Case-case | CC | NCCCS.486 CC, 0 non-cancer controls | MTHFR SNPs | Dietary and supplement folate | MSI in CRC | Among high folate intake group (≥400 ug/day), the presence of either MTHFR SNP variant is associated with MSS. |
| [54] | Fernandez-Peralta | 2010 | Case-case | CRC | 143 CRC | MTHFR SNPs | MSI, LOH at APC, DCC, TP53, MLH1, MSH2, mutation in KRAS, BAX, TGFBR2 in CRC | None of molecular feature in CRC is differentially related to MTHFR SNP with certainty. | |
| [55] | Ferraz | 2004 | Case-case | CRC | 165 CRC, 0 non-cancer controls | GSTM1, GSTT1, GSTP1, NAT2 genotypes | KRAS, TP53 mutations in CRC | GSTT1 or GSTP1 SNPs may be associated with KRAS or TP53 mutations in CRC. | |
| [57] | Firestein | 2010 | Case-case(in PCS) | CRC | 470 CRC, 0 non-cancer controls | BMI (prediagnosis) | CDK8 expression in CRC | Female sex is associated with CDK8 expression in CRC. BMI (prediagnosis) is not associated with CDK8 expression in CRC. | |
| [58] | Gonzalo | 2010 | Case-case | CRC | 82 CRC patients (37 synchronous CRC patients, 4 metachronous CRC patients) | Tumor synchronicity/metachronicity | Methylation in MGMT, CDKN2A, SFRP1, TMEFF2, HS3ST2, RASSF1, GATA4 in CRC | Tumor synchronicity/metachronicity is associated with methylation in MGMT and RASSF1 in CRC. | |
| [59] | Gruber | 2007 | Case-case | CRC | MECCS (northern Israel). 133 CRC | SNP rs10505477 in 8q24 | mRNA expression of genes in 8q24 in CRC | SNP rs10505477 is not associated with any difference in expression of examined genes in 8q24. | |
| [60] | Hansen | 2010 | Case-case | CRC | 109 CRC, 0 non-cancer controls | KDR SNPs | Microvessel density (assessed by immunohisto-chemistry for ENG and CD34) in CRC | KDR rs2305948 SNP T variant is associated with high microvessel density. | |
| [61] | Hazra | 2010 | Case-case (in PCS) | CRC | NHS, HPFS.182 CRC, 0 non-cancer controls | SNPs in one-carbon metabolism genes | CIMP, LINE-1 methylation in CRC | MTHFR rs1801131 (codon 429) and TCN2 rs1801198 SNP variants are associated with CIMP-high in CRC. | |
| [62] | Huang | 2009 | Case-case | CRC | 151 CRC, 0 non-cancer controls | NAT2 genotypes | KRAS mutation in CRC | NAT2 genotype may be associated with KRAS mutation in CRC in female. | |
| [65] | Irahara | 2010 | Case-case (in PCS) | CRC | NHS, HPFS. 225 CRC, 0 non-cancer controls | BMI (prediagnosis), family history of CRC | NRAS mutation in CRC | There is no association between BMI or family history of CRC and NRAS mutation in CRC. | |
| [67] | Jensen | 2008 | Case-case | CRC | 130 CRC, 0 non-cancer controls | Plasma homocysteine | MSI in CRC | MSI-H cases show higher plasma homocysteine level than MSS cases. | |
| [68] | Kang | 2008 | Case-case | CRC | 188 CRC | p14 (CDKN2A/ARF) SNPs | p14 methylation in CRC | p14 promoter SNP haplotype is associated with p14 methylation in CRC. | |
| [70] | Kawakami | 2003 | Case-case | CRC | 103 CRC, 0 non-cancer controls | TYMS, MTHFR, MTR, CBS genotypes | 5, 10-methylene-tetrahydrofolate, tetrahydrofolate, methylation in MLH1, TIMP3, p14 (CDKN2A/ARF), CDKN2A, MINT-2, DAPK, APC in CRC | MTHFR rs1801133 SNP (codon 222) with decreased 5,10-methylene-tetrahydrofolate and tetrahydrofolate contents in CRC. homozygous variant is associated | |
| [71] | Konishi | 2009 | Case-case | CRC | 97 CRC patients (28 synchronous CRC patients) | Tumor synchronicity | Methylation in MINT-1, MINT-2, MINT-31, MLH1, CDKN2A, p14, MGMT, ESR1 in CRC | Synchronous CRC is associated with higher methylation levels at p14 methylation level at MINT-31 in CRC. (CDKN2A/ARF) and MGMT and lower | |
| [72] | Kure | 2009 | Case-case (in PCS) | CRC | NHS, HPFS. 619 CRC, 0 non-cancer controls | BMI (prediagnosis), family history of CRC | VDR expression in CRC | BMI or family history of CRC is not significantly associated with VDR expression in CRC. | |
| [74] | Langerod | 2002 | Case-case | CRC | 162 CRC, 0 controls | TP53 codon 72 SNP | TP53 mutation in CRC | TP53 codon 72 SNP is not related to TP53 mutation in CRC, but to TP53 mutation in breast cancer (N=390). | |
| [79] | Lindor | 2010 | Case-case | CRC | CCFR. 789 CRC | Parent of origin family history of CRC | MSI in CRC | Among overall CRC cases, HNPCC, or MSS cancer cases, family history of CRC in father is associated with lower age of onset of CRC in daughters than in family history of CRC in mother, but no such difference in age of onset is present among affected sons. | |
| [81] | Lubbe | 2009 | Case-case | CRC | NSCCG. 488 CRC | Family history of CRC in first degree relatives | MSI in CRC | Family history of CRC in first degree relatives is associated with MSI-H CRC. | |
| [84] | Luchtenborg | 2005 | Case-case (in PCS) | CRC | NLCS. 656 CRC | Family history of CRC | APC, KRAS mutation, MLH1 loss in CRC | APC, KRAS or MLH1 alteration is not associated with family history of CRC. | |
| [85] | Martinez | 1999 | Case-case | CRA | WBFT. 678 CRA, 0 non-cancer controls | Various nutrients, alcohol, family history, aspirin use, smoking, BMI, physical activity, hormone use | KRAS mutation in CRA | Folate intake is inversely associated with KRAS mutation in CRA. | |
| [86] | Mas | 2007 | Case-case | CRC | 120 CRC, 0 con-cancer controls | Various nutrients | CDKN2A (p16), p14, MLH1 methylation in CRC | Patents with CDKN2A methylation consumed less folate, vitamin A, vitamin B1, potassium and iron. Patients with p14 or MLH1 methylation consumed less vitamin A. |
|
| [87] | Mokarram | 2008 | Case-case | CC | 151 CC, 0 non-cancer controls | Folate, vitamin B12 in serum | MTHFR rs1801133 SNP | Methylation in MLH1, MSH2, CDKN2A (p16) in CC | Relation between folate/B12 and methylation in CC may be modified by MTHFR rs1801133 (codon 222) SNP. |
| [89] | Naguib | 2010 | Case-case (in PCS) | CRC | EPIC-Norfolk Study. 186 CRC, 0 non-cancer controls | BMI, smoking, physical activity, HRT, alcohol, dietary factors | KRAS and BRAF mutations in CRC | KRAS-mutated tumors are associated with higher white meat consumption, compared to KRAS-wild-type tumors. | |
| [91] | Nosho | 2009 | Case-case (in PCS) | CRC | NHS, HPFS. 863 CRC, 0 non-cancer controls | Tumor synchronicity | BMI, family history of CRC | MSI, CIMP, LINE-1 methylation, 18q LOH, KRAS, BRAF, PIK3CA mutation, expression of TP53, CTNNB1, CDKN1A (p21), CDKN1B (p27), CCND1, FASN, PTGS2 (COX-2) in CRC | Tumor synchronicity is associated with CIMP-high, MSI-H, and BRAF mutation. There is no significant modifying effect by BMI or family history of CRC. |
| [92] | Nosho | 2009 | Case-case (in PCS) | CRC | NHS, HPFS. 485 CRC, 0 non-cancer controls | BMI (prediagnosis), family history of CRC | SIRT1 expression in CRC | BMI or family history of CRC is not significantly associated with SIRT1 expression in CRC. | |
| [93] | Nosho | 2009 | Case-case (in PCS) | CRC | NHS, HPFS. 766 CRC, 0 non-cancer controls | BMI (prediagnosis), family history of CRC | JC virus T antigen expression in CRC | Family history of CRC may be inversely associated with JC virus T antigen expression in CRC. | |
| [94] | Ogino | 2007 | Case-case (in PCS) | CRC | NHS, HPFS. 182 CRC, 0 non-cancer controls | MGMT SNPs | MGMT methylation, CIMP, MSI, 18q LOH, KRAS, BRAF mutation in CRC | MGMT rs16906252 SNP variant is associated with MGMT methylation (adjusted OR=18; 95% CI, 6.2–52) and loss of expression. | |
| [2] | Ogino | 2008 | Case-case (in PCS) | CC | NHS, HPFS. 623 CC, 0 non-cancer controls | BMI (prediagnosis) | FASN expression in CRC | There is an inverse relation between BMI and FASN expression in CRC. | |
| [95] | Ogino | 2009 | Case-case (in PCS) | CRC | NHS, HPFS. 470 CRC, 0 non-cancer controls | BMI (prediagnosis), family history of CRC | PPARG expression in CRC | There is no relation between BMI or family history of CRC and PPARG expression in CRC. | |
| [96] | Ogino | 2009 | Case-case (in PCS) | CRC | NHS, HPFS. 546 CRC, 0 non-cancer controls | BMI (prediagnosis), family history of CRC | STMN1 expression in CRC | There is no relation between BMI or family history of CRC and STMN1 expression in CRC. | |
| [97] | Ogino | 2009 | Case-case (in PCS) | CC | NHS, HPFS. 450 CC, 0 non-cancer controls | BMI (prediagnosis) | PIK3CA mutation in CC | There is no relation between BMI and PIK3CA mutation in CC. | |
| [98] | Ogino | 2009 | Case-case (in PCS) | CC | NHS, HPFS. 630 CC, 0 non-cancer controls | BMI (prediagnosis), family history of CRC | CDKN1B (p27) localization in CC | There is no relation between BMI or family history of CRC and CDKN1B (p27) localization in CC. | |
| [99] | Ogino | 2009 | Case-case (in PCS) | CC | NHS, HPFS. 647 CC, 0 non-cancer controls | BMI (prediagnosis), family history of CRC | CDKN1A (p21) expression in CC | There is no relation between BMI or family history of CRC and CDKN1A (p21) expression in CC. | |
| [100] | Ogino | 2009 | Case-case (in PCS) | CC | NHS, HPFS. 602 CC, 0 non-cancer controls | BMI (prediagnosis), family history of CRC | CCND1 (cyclin D1) expression in CC | There is no relation between BMI or family history of CRC and CCND1 expression in CC. | |
| [101] | Ogino | 2009 | Case-case (in PCS) | CRC | NHS, HPFS. 555 CRC, 0 non-cancer controls | BMI (prediagnosis), family history of CRC | 18q LOH in CRC | Obesity (prediagnosis) is associated with 18q LOH in CRC. | |
| [102] | Oyama | 2004 | Case-case | CRC | 194 CRC, 0 non-cancer controls | MTHFR SNPs | Methylation in CDKN2A, MLH1, TIMP3, p14 in CRC | MTHFR codon 429 SNP variant is associated with CDKN2A methylation in CRC. | |
| [103] | Park | 2010 | Case-case (in PCS) | CRC | EPIC-Norfolk Study. 185 CRC, 0 non-cancer controls | Dietary factors, family history, BMI, physical activity, smoking | TP53 mutation in CRC | There is a positive relation between meat intake and TP53 mutation in Duke’s stage C and D cases, while there is a positive relation between meat intake and wild-type TP53 in Duke’s stage A and B cases. | |
| [104] | Paz | 2002 | Case-case | CRC | 118 CRC, 0 non-cancer controls | Genotypes of one-carbon metabolism genes | Methylation in CDKN2A, p14, MLH1, MGMT, APC, STK11, DAPK1, GSTP1, BRCA1, RARB, CDH1, RASSF1 in CRC | Results on all cancers (CRC, breast presented, and CRC-specific results are not presented. cancers, and lung cancers) are | |
| [109] | Ricciardiello | 2003 | Case-case | CRA | 70 CRA | Family history of CC | MSI, MLH1 methylation, expression of MLH1 and MSH2 in CRA | Family history of CC is associated with MLH1 methylation and loss of MLH1 in CRA. | |
| [110] | Rozek | 2008 | Case-case | CRC | MECCS (northern Isreal). 82 CRC | CDX2 SNPs and haplotypes | CDX2 mRNA expression in CRC | CDX2 SNPs or haplotypes are not associated with CDX2 mRNA expression in CRC. | |
| [112] | Samowitz | 1995 | Case-case | CC | 188 CC | Family history of CRC, GSTM1 genotype | MSI in CC | Family history of CRC or GSTM1 genotype is not associated with MSI in CC. | |
| [121] | Shima | 2010 | Case-case (in PCS) | CRC | HPFS, NHS. 902 CRC, 0 non-cancer controls | BMI, family history of CRC | CDKN2A (p16) promoter methylation, loss of CDKN2A in CRC | There is no relation between BMI or family history of CRC and CDKN2A methylation (or loss of expression) in CRC. | |
| [122] | Sinicrope | 2010 | Case-case | CC | 7 colon cancer adjuvant therapy trials. 2222 CC, 0 non-cancer controls | BMI | Mismatch repair protein loss (or MSI-H) in CC | High BMI is inversely associated with MSI in CC. | |
| [141] | van Engeland | 2003 | Case-case | CRC | NLCS. 121 CRCs,0 non-cancer controls. | Various nutrients, alcohol | Methylation in APC, CDKN2A (p16), p14, MLH1, MGMT, RASSF1A in CRC | Folate and alcohol intake may be associated with promoter hypermethylation in CRC. | |
| [143] | Ward | 2004 | Case-case | CRC | 547 CRC | Family history of CRC, family history of any cancer | CIMP in CRC | CIMP in CRC is not associated with family history of CRC or any cancer. | |
| [149] | Wu | 2001 | Case-case | CC | Los Angeles County Cancer Surveillance Program (a part of SEER). 276 CC, 0 non-cancer controls | Smoking, red meat cooking practice | MSI in CC | Certain red meat cooking (well-doing) and heterocyclic amine score are associated with MSI-H CC. Smoking is associated with MSI-H CC. | |
| [150] | Wu | 2010 | Case-case | CC | Los Angeles County Cancer Surveillance Program (a part of SEER). 280 CC | Hormone therapy | ESR1, ESR2, PGR, CDKN2A, MGMT, MYOD1, MLH1 methylation in CC | There may be an inverse association between hormone therapy and ESR1 methylation in CC. | |
| Case-cohort studies | |||||||||
| [28] | Bongaerts | 2006 | Case-cohort study | CRC | NLCS. 4076 subcohort, 578 CRC | Alcohol intake | KRAS mutation in CRC | Alcohol intake does not influence KRAS mutation in CRC. | |
| [29] | Bongaerts | 2007 | Case-cohort study | CRC | NLCS. 4076 subcohort, 573 CRC | Alcohol intake | KRAS, APC mutation, TP53 expression, MLH1 loss in CRC | Alcohol intake does not influence KRAS, APC mutation, TP53 or MLH1 alteration in CRC. | |
| [31] | Brink | 2004 | Case-cohort study | CRC | NLCS. 2948 subcohort, 608 CRC | Various fat components | KRAS mutation in CRC | High intake of polyunsaturated fat is associated with risk of KRAS-mutated CC. | |
| [32] | Brink | 2005 | Case-cohort study | CRC | NLCS. 2948 subcohort, 608 CRC | Meat consumption | KRAS mutation in CRC | There may be an inverse association between pork consumption and KRAS wild-type CRC. | |
| [33] | Brink | 2005 | Case-cohort study | CRC | NLCS. 3048 subcohort, 330 CRC | Various nutrients | KRAS mutation in CRC | Folate intake is associated with lower risk of KRAS-mutated CRC in men, but not in women. | |
| [46] | de Vogel | 2006 | Case-cohort study | CRC | NLCS. 4343 subcohort. 547 CRC with APC data | Various nutrients | APC mutation in CRC | Folate may influence the occurrence of APC mutation in CRC. | |
| [47] | de Vogel | 2008 | Case-cohort study | CRC | NLCS. 4059 subcohort. 648 CRC | Various nutrients | MLH1 methylation, MLH1 expression, MSI, BRAF mutation in CRC | Among men, folate intake may increase risk of BRAF-mutated CRC, and vitamin B6 may increase risk of MLH1 methylated CRC. | |
| [48] | de Vogel | 2009 | Case-cohort study | CRC | NLCS. 4774 subcohort. 373 CRC | SNPs in folate enzyme genes metabolizing | CIMP, MLH1 methylation, MSI in CRC | MTR rs1805087 (A2756G) SNP is inversely associated with CIMP in men. | |
| [64] | Hughes | 2009 | Case-cohort study | CRC | NLCS. 4650 subcohort, 662 CRC | Hunger in adolescence and young adulthood | CIMP, MSI in CRC | Exposure to hunger in young age is associated with decreased risk of CIMP+ CRC, but not associated with CIMP-negative CRC. | |
| [82] | Luchtenborg | 2005 | Case-cohort study | CRC | NLCS. Subcohort 2948. 588 CRC | Meat and fish consumption | APC mutation, MLH1 loss in CRC | Beef consumption is associated with risk of CC without APC mutation. | |
| [83] | Luchtenborg | 2005 | Case-cohort study | CRC | NLCS. Subcohort 2948. 650 CRC | Smoking | GSTM1, GSTT1 genotypes | APC mutation, MLH1 loss in CRC | Smoking increases risk of APC-WT CRC, and there is no modifying effect of GSTM1 or GSTT1 genotypes. |
| [144] | Wark | 2005 | Case-cohort study | CRC | NLCS. 3048 subcohort, 441 CC | Fruits, vegetable consumption | MLH1 loss in CC | Fruits consumption decrease risk of MLH1-lost CC, but not that of MLH1-expressing CC. | |
| [146] | Weijenberg | 2007 | Case-cohort study | CRC | NLCS. 2948 subcohort, 531 CRC | Various fat components | APC, KRAS mutation, MLH1 loss in CRC | High intakes of polyunsaturated fatty acid and linoleic acid increase risk of KRAS-mutated CC. | |
| [147] | Weijenberg | 2008 | Case-cohort study | CRC | NLCS. 4083 subcohort, 428 CRC | Smoking | KRAS mutation in CRC | Effect of smoking on CRC risk is not different according to KRAS mutational status. | |
| Case-control studies (CCS) | |||||||||
| [27] | Bautista | 1997 | CCS | CRC | 106 CRC, 295 controls | Various nutrients | KRAS mutation in CRC | Monounsaturated fat is inversely associated with KRAS wild-type CRC compared to controls, but no such association is present for KRAS-mutated CRC. | |
| [34] | Campbell | 2009 | CCS | CC | KPMCP-UT-MN. 1211 CC, 1972 controls | SNPs in MLH1, MSH6 | Smoking, dietary pattern | MSI in CC | Smoking does not modify MSI-H CC risk that is conferred by MLH1 rs1800734 (−93G>A) SNP. |
| [35] | Campbell | 2010 | CCS | CRC | CCFR. 1250 CRC, 1880 controls (unaffected siblings) | BMI, BMI at age 20, weight gain | MSI in CRC | Obesity is associated with MSS CRC risk, but not with MSI-H CRC risk. | |
| [39] | Chia | 2006 | CCS | CRC | CCFR. 1792 CRC, 1501 controls. | Smoking, NSAIDs | MSI in CRC | Smoking is associated with increased risk of MSI-H CRC, but not strongly with that of MSI-L/MSS CRC. | |
| [41] | Curtin | 2007 | CCS | CC | KPMCP-UT-MN. 916 CC, 1972 controls | SNPs in one-carbon metabolism genes | One-carbon nutrients, alcohol, dietary pattern | CIMP in CC | MTHFR rs1801131 (codon 429) SNP may interact with alcohol intake and dietary pattern to modify CIMP+ CC risk. |
| [42] | Curtin | 2007 | CCS | CC | KPMCP-UT-MN. 1206 CC, 1962 controls | TYMS SNPs | MSI, TP53, KRAS mutations in CC | TYMS SNPs are not differentially associated with CC by MSI, TP53 or KRAS status. | |
| [43] | Curtin | 2009 | CCS | CC | KPMCP-UT-MN. 1604 CC, 1969 controls | SNPs in base excision repair genes | Smoking | MSI, CIMP, mutations in BRAF, KRAS, TP53 in CC | There is no significant effect modification by smoking status. |
| [44] | Curtin | 2009 | CCS | CC | KPMCP-UT-MN. 1048 CC, 1964 controls | MSH6 rs1042821 SNP | Alcohol intake, age, family history | CIMP, MSI, BRAF mutation in CC | MSH6 rs1042821 SNP is associated with CIMP+ CC, and this relation is not modified by alcohol intake, age at diagnosis or family history. |
| [45] | Curtin | 2009 | CCS | Rectal cancer | KPMCP-UT-MN. 750 rectal cancers, 1201 controls | GSTM1, NAT2 genotypes | Smoking | MSI, CIMP, TP53, KRAS, BRAF mutation in rectal cancers | Smoking is associated with CIMP, TP53, BRAF mutation in rectal cancer. |
| [49] | Diergaarde | 2003 | CCS | CC | Population-based case-control study in The Netherlands. 176 CC, 249 controls | Smoking | KRAS, TP53, APC mutations, MSI in CC | Smoking may be associated with transversion mutations and with TP53-negative CC. | |
| [50] | Diergaarde | 2003 | CCS | CC | Population-based case-control study in The Netherlands. 184 CC, 259 controls | Various food and nutrients | MSI, MLH1 methylation, expression of MLH1 and MSH2 in CC | Red meat intake may differentially modify CC risk stratified by MSI status. | |
| [51] | Diergaarde | 2003 | CCS | CC | Population-based case-control study in The Netherlands. 184 CC, 259 controls | Various food and nutrients | APC mutation in CC | Alcohol intake may differentially modify CC risk stratified by APC mutation status. | |
| [56] | Figueiredo | 2010 | CCS | CRC | CCFR. 1200 CRC, 1880 matched unaffected sibling controls. | FOLR1, FPGS, GGH, SLC19A1 SNPs | Dietary one-carbon nutrients | MSI in CRC | CRC risks associated with any SNP do not significantly differ by MSI status. |
| [63] | Hubner | 2007 | CCS | CRC | NSCCG. 1649 CRC, 2692 non-cancer controls | MTHFR rs1801133 SNP | MSI in CRC | MTHFR rs1801133 SNP (codon 222) variant is associated with MSI-H CRC compared to controls, but not with MSS CRC. | |
| [66] | Jacobs | 2010 | CCS | CRC | CCFR. 1182 CRC, 1880 matched unaffected sibling controls. | SNPs in RXRA, CASR | MSI in CRC | RXRA SNP rs12004589 is associated with MSI-high cancer, but not with MSS/MSI-low cancer. | |
| [69] | Karpinski | 2010 | CCS | CRC | 186 CRC, 140 con-cancer controls | MTHFR, TYMS, DNMT3B genotypes | CIMP in CRC | Compared to controls, DNMT3B - 283T>C SNP is associated inversely with CIMP+ CRC, but not with CIMP− CRC. | |
| [73] | Lafuente | 2000 | CCS | CRC | 117 CRC, 296 controls | NQO1 SNP | KRAS mutation in CRC | KRAS codon 12 mutations are associated with NQO C609T SNP. | |
| [75] | Laso | 2004 | CCS | CRC | 117 CRC, 296 controls | Micro-nutrients | KRAS mutation in CRC | KRAS codon 12 mutations are associated with lower intake of vitamin A, B1, D and iron than controls. | |
| [76] | Levine | 2010 | CCS | CRC | CCFR. 1133 CRC, 1787 controls (unaffected siblings) | MTHFR SNPs | MSI in CRC | MTHFR rs1801133 (codon 222) SNP variant is associated with a decreased risk of MSI-L/MSS CRC. | |
| [77] | Levine | 2010 | CCS | CRC | CCFR. 1185 CRC, 1787? controls (unaffected siblings) | SNPs of one-carbon metabolism genes | Folate and multi-vitamin supplement use, dietary folate, family history of CRC | MSI in CRC | SNPs of one-carbon metabolism genes are not associated with CRC differently by MSI status. |
| [80] | Lindor | 2010 | CCS | CRC | CCFR. 940 CRC, 940 controls | Smoking, SERPINA1 SNP | MSI in CRC | Smoking is associated with MSI-H CRC in patients ≥age 50. | |
| [88] | Naghibalhos saini | 2010 | CCS | CRC | 151 CRC, 231 controls | MTHFR SNPs (rs1801133, rs1801131) | MSI in CRC | There is no significant difference in risks associated with MTHFR SNPs between MSI and MSS cancers. | |
| [90] | Newcomb | 2007 | CCS | CRC | Cancer Surveillance System (a part of SEER). 311 CRC, 1062 controls | Exogenous hormone use | MSI in CRC | The relation between hormone use and CRC risk does not differ by MSI status. | |
| [105] | Plaschke | 2003 | CCS | CRC | 287 CRC, 346 controls | MTHFR SNPs | MSI in CRC | MTHFR SNPs are not associated with MSI-H CRC. | |
| [106] | Poynter | 2009 | CCS | CRC | CCFR. Case-unaffected sibling design. 1564 CRC, 4486 controls | Smoking, alcohol | MSI in CRC | Smoking is associated with increased risk of MSI-H CRC (OR, 1.94; 95% CI, 1.09–3.46). Alcohol intake is associated with increased risk of MSI-L CRC (OR, 1.85; 95% CI, 1.06–3.24). | |
| [107] | Poynter | 2010 | CCS | CRC | CCFR. Case-unaffected sibling design. 1200 CRC, 1880 controls | VDR, GC SNPs | MSI in CRC | GC rs222029, rs222016 and rs16847039 SNPs are associated with lower risk of MSI-H CRC, but not associated with MSS CRC. | |
| [108] | Raptis | 2007 | CCS | CRC | 766 CRC, 1098 controls | MLH1, MSH2 SNPs | MSI in CRC | MLH1 rs1800734 (−93G>A) SNP is associated with MSI-H CRC. | |
| [111] | Rozek | 2010 | CCS | CRC | MECCS (northern Isreal). 1297 CRC, 2019 matched controls | Ethnicity, smoking, family history of CRC | BRAF mutation in CRC | Men who smoked are more likely to have BRAF-mutated tumor than women who never smoked. | |
| [113] | Samowitz | 2006 | CCS | CC | KPMCP-UT-MN. 1510 CC, 1981 controls | IRS1, IRS2, IGF1, IGFBP3 SNPs | MSI, KRAS, TP53 mutations in CC | IRS1 G972R SNP is associated with MSI CC. | |
| [114] | Samowitz | 2006 | CCS | CC | KPMCP-UT-MN. 1315 CC, 2392 controls | Smoking | CIMP, BRAF mutation in CC | Smoking ≥20 cigarettes/day is associated with CIMP+ (OR, 2.06; 95% CI, 1.43–2.97) and BRAF mutation (OR, 3.16; 95% CI, 1.80–5.54) compared to controls, but smoking is not associated with CIMP-negative or BRAF-WT. | |
| [115] | Samowitz | 2008 | CCS | CC | KPMCP-UT-MN. 795 CC, 1968 controls | MLH1 rs1800734 SNP | MSI, CIMP, BRAF mutation in CC | MLH1 rs1800734 (−93G>A) SNP is associated with CIMP, MLH1 methylation and BRAF mutation in MSI-H CC. | |
| [116] | Satia | 2005 | CCS | CC | NCCCS. 486 CC, 1048 controls | Various food and nutriens, BMI, smoking, physical activity, family history, NSAIDs, vitamin mineral supplements | MSI in CC | No dietary factor is differentially related to MSI-H compared to MSI-L/MSS CC. | |
| [120] | Shannon | 2002 | CCS | CRC | 456 CRC, 1207 controls | MTHFR SNP, CBS polymorphisms | MSI in CRC | CBS 844ins68 variant is inversely associated with MSI in proximal CRC. | |
| [123] | Slattery | 2000 | CCS | CC | KPMCP-UT-MN. 1510 CC, 2410 controls | BMI, physical activity, smoking, aspirin, NSAIDs | MSI in CC | Among both men and women, cigarette smoking is associated with MSI but not with MSS. | |
| [124] | Slattery | 2000 | CCS | CC | KPMCP-UT-MN. 1428 CC, 2410 controls | Various food and nutrients | KRAS mutation in CC | Low cruciferous vegetable intake may be differentially associated with KRAS mutation vs. WT (p=0.01). | |
| [125] | Slattery | 2001 | CCS | CC | KPMCP-UT-MN. 1428 CC, 2410 controls | BMI, dietary pattern, physical activity, smoking, aspirin, NSAIDs | KRAS mutation in CC | Among men, but not women, low physical activity is associated with KRAS mutation but not with KRAS-WT. | |
| [126] | Slattery | 2001 | CCS | CC | KPMCP-UT-MN. 1510 CC, 2410 controls | Various food and nutrients | MSI in CC | Alcohol intake may increase MSI cancer risk. | |
| [127] | Slattery | 2001 | CCS | CC | KPMCP-UT-MN. 1510 CC, 2410 controls | Oral contraceptive use, Estrogen replacement, number of pregnancies, BMI, physical activity | MSI in CC | Estrogen exposure in women may decrease MSI cancer risk. | |
| [128] | Slattery | 2002 | CCS | CC | KPMCP-UT-MN. 1457 CC, 2410 controls | Family history of CRC | MSI, KRAS, TP53 mutations in CC | Family history of CRC is not differentially associated with CC risk by MSI, KRAS or TP53 status. | |
| [129] | Slattery | 2002 | CCS | CC | KPMCP-UT-MN. 1458 CC, 2410 controls | Diet, physical activity, BMI, smoking, aspirin/NSAIDs use, | TP53 mutation in CC | Western dietary pattern, red meat, and high glycemic load are associated with TP53 mutation in CC. | |
| [130] | Slattery | 2002 | CCS | CC | KPMCP-UT-MN. 1344 CC, 1958 controls | GSTM1, NAT2 genotypes | Smoking | MSI, TP53, KRAS mutation in CC | GSTM1 genotype and smoking may interact to influence occurrence of KRAS mutation in CC. |
| [131] | Slattery | 2006 | CCS | CRC | KPMCP-UT-MN. 1577 CC (unknown number for molecular data), 1971 controls | PPARG P12A SNP | MSI, TP53, KRAS mutations in CC | It is unknown whether PPARG SNP differentially relates to CC risk by MSI, TP53 or KRAS status. | |
| [132] | Slattery | 2007 | CCS | CC | KPMCP-UT-MN. 1154 CC, 2410 controls | BMI, nutrients, physical activity, smoking, aspirin, NSAIDs | MSI, CIMP, BRAF mutation in CC | Obesity is associated with CIMP-negative, but not CIMP+ (OR, 2.0; 95% CI, 1.5–2.6). Among MSI-high tumors, high alcohol intake is associated with BRAF-WT (OR 2.2; 95% CI, 1.2–3.7), but not among MSS tumors. | |
| [133] | Slattery | 2009 | CCS | CC | KPMCP-UT-MN. 1375 CC, 2014 controls | Polymorphisms in various genes | MSI, CIMP, KRAS, TP53 mutations in CC | Variants of insulin-related genes are associated with CIMP and MSI-H CC, especially among aspirin users. | |
| [134] | Slattery | 2010 | CCS | CC | KPMCP-UT-MN. 1198 CC, 1987 controls | SMAD7 SNPs (rs4939827, rs12953717, rs4464148) | MSI, CIMP, KRAS, TP53 mutations in CC | SMAD7 SNPs were not differentially associated with CC risk by MSI, CIMP, KRAS or TP53 status. | |
| [135] | Slattery | 2010 | CCS | Rectal cancer | KPMCP-UT-MN. 750 rectal cancers, 1205 controls | Diet, physical activity, body size | CIMP, TP53 mutation, KRAS mutation in rectal cancer | Certain dietary factors and physical activity are associated with CIMP, TP53 mutation or KRAS mutation in rectal cancer. However, no comparison (CIMP+ vs. CIMP−; TP53 mutation vs. WT; KRAS mutation vs. WT) is performed. | |
| [136] | Slattery | 2010 | CCS | Rectal cancer | KPMCP-UT-MN. 750 rectal cancers, 1250 controls | Calcium, vitamin D, VDR genotypes | CIMP, TP53 mutation, KRAS mutation in rectal cancer | Vitamin D intake and certain VDR genotypes are associated with certain TP53 mutations in rectal cancer | |
| [137] | Slattery | 2010 | CCS | Rectal cancer | KPMCP-UT-MN. 337 rectal cancers, 1192 controls | Alcohol intake | CIMP, TP53 mutation, KRAS mutation in rectal cancer | Recent high beer consumption is associated with TP53 mutation in rectal cancer. However, no comparison (TP53 mutation vs. WT) is performed. | |
| [138] | Slattery | CCS | CRC | KPMCP-UT-MN. 794 CRC, 1956 controls | SNPs in metabolic signaling pathway genes (MTOR, PTEN, STK11, PRKAA1, PRKAG2, TSC1, TSC2, PIK3CA, AKT1) | CIMP, MSI, KRAS mutation, TP53 mutation in CRC | PRKAA1 SNP (rs461404) is inversely associated with CIMP, and PRKAA1 SNP rs13167906 is positively associated with CIMP. However, no comparison (CIMP+ vs. CIMP−; MSI-high vs. MSS; TP53 mutation vs. WT; KRAS mutation vs. WT) is performed. | ||
| [139] | Urlich | 2005 | CCS | CC | KPMCP-UT-MN. 1248 CC, 1972 controls | MTHFR SNPs | TP53, KRAS mutations in CC | MTHFR codon 222 SNP variant is inversely associated with G>A mutations at CpG sites in TP53 in CC. | |
| [140] | van den Donk | 2007 | CCS | CRA | POLIER study. 149 CRA, 286 controls | Various nutrients, MTHFR codon 222 SNP | Methylation in APC, CDKN2A (p16), p14, MLH1, MGMT, RASSF1A in CRC | Folate intake may increase risk of adenoma without promoter methylation. | |
| [145] | Wark | 2006 | CCS | CRA | 534 CRA, 709 controls | Smoking, various food and nutrients | KRAS mutation in CRA | Smoking may increase risk of KRAS-WT CRA, but not that of KRAS-mutated CRA. | |
| [151] | Yang | 2000 | CCS | CRC | 161 CRC, 191 controls | SERPINA1 (A1AT) SNP | smoking | MSI in CRC | SERPINA1 SNP variant and smoking may synergistically increase risk of MSI-H CRC. |
| Nested case-control study | |||||||||
| [142] | Van Guelpen | 2010 | Nested CCS (in PCS) | CRC | NSHDS. 190 CRC, 380 (?) controls | Plasma folate, vitamin B12, homocysteine; MTHFR SNPs | CIMP, MSI, BRAF mutation in CRC | MTHFR rs1801131 (codon 429) SNP variant may be associated with CIMP-negative CRC, but not with CIMP-high or CIMP-low CRC. | |
| Prospective cohort studies (PCS) | |||||||||
| [36] | Chan | 2007 | PCS | CRC | NHS, HPFS. 13,0274 participants, 636 CRC | Aspirin | PTGS2 (COX-2) expression in CRC | Aspirin is associated with decreased risk of PTGS2 (COX-2)-positive CRC, but not with PTGS2-negative CRC. | |
| [53] | English | 2008 | PCS | CRC | MCCS. 41528 participants, 582 CRC | Ethnicity (Anglo-Celtic vs. southern European origins) | CIMP, BRAF mutation in CRC | Southern European origin is associated with lower risk for CIMP+ or BRAF-mutated CRC, but not with risk for CIMP-negative or BRAF-wild-type CRC. | |
| [78] | Limsui | 2010 | PCS | CRC | IWHS. 37,399 participants, 540 CRC | Smoking | MSI, CIMP, BRAF mutation in CRC | Smoking increases risks of MSI-high cancer, CIMP-high cancer, and BRAF-mutated cancer, but not MSS-low/MSS, non-CIMP-high or BRAF-wild-type cancer. | |
| [117] | Schernhammer | 2008 | PCS | CC | NHS. 88,691 participants, 399 CC | Dietary one-carbon nutrients, alcohol | TP53 expression in CC | Folate intake decreases TP53-positive CC risk, but not TP53-negative CC risk. | |
| [118] | Schernhammer | 2008 | PCS | CC | NHS, HPFS. 136,062 participants, 669 CC | Dietary one-carbon nutrients, alcohol | MSI, KRAS mutation in CC | CC risk does not significantly differ by MSI or KRAS mutation status. | |
| [119] | Schernhammer | 2010 | PCS | CC | NHS, HPFS. 136,054 participants, 609 CC | Dietary one-carbon nutrients, alcohol | LINE-1 methylation level in CC | Folate intake decreases LINE-1 hypomethylated CC risk, but not LINE-1 hypermethylated CC risk. | |
| [148] | Wish | 2010 | PCS | CRC | 4337 at-risk first degree relatives of 552 index CRC patients in the Newfoundland Cancer Registry | MSI, BRAF mutation in CRC | CRC events in first degree relatives | Compared to family members of patients with MSS BRAF-wild-type CRC, family members of patients with MSI-high BRAF-mutated CRC and those with MSS BRAF-mutated CRC show higher risks of developing CRC. | |
Official gene and protein symbols are described in the HUGO-Gene Nomenclature Committee (HGNC) website (www.genenames.org). Studies with less than 100 cases with tumor tissue data are not listed, except for studies on rarely examined exposures or outcome. Studies on etiologically well-known types (polyposis syndromes, hereditary nonpolyposis colorectal cancer, inflammatory bowel disease-associated CRC) are not listed.
*
Sample size is based on cases with available tumor tissue data.
Abbreviations: A1AT, alpha-1-antitrypsin; BMI, body mass index; CC, colon cancer; CCFR, Colon Cancer Family Registry; CCS, case-control study; CGH, comparative genomic hybridization; CI, confidence interval; CIMP, CpG island methylator phenotype; COX-2, cyclooxygenase 2; CRA, colorectal adenoma; CRC, colorectal cancer; DMR, differentially methylated region; EPIC, European Prospective Investigation into Cancer and Nutrition; HPFS, Health Professionals Follow-up Study; HR, hazard ratio; HRT, hormone replacement therapy; IWHS, Iowa Women’s Health Study; KPMCP-UT-MN, Kaiser Permanente Medical Care Program of Northern California, the state of Utah and the Twin City Metropolitan area of Minnesota (the M. Slattery group’s case-control study); LOH, loss of heterozygosity; MCCS, Melbourne Collaborative Cohort Study; MECCS, Molecular Epidemiology of Colorectal Cancer Study; MSI, microsatellite instability; MSI-H, microsatellite instability-high; MSI-L, microsatellite instability-low; MSS, microsatellite stability; NCCCS, North Carolina Colon Cancer Study; NHS, Nurses’ Health Study; NLCS, The Netherlands Cohort Study; NSAID, non-steroidal anti-inflammatory drug; NSCCG, National Study of Colorectal Cancer Genetics (UK); NSHDS, Northern Sweden Health and Disease Study; OR, odds ratio; RR, incidence rate ratio; PCS, prospective cohort study; PTGS2, prostaglandin endoperoxide synthase 2; RCT, randomized, placebo-controlled trial; SEER, Surveillance Epidemiology, and End Results; SERPINA1, serpin peptidase inhibitor, clade A (alpha-1 antiproteinase, antitrypsin), member 1; SNP, single nucleotide polymorphism; WBFT, Wheat Bran Fiber Trial; WT, wild-type.