Table 2 Main results of included studies
Author, Year, and Reference | Study Design | Country and Setting | Sample size | Ethnicity | Main Focus | Relevant Exposures | Confounder Factors | Comparison Groups | Main Findings and Effects |
|---|---|---|---|---|---|---|---|---|---|
He et al., 2019 [21] | Two large prospective cohort studies: Nurses’ Health Study (NHS), 1980–2012) and Health Professionals Follow-up Study (HPFS), (1986–2012). | USA: - Nurses’ Health Study (NHS): 11 US States (California, Connecticut, Florida, Maryland, Massachusetts, Michigan, New Jersey, New York, Ohio, Pennsylvania, and Texas). - Health Professionals Follow-up Study (HPFS): 50 US states. | - A total of 138,793 participants were included: 90,869 from the NHS and 47,924 from the HPFS. - 1337 cases with data for KRAS Mutation. | Unspecified | Dietary intake of fiber, whole grains and risk of colorectal cancer. | - Total fiber (per 5 g/day) - Cereal fiber (per 5 g/day) - Fruit fiber (per 5 g/day) - Vegetable fiber (per 5 g/day) - Whole grain (per 20 g/day). | Age, family history of CRC, history of lower gastrointestinal endoscopy, smoking, body mass index, physical activity, alcohol intake, regular aspirin use, regular multivitamin use, total folate intake, calcium intake, vitamin D intake, glycemic load, processed red meat intake, hormone use. | - Group I: KRAS+ - Group II: KRAS- | No association |
Keum et al.,2019 [22] | Two ongoing prospective cohort studies: the Nurses’ Health Study (NHS) (1980–2010), and the Health Professionals Follow-up Study (HPFS) (1986–2010). | USA: - NHS: 11 US States. - HPFS: 50 US states. | - 88,506 women and 47,733 men. - 853 colon cancer cases. | Unspecified | Calcium intake and colon cancer risk subtypes by tumor molecular characteristics. | Total calcium intake (mg/day). | Age, questionnaire cycle, sex; Caucasian (yes vs. no), family history of colorectal cancer, history of sigmoidoscopy/colonoscopy, regular aspirin use, smoking, BMI, physical activity, 25-hydroxyvitamin D scores, intakes of energy, alcohol, red and processed meat and folate. | - Group I: KRAS+ - Group II: KRAS- | No association |
Mehta et al., 2017 [23] | Two ongoing cohorts, the Health Professionals Follow-up Study (HPFS) and the Nurses’ Health Study (NHS). | USA: - NHS: 11 US States. - HPFS: 50 US states. | - 137,217 participants (47,449 men and 89,768 women). - 1285 tumors for KRAS mutation status. | Unspecified | Western and prudent dietary patterns and risk of CRC. | Western and prudent dietary patterns score. | Age, sex, CRC family history, history of previous lower gastrointestinal endoscopy, smoking, body mass index, physical activity, NSAID, and total caloric intake. | - Group I: KRAS+ - Group II: KRAS- | No association with tumors harboring KRAS mutation. |
Carr et al., 2017 [24] | Case–control study | Southwest of Germany | - 2449 cases and 2479 controls. | Unspecified | Associations of red and processed meat intake with major molecular pathological . | Red and processed meat (frequency: times/day). | Age, sex, school education, BMI, family history of colorectal cancer, history of large–bowel endoscopy, participation in health checkup, smoking, ever regular use of NSAIDs, fruit intake, and wholegrain intake. | - Group I: KRAS+ - Group II: KRAS- | Positive association with higher red and processed meat intake and KRAS mutation (OR > 1 time/day vs ≤ 1 time/week: 1.49, 95% CI 1.09–2.03). |
Hogervorst et al., 2014 [25] | Case cohort study embedded in the Netherlands Cohort Study on diet and cancer (NLCS). | Netherlands (204 municipalities with computerized population registries). | - 120,852 participants (58,279 men + 62,573 women) - Subcohort (n = 5000) - 733 CRC cases were available for the molecular analysis. | Unspecified | Acrylamide and CRC risk characterized by mutations in KRAS and APC. | - Acrylamide intake (g/day). | Age, smoking, BMI, family history of CRC, total energy intake. | - Group I: KRAS+ - Group II: KRAS− | - Positive association with acrylamide intake among men (HR [4th quartile vs. 1st] = 2.12; 95% CI, 1.16–3.87; p = .01). |
Jung et al., 2014 [26] | Two cohorts, the Health Professionals Follow-up Study (HPFS) and the Nurses’ Health Study (NHS) (1986–2008). | USA: - NHS: 11 US States. - HPFS: 50 US states. | - 140,418 participants. - 1059 incident CRC cases with tumor molecular data. | Unspecified | Association between vitamin D and CRC risk. | - Predicted vitamin D score (ng/mL) | Age, sex, family, history of endoscopy, aspirin use, smoking, intake of total fruits and vegetables, total calories. | - Group I: KRAS+ - Group II: KRAS−. | Negative association between higher predicted vitamin D score and KRAS mutation (HR = 0.70; 95% CI, 0.50–0.98). |
Gilsing et al., 2013 [27] | Cohort Study initiated in September 1986. | Netherlands (204 municipalities with computerized population registries). | - Case subjects were enumerated from the entire cohort (120,852 men and women). - the accumulated person years of the entire cohort were estimated from a random subcohort of 5000 men and women. - 733 CRC cases were available for the molecular analysis. | Unspecified | Dietary heme iron intake and risk of CRC with mutations in APC and KRAS and p53 overexpression | - Heme iron intake (g/day) | Age, sex, BMI, family history of CRC, smoking, nonoccupational physical activity, total energy intake, alcohol consumption, total vegetable consumption | - Group I: wild-type KRAS - Group II: activating mutant KRAS | Positive association with heme iron intake (HR = 1.71; 95% CI, 1.15–2.57; P = .03) |
Kamal et al., 2012 [28] | Retrospective cohort study | Egypt. Kasr El Aini Hospital, Cairo University. | 80 CRC patients (56 males and 24 females). | Unspecified | Associations between KRAS mutation and potential variables known or suspected to be related to the risk of CRC. | - Meat, green leafy vegetables, tea, and coffee at < 3 times/week versus more than 3 times/week. - Red blood cell folic acid (ng/mL). | not mentioned | - Group I: KRAS+ - Group II: KRAS− | Potential link between folic acid and KRAS mutation, suggesting that folic acid may be a risk factor for KRAS mutation development - OR for folic acid was 0.983 for each 1 ng/mL higher folate. |
Razzak et al., 2012 [29] | Cohort study from the Iowa Women’s Health Study. | Iowa, USA. | - n = 41,836 - 514 incident CRC cases were available for the molecular marker assays. | Caucasian women. | Associations between dietary folate, vitamin B6, vitamin B12, and methionine with different pathways in CRC. | - Folate (μg/day) - Vitamin B6 (mg/day) - Vitamin B12 (μg/day) - Methionine (g/day). | Age,, BMI, waist-to-hip ratio, smoking status, exogenous estrogen use, physical activity level, and daily intake of total energy, total fat, sucrose, red meat, calcium, methionine, vitamin E, alcohol. | - Group I: KRAS+ - Group II: KRAS− | None of the dietary exposures were associated with KRAS-defined CRC subtypes. |
Ottini et al., 2011 [30] | Case study | Italy | 1 individual (King Ferrante I of Aragon). | Caucasian | Explanation of the death of King Ferrante I | Carbon (δ-13C) and nitrogen (δ-15N) isotope analysis. | not mentioned | – | Possible abundance of dietary carcinogens, related to meat consumption, could explain KRAS mutation causing the colorectal tumor that killed Ferrante I more than 5 centuries ago. |
Naguib et al., 2010 [31] | Case series. | Norfolk, United Kingdom. | −25,639 from The EPIC Norfolk cohort (1993–1997). - 202 CRC cases were tested for Kras mutations. | Unspecified | Associations between BRAF and KRAS mutations and clinicopathologic, lifestyle, and dietary factors in CRC. | - Alcohol (g/day) - Meat (g/day), including red meat, red processed meat, white meat, white fish, fatty fish - Fruit and vegetables - Fat, total fat, PUFA, MUFA, SFA -Vitamins B2, B3, B6, B9, B12, C, and D - Fiber and macronutrients: total energy (MJ/day), carbohydrates (g/day), protein (g/day), nonstarch polysaccharide (g/day), calcium (mg/day). | Not mentioned | - Group I: Patients with KRAS+ - Group II: Patients with KRAS− | - KRAS mutation was associated with increased white meat consumption (P < .001; ANOVA) - KRAS (G to A) associations were found in individuals with significantly lower consumption of fruits or vegetables (P = .02). |
Slattery et al., 2010 [32] | Case control study of participants in Kaiser Permanente Medical Care Program study | Northern California and Utah, USA. | - 951 cases - 1205 controls | 82% white, non-Hispanic, 4.1% African American, 7.6% Hispanic, 4.6% Asian, 0.7% American Indian, and 1% multiple races/ethnicity. | Diet, physical activity, and body size associations with rectal tumor mutations and epigenetic changes. | - Foods and dietary patterns involving dairy high fat, low fat, fruit, vegetables, red meat, fish, whole grains, refined grains, Western diet, prudent diet. - Nutrients: calories, PUFA, MUFA, SFA, trans fats, omega-3 fats, animal protein, vegetable protein, carbohydrates, dietary fiber. | Age, sex, recent aspirin use, long-term activity level, pack-years of cigarette smoking, dietary calcium, energy intake. | - Group I: CpG Island methylator phenotype CIMP+ - Group II: TP53 mutation - Group III: KRAS2+ mutations - Group IV: controls. | - High levels of vegetable intake reduced risk of KRAS mutations (OR = 0.60; 95% CI, 0.40–0.89; P < .01) - Dietary fiber was associated with reduced risk of KRAS rectal tumor mutations - Prudent dietary pattern significantly reduced the KRAS mutation risk (OR = 0.68, 95% CI, 0.47–0.98; P < .03). - No significant result for the other factors. |
Schernhammer et al., 2008 [33] | Two prospective cohort studies: NHS and HPFS. | USA: - NHS: 11 US States. - HPFS: 50 US states. | - 88,691 women and 47,371 men. - 669 incident cases of CRC were available for the molecular analysis. | Unspecified | Association between dietary folate intake, vitamin B, and incidence of KRAS mutation in colon cancers. | - Folate (μg/day). | Age, sex, energy intake, screening sigmoidoscopy, family history, aspirin use, smoking, physical activity, BMI in 5 categories, colon polyps, beef intake, calcium intake, multivitamin use, alcohol use, and intake of vitamin B6, B12, and methionine. | - Group I: KRAS− cancer cases - Group II: KRAS+ cancer cases | Low folate and vitamin B6 intakes were associated an increased risk of colon cancer, but these effects did not differ significantly by KRAS mutational status. |
Weijenberg et al., 2007 [34] | Cohort study: Netherlands Cohort Study on diet and cancer (NLCS). | Netherlands (204 municipalities with computerized population registries). | - 531 incident cases of CRC were available for the molecular analysis. | Unspecified | Baseline fat intake versus risk of colon and rectal tumors with some gene alterations. | - Fat variables (g/day), including total fat, SFA, MUFA, PUFA, linolenic acid, linoleic acid. | Age, sex, BMI, family history of CRC, daily energy intake, daily linoleic acid intake, daily calcium intake, smoking. | - Group I: colon cancer with no gene aberrations - Group II: colon cancer with activating KRAS gene mutations. | - No association with total, saturated, MUFA, and PUFA - Linoleic acid showed a positive association with KRAS mutation (RR = 1.41; 95% CI, 1.18–1.69). |
Bongaerts et al., 2006 [35] | Prospective Cohort study: Netherlands Cohort Study on diet and cancer (NLCS). | Netherlands (204 municipalities with computerized population registries). | - The cohort included 58,279 men and 62,573 women. - 578 incident cases of CRC were available for the molecular analysis. | Unspecified | Associations between consumption of alcohol and alcoholic beverages and risk of CRC without and with specific KRAS gene mutations. | - Alcohol consumption: total alcohol (g/day), beer (glasses/week), wine (glasses/week), liquor (glasses/week). | Age, family history of CRC, BMI, calcium intake, linoleic intake, smoking, total alcohol consumption. | - Group I: colon cancer, KRAS+ - Group II: colon cancer, KRAS− - Group III: rectal cancer, KRAS+ - Group IV: rectal cancer, KRAS- - Men and women analyzed separately. | - No association between alcohol and KRAS mutations - Positive association with beer drinking (RR: 3.48; 95% CI, 1.1–11.0). |
Wark et al., 2006 [36] | Case-control study | Netherlands (outpatient clinics of 10 hospitals). | - 658 cases - 709 controls | Unspecified | Associations between diet, lifestyle, and KRAS mutations. | - Foods (g/day): dairy products, red meat, tea - Macronutrients (g/day): total dietary fat, PUFA, MUFA, protein - Micronutrients (mg/day): calcium, vitamin B2. | Sex, age, total energy. | - Group I: patients with KRAS+ - Group II: patients with KRAS− - Group III: controls. | No significant results: - Red meat OR = 1.70 (95% CI, 0.94–3.09), potential risk, not statistically significant result - Total dietary fat OR = 0.55 (95% CI, 0.28–1.06) - PUFA OR = 0.58 (95% CI, 0.31–1.10) - No differences versus risk of KRAS adenomas could be detected for other factors. |
Brink et al., 2005 [37] | Cohort study: Netherlands Cohort Study on diet and cancer (NLCS). | Netherlands (204 Dutch municipalities with computerised population registries). | − 2948 subcohort members. − 608 incident colon and rectal cancer cases were available for the molecular analysis. | Unspecified | Association between meat and KRAS mutations in sporadic colon and rectal cancer. | Meat (g/day): total fresh meat, beef, pork, minced meat, liver, chicken, other meat, meat product, fish. | Age, sex, Quetelet Index, smoking, energy intake, family history of CRC. | - Group I: patients with KRAS mutation - Group II: patients with G > C or G > T activating KRAS mutation - Group III: patients with G > A activating KRAS mutation - Group IV: patients with KRAS−. | - For meat products, positive association shown (RR for highest vs lowest quartile of intake = 2.37; 95% CI, 0.75–7.51; P = 0.07) - No clear associations were observed for total fresh meat, different types of fresh meat, meat products, and fish. |
Brink et al., 2005 [38] | Cohort study: Netherlands Cohort Study on diet and cancer (NLCS). | Netherlands (204 municipalities with computerized population registries). | - 3048 Subcohort members (1475 men and 1573 women). - 608 incident CRC cases were available for the molecular analysis. | Unspecified | Association between dietary folate and specific KRAS mutations in CRC. | - Folate (μg /day). | Age, sex, BMI, smoking, alcohol, fresh meat, energy intake, family history of CRC, vitamin C, iron, fiber. | - Group I: colon cancer, KRAS+ - Group II: colon cancer, KRAS− - Group III: rectal cancer, KRAS+ - Group IV: rectal cancer, KRAS−. | - For women: folate intake was associated with an increased risk of KRAS mutation G > T and G > C (RR = 2.69; 95% CI, 1.43–5.09) but inversely associated with G > A (RR = 0.08; 95% CI, 0.01–0.53) - For men: folate intake was associated with decreased risk of KRAS mutation (RR = 0.40; 95% CI, 0.17–0.89). |
Brink et al., 2004 [39] | Cohort study: Netherlands Cohort Study on diet and cancer (NLCS). | Netherlands (204 municipalities with computerized population registries). | - 2948 Subcohort members. - 608 incident CRC cases were available for the molecular analysis. | Unspecified | Associations between dietary intake of various fats and specific KRAS mutations in CRC. | Fat variables (g/day): - Total fat - SFA - MUFA - PUFA - Linolenic acid - Linoleic acid. | Age, sex, Quetelet Index, smoking, energy intake, family history of CRC. | - Group I: colon cancer, KRAS+ - Group II: colon cancer, KRAS− - Group III: rectal cancer, KRAS+ - Group IV: rectal cancer, KRAS−. | - No association with intake of total fats, SFA, and MUFA - Positive association with high intake of PUFA and linoleic acid (RRs for 1 SD of increase of PUFA and linoleic acid = 1.21; 95% CI, 1.05–1.41; and 1.22; 95% CI, 1.05–1.42). |
Howsam et al., 2004 [40] | Case control study | Barcelona, Catalonia, Spain. | Subsample of cases (n = 132) and hospital controls (n = 76) selected from a larger case-control study. | Unspecified | Association between risk of CRC and exposure to organochlorine compounds. | Different types of organochlorines: - p,p’-DDE (low, medium, high) - α-HCH (low, medium, high) - PCB-28 (low, medium, high) - PCB-118 (low, medium, high). | Age, sex, BMI, energy intake. | - Group I: KRAS− - Group II: KRAS+ | - Exposure to mono-ortho PCB-28 and PCB-118 increased risk of tumor KRAS+ - PCB-28 OR = 2.83 (95% CI, 1.13–7.06). - PCB-118 OR = 1.64 (95% CI, 0.67–4.01). |
Laso et al., 2004 [41] | Case-control study | Catalonia, Spain. | - 246 cases - 296 controls | Unspecified | Association between specific micronutrient intake and CRC and KRAS mutation | - Fiber (g/day) - Folate (μg/day) - Vitamins A (μg/day), B1 (mg/day), D (μg/day), E (mg/day) - Potassium (mg/day) - Calcium (mg/day) - Iron (g/day) | Not mentioned | - Group I: control - Group II: patients with CRC - Group III: patients with KRAS mutation | - Low intake of vitamin E (OR = 2.3; 95%CI, 1.2–4.6) - Low intake of vitamin D OR = 2 (95% CI, 1.1–4.2) - Low intake of vitamin B1 OR = 2.5 (95% CI, 1.2–5.1) - Low intake of vitamin A OR = 2.5 (95% CI, 1.2–5.1) - Low intake of folate OR = 2 (95% CI, 1.1–3.9) - Low intake of fiber OR = 2.7 (95% CI, 1.4–5.1) - Low intake of calcium OR = 2.3 (95% CI, 1.1–4.6) - Low intake of vitamin A OR = 2.5 (95% CI, 1.2–5.1). |
Slattery et al., 2002 [42] | Case-control study | USA: Northern California, Utah, Minnesota. | - 1836 cases - 1958 controls | white, African-American Hispanic | Association between GSTM-1 and NAT2 and colon tumors | -Cruciferous vegetables (high, intermediate, low) -Red meat frequency/day (< 0.86, 0.86–3.5, > 3.5) | Age, sex. | - Group I: KRAS only - Group II: KRAS + MSI (microsatellite instability) - Group III: KRAS + p53 + MSI | No significant result: - Red meat OR = 0.7 (95% CI, 0.5–1.1) - Cruciferous vegetable OR = 0.7 (95% CI 0.5–1.2) |
Slattery et al., 2001 [43] | Case-control study | USA: Northern California, Utah, Minnesota. | - 1428 cases - 2410 control | White African American Hispanic | Association between lifestyle factors and KRAS mutations in colon cancer tumors. | - caffeine (low, intermediate, and high) - Western diet and prudent diet patterns (low, intermediate, and high). | Age. | - Group I: patients with KRAS+ - Group II: patients with KRAS− - Group III: controls. | - For Western diet pattern, low OR = 1.0, intermediate OR = 1.2 (95% CI, 0.95–1.6), and high OR = 1.5 (95% CI, 1.2–1.9) - Prudent diet pattern showed no clear association. |
Slattery et al., 2000 [44] | Case-control study | USA: Northern California, Utah, Minnesota. | - 1836 cases - 1958 controls | African-American, white, Hispanic. | Associations between dietary intake and KRAS mutations in colon tumors. | - Dietary fat (g/1000 kcal): fat, SFA, MUFA, PUFA, cholesterol - Insulin-related factors: Carbohydrate (g/1000 kcal), Refined grains (servings/day) - DNA methylation factors: folate (mg/1000 kcal), vitamin B6 (mg/1000 kcal), methionine (g/1000 kcal), alcohol (g/day) - Carcinogen detoxification: cruciferous vegetables. | Age, sex, energy intake, BMI, physical activity, dietary calcium, fiber. | - Group I: patients with KRAS+ - Group II: patients with KRAS− - Group III: controls. | Low levels of vegetables OR = 0.6 (95% CI, 0.4–0.9; P = .01). |
Kampman et al., 2000 [45] | Case control study | Netherlands | - 204 cases - 259 controls | Caucasian | Associations between animal product and KRAS codon 12 and 13 mutations in colon carcinomas. | - Foods: total red meat, beef, processed meat, poultry, fish, dairy products - Nutrients: total fat, SFA, cholesterol, total protein, animal protein, calcium. | Age, sex, total energy intake | - Group I: patients with KRAS+ - Group II: patients with KRAS− - Group III: controls. | - Animal protein OR = 1.5 (95% CI, 1–2.1) for codon 12 but OR = 0.4 (95% CI, 0.2–1) for codon 13 - Calcium OR = 1.2 (95% CI, 0.9–1.6) for codon 12 but OR = 0.6 (95% CI, 0.3–1.2) for codon 13. |
O’Brien et al., 2000 [46] | Case series | Norwich, United Kingdom. | 51 participants (26 males and 26 females). | Unspecified | Associations between KRAS mutations and meat consumption in patients with left-sided CRC | Red meat (g/day) |  | - Group I: KRAS+ - Group II: KRAS− | No correlation between KRAS mutations and red meat consumption |
Martinez et al., 1999 [47] | Case series | USA: Phoenix metropolitan area, Arizona. | 678 participants | 96% were white. | Associations between variables known or suspected to be related to risk of CRC and occurrence of KRAS mutations in colorectal adenomas. | -Total fat, SFA, dietary fiber, red meat, alcohol (g/day) - Dietary calcium, total calcium, dietary folate, total folate (mg/day). | Age, sex, energy intake. | - Group I: KRAS+ - Group II: KRAS− | - Only intake of total folate was associated with KRAS mutation; compared with individuals in the lower tertile, those in the upper tertile had 50% lower risk of having KRAS mutation (OR = 0.52; 95% CI, 0.30–0.88; P = 0.02). |
Bautista et al., 1997 [48] | Case control study | Spain, Island of Majorca. | - 286 cases and 295 controls. - 106 CRC cases were available for the molecular analysis. | Unspecified | Possible associations between dietary factors and KRAS mutation in CRC tumors | - Total fats, PUFA, MUFA, SFA - calcium | Age, physical activity, number of meals, total caloric intake; fats were also adjusted for calcium, and calcium was adjusted for MUFA | - Group I: KRAS+ - Group II: KRAS- - Group III: controls | -High calcium intake was associated with a decreased risk of KRAS-mutated tumors (OR = 0.36; 95% CI, 0.14–0.97) - No association between KRAS+ and other nutrients |