Oncotarget

Meta-Analysis:

Associations between dietary folate intake and risks of esophageal, gastric and pancreatic cancers: an overall and dose-response meta-analysis

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Oncotarget. 2017; 8:86828-86842. https://doi.org/10.18632/oncotarget.18775

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Wen Liu, Heng Zhou, Yaoqi Zhu, Chaorong Tie _

Abstract

Wen Liu1,*, Heng Zhou1,*, Yaoqi Zhu2,3 and Chaorong Tie3

1Department of Pathology, Renmin Hospital of Wuhan University, Wuhan, 430060, Hubei Province, P. R. China

2Department of Stomatology, Zhongnan Hospital of Wuhan University, Wuhan, 430071, Hubei Province, P. R. China

3Department of Stomatology, Taikang Tongji Hospital, Wuhan, 430000, Hubei Province, P. R. China

*These authors have contributed equally to this work

Correspondence to:

Chaorong Tie, email: 414825917@qq.com

Heng Zhou, email: hengzhou117@163.com

Keywords: esophageal cancer, gastric cancer, pancreatic cancer, dose-response analysis, meta-analysis

Received: February 20, 2017    Accepted: May 22, 2017    Published: June 28, 2017

ABSTRACT

There are still some controversies on the association between dietary folate intake and the risk of upper gastrointestinal cancers including esophageal, gastric and pancreatic cancers. Hence, a comprehensive meta-analysis on all available literatures was performed to clarify the relationship between dietary folate intake and risks of upper gastrointestinal cancers. An electric search was performed up to December 12th, 2016 within the PubMed, MEDLINE AND EMBASE databases. Ultimately, a total of 46 studies which evaluated the association between folate intake and risks of upper gastrointestinal cancers were included. According to the data from included studies, the pooled results showed significant association between folate intake and esophageal (OR = 0.545, 95%CI = 0.432-0.658), gastric (OR=0.762, 95%CI=0.648-0.876) and pancreatic (OR=0.731, 95%CI=0.555-0.907) cancers. Linearity dose-response analysis indicated that with 100μg/day increment in dietary folate intake, the risk of esophageal, gastric and pancreatic cancers would decrease by 9%, 1.5% and 6%, respectively. These findings indicated that higher level of dietary folate intake could help for preventing upper gastrointestinal cancers including esophageal, gastric and pancreatic cancers.


Associations between dietary folate intake and risks of esophageal, gastric and pancreatic cancers: an overall and dose-response meta-analysis | Liu | Oncotarget

INTRODUCTION

Folate, also named vitamin B9, is a naturally occurring nutrient and is found in many foods including fruits, vegetables legumes, cereals, and liver. Human can’t produce folate de novo and need to uptake folate from dietary intake. Evidences implicated deficient folate is related to increased risks of many cancers [1].

Folate plays an important role in the process of DNA synthesis, repair, and methylation, and was hypothesized to decrease risks of gastrointestinal cancers. The main carcinogenesis mechanisms of folate are inducing DNA strand breaks by causing uracil mis-incorporation into DNA and changing levels of DNA methylation [2]. These aberrant changes may result in potential alterations of critical proto-oncogene and tumor suppressor gene expressions [3]. Animal experiments referring mice and dogs suggested that high levels of folate intake affected DNA methylation and eventually decreased the risks of gastric cancer [4, 5]. In addition, the polymorphisms of genes in folate metabolizing pathway may modulate the susceptibility of several cancers.

Previous studies have summarized published data and indicated that increased folate intake was associated with the increased risks of prostate [6] and breast [7] cancers, but decreased the risks of colorectal [8] and cervical [9] cancers. Two previous meta-analysis have estimated the associations of folate intakes and risks of esophageal, gastric and pancreatic carcinomas and indicated that increased folate intakes were associated with decreased risks of esophageal and pancreatic cancers [10, 11]. However, the results of these studies about the relationship between folate intake and gastric cancer risk remained inconsistent. Larsson et al. indicated that increased folate intake were associated with decreased risks of cardia and non-cardia gastric cancers [11]. Basing on more studies, another systematic review showed no relationship between dietary folate intake and risks of gastric cancers [10]. Therefore, to clarify the associations between folate intake and upper gastrointestinal cancers and evaluate the dose-response relationship between them, we performed an overall meta-analysis based on current observational studies.

RESULTS

Summary of studies’ characteristics

Total 1284 studies were collected from our initial search including studies about esophageal cancer (n=398), gastric cancer (n=335) and pancreatic cancer (n=551). After duplicates automatically removing with EndNote, total 1154 potential articles were remained. Then, after screening titles and abstracts, 983 irrelevant studies were excluded; the remained 171 records, which investigated the associations between upper gastrointestinal cancers and folate intake, were eligibly evaluated with full text reading. Based on our inclusive criteria mentioned in Materials and Methods, 46 articles were eventually included in our meta-analysis. Among all the selected studies, 19 were conducted in patients of esophageal cancer [12-30], 21 were in patients of gastric cancer [12, 14, 15, 22, 26, 28, 31-45] and 12 were in patients of pancreatic cancer [46-57]. Figure 1 shows the eligible selecting process. Main characteristics of all include articles were showed in Table 1.

Flow chart of the literature search used in this meta-analysis.

Figure 1: Flow chart of the literature search used in this meta-analysis.

Table 1: Characteristics of studies included in the meta-analysis

Studies

Country

Study Design

Year

Age

Sex

Sample Size (cases/ controls)

Disease type

Exposure range (μg/day)

Measurement

Dose-
response

2014 Xiao

USA

Cohort

1995-2004

50-71

M/W

GC: 939/492292

EC: 759/492292

GC/EC

566 vs 288

FFQ (Supplement and diet)

No

2014 Chen

China

Case-control

2008-2011

-

M/W

767/765

GCA/Non-GCA

>310 vs <230

FFQ (Diet)

Yes

2013 Gao

China

Case-control

2008-2012

28-76

M/W

264/535

Non-GCA

>310 vs < 230

FFQ (Diet)

Yes

2011 Aune

Uruguay

Case-control

1996-2004

23-89

M/W

GC: 275/2032

EC: 234/2032

GC

275.31 vs 123.83

FFQ (Diet)

Yes

2010 Epplein

China

Cohort

1996-2006

40-70

M/W

338/136442

GCA/Non-GCA

>346.5 vs <218.7

FFQ (Diet)

Yes

2009 Pelucchi

Italy

Case-control

1997-2007

22-80

M/W

230/547

GC

The highest vs the lowest quintile

FFQ (Diet)

No

2005 Kim

Korea

Case-control

1997-1998

-

M/W

136/136

GCA/Non-GCA

>354 vs <234

FFQ (Diet)

No

2003 Nomura

USA

Case-control

1993–1999

-

M/W

300/446

GC

>315 vs <236

FFQ (Diet)

No

2002 Chen

USA

Case-control

1988-1994

-

M/W

GC: 154/449

EC: 124/449

GC/EC

The highest vs the lowest quintile

FFQ (Diet)

No

2000 Botterweck

Netherlands

Cohort

1986-1992

55-69

M/W

310/120852

GC

>384.16 vs <201.96

FFQ (Diet)

Yes

2006 Larsson

Sweden

Cohort

1987-2004

40-76

W

156/61433

GC

>260 vs < 203

FFQ (Supplement and diet)

No

2001 Mayne

USA

Case-control

1993-1995

30-79

M/W

GC: 607/687

EC: 488/687

GC/EC

The highest vs the lowest quintile

FFQ (Diet)

No

2001 Munoz

Venezuela

Case-control

1991-1997

>35

M/W

302/485

GC

The highest vs the lowest quintile

FFQ (Diet)

No

1999 Lizbeth

Mexico

Case-control

1989-1990

24-88

M/W

220/752

GC

>466.26 vs <257.4

FFQ (Diet)

Yes

1994 Vecchia

Italy

Case-control

1985-1992

19-74

M/W

723/2024

GC

>262 vs <163

FFQ (Diet)

Yes

1997 Harrison

USA

Case-control

1992-1994

-

M/W

31/132

GC

The highest vs the lowest quintile

FFQ (Diet)

No

2004 Lissowska

Poland

Case-control

1994-1996

-

M/W

274/463

GC

The highest vs the lowest quintile

FFQ (Diet)

No

2016 Ren

China

Cohort

1985-1991

40-69

M/W

GC: 255/29584

ESCC: 498/29584

GC/ESCC

The highest vs the lowest quintile

serum

No

2015 Chang

China

Case-control

2000

>20

M/W

GC: 206/415

EC: 218/415

GC/EC

The highest vs the lowest quintile

serum

No

2007 Vollset

Europe

Case-control

1992-1998

42.7-71.4

M/W

245/631

GCA/Non-GCA

The highest vs the lowest quintile

serum

No

2014 Lee

China

Case-control

1998-2006

-

M/W

149/155

GC

The highest vs the lowest quintile

serum

No

2015 Fanidi

Europe

Case-control

1992-2000

41-71

M/W

ESCC: 126/255

EAC: 26/274

ESCC/EAC

The highest vs the lowest quintile

serum

No

2013 Sharp

Northern Ireland

Case-control

2002-2005

<85

M/W

223/256

EAC

≥421 vs ≤318

FFQ (Supplement and diet)

No

2013 Huang

China

Case-control

2010-2012

-

M/W

126/167

ESCC

The highest vsthe lowest quintile

serum

No

2012 Tavani

Italy

Case-control

1991-2009

-

M/W

505/22828

EC

≥312.5 vs ≤257.3

FFQ (Diet)

Yes

2011 Zhao

China

Case-control

2008-2010

-

M/W

155/310

ESCC

>300 vs <230

FFQ (Diet)

Yes

2011 Jessri

Iran

Case-control

-

40-75

M/W

47/96

ESCC

The highest vsthe lowest quintile

FFQ (Diet)

No

2011 Ibiebele

Australia

Case-control

2003-2006

18-79

M/W

267/393

ESCC/EAC

379 vs 196

FFQ (Diet)

Yes

2006 Galeone

Italy

Case-control

1992-1999

<80

Men

351/875

ESCC

The highest vs the lowest quintile

FFQ (Diet)

No

2006 De Stefani

Uruguay

Case-control

1996-2004

40-89

M/W

234/1032

ESCC

The highest vs the lowest quintile

FFQ (Diet)

No

2005 Yang

Japan

Case-control

2001-2004

18-80

M/W

165/495

EC

>400 vs <300

FFQ (Diet)

Yes

2002 Bollschweiler

Germany

Case-control

1997-2000

-

M/W

117/100

ESCC/EAC

>164 vs <100

EBIS (Diet)

Yes

2013 Bao

China

Case-control

2010-2011

-

M/W

106/106

ESCC

The highest vs the lowest quintile

serum

No

1988 Brown

USA

Case-control

1982-1984

<79

M

74/157

EC

The highest vs the lowest quintile

FFQ (Supplement and diet)

No

2011 Chuang

Europe

Cohort

1994

25-70

M/W

638/520000

PC

The highest vs the lowest quintile

serum

No

2011 Bravi

Italy

Case-control

1991-2008

34-80

M/W

326/652

PC

The highest vs the lowest quintile

FFQ (Diet)

No

2010 Oaks

USA

Cohort

1993-2001

55-74

M/W

266/51988

PC

The highest vs the lowest quintile

FFQ (Supplement and diet)

No

2009 Keszei

Netherlands

Cohort

1986-1999

55-69

M/W

363/120852

PC

>259.1 vs <176.3

FFQ (Diet)

Yes

2009 Gong

USA

Case-control

1995-1999

21-85

M/W

532/1701

PC

≥738 vs <280

FFQ (Supplement and diet)

No

2007 Schernhammer

USA

Case-control

1989-1990

40-75

M/W

247/740

PC

The highest vs the lowest quintile

serum

No

2006 Larsson

Sweden

Cohort

1987-1990

45-83

W

135/81922

PC

≥350 vs <200

FFQ (Diet)

Yes

2004 Skinner

USA

Cohort

1976-1986

40-75

M/W

187/125480

PC

≥500 vs <300

FFQ (Supplement and diet)

Yes

2001 Stolzenberg

Finland

Cohort

1985-1988

50-69

M/W

157/27101

PC

≥373 vs <280

FFQ (Diet)

Yes

1999 Stolzenberg

Finland

Case-control

1985-1988

50-69

M/W

126/247

PC

The highest vs the lowest quintile

serum

No

2016 Huang

China

Cohort

1993-1998

45-74

M/W

271/63257

PC

207 vs 108

FFQ (Diet)

Yes

2009 Anerson

Canada

Case-control

2003-2007

<75

M/W

422/312

PC

Folate supplement vs non-folate supplement

FFQ (Supplement and diet)

No

Abbreviations: EBIS, ErnahrungsBeratungs und Informations-System; EC, Esophageal Cancer; EAC, esophageal adenocarcinoma; ESCC, Esophageal squamous cell cancer; FFQ, food frequency questionnaire; GC, Gastric Cancer; GCA, Gastric cardiac adenocarcinoma; PC, Pancreatic Cancer.

Esophageal cancer

Probands of 4 studies were in American participants [15, 26, 28, 29], 5 in Chinese [12, 14, 17, 19, 30] and 5 in Europeans [13, 16, 18, 23, 27]. In terms of the study design, 2 were cohort studies [12, 15, 18] and 17 were case-control studies [13, 14, 16-25, 58]. Seven studies clearly reported patients with Esophageal squamous cell cancer (ESCC) [12, 13, 15, 17, 19-21, 23, 24, 27, 28, 30] and six studies were about esophageal adenocarcinoma (EAC) [13, 15, 16, 21, 26-28]. Eleven studies investigated dietary folate intake from food [18-28] and 3 studies further examined dietary folate intake from food and supplement [15, 16, 29]. Five studies reported detecting folate concentration in serum samples from patients [12-14, 17, 30]. Six case-control studies [18, 19, 21, 22, 25, 27] and 1 cohort study [15] which evaluated the association between dietary folate intake without supplement and risk of esophageal cancer were included in dose-response analysis. Two studies didn’t set the lowest dose concentration group as reference group [15, 27]. The reference group transformation has been described above.

To assess the relationship between the risk of esophageal cancer and dietary folate intake, total 19 studies including 2036 patients and 7086 controls were collected. The forest plot is shown in Figure 2A. Significant heterogeneity (p<0.001, I2 = 73.7%) between these studies suggested that a random effect model was selected. The pooled results showed that dietary folate intake comparing highest levels vs. lowest levels was associated with the decreased risk of esophageal cancer (odds ratio (OR) = 0.545, 95% confidence interval (CI) = 0.432-0.658, Table 2).

Forest plots of the association between dietary folate intake and risk of esophageal cancer (A), gastric cancer (B) and pancreatic cancer (C).

Figure 2: Forest plots of the association between dietary folate intake and risk of esophageal cancer (A), gastric cancer (B) and pancreatic cancer (C).

Table 2: Results including overall and subgroup analysis of pooled OR, 95%CI, heterogeneity test and publication bias

Overall and subgroup analysis

Numbers of studies

Pooled OR

95%CI

Heterogeneity Test

Publication Bias (P)

Q

P

I2, %

Egger’s test

Begg’s test

Esophageal cancer

Total

20

0.545

0.432-0.658

87.57

<0.001

73.7

0.027

0.023

Study design

Cohort

2

0.821

0.569-1.073

4.11

0.128

51.4

0.466

0.602

Case-control

17

0.496

0.386-0.606

59.90

<0.001

68.3

0.080

0.130

Histological type

ESCC

7

0.551

0.370-0.731

51.39

<0.001

80.5

0.152

0.091

EAC

6

0.561

0.373-0.749

20.15

0.003

70.2

0.141

0.142

Country

USA

4

0.573

0.474-0.673

5.70

0.336

12.3

0.573

0.708

China

5

0.596

0.255-0.938

36.06

<0.001

91.7

0.174

0.125

Europe

5

0.443

0.238-0.647

15.91

0.014

62.3

0.348

0.125

Others

6

0.770

0.450-1.310

15.35

0.009

67.4

0.188

0.043

Measurement

 Diet

11

0.547

0.426-0.667

33.92

0.001

61.7

0.01

0.01

 Supplement and diet

3

0.692

0.530-0.853

1.99

0.574

0

0.412

0.327

 Serum

5

0.708

0.329-1.088

40.56

<0.001

87.7

0.458

0.117

Gastric cancer

 Total

21

0.762

0.648-0.876

77.08

<0.001

67.6

0.808

0.270

Study design

 Cohort

5

0.967

0.801-1.134

4.46

0.615

0

0.548

0.652

 Case-control

16

0.696

0.563-0.829

65.83

<0.001

72.7

0.960

0.248

Histological type

 GCA

3

0.729

0.531-0.927

1.14

0.566

0

0.590

0.117

 Non-GCA

4

0.681

0.549-0.813

4.09

0.252

26.6

0.761

1

 Other GC

17

0.796

0.646-0.947

70.20

<0.001

74.4

0.725

0.278

Country

 USA

5

0.627

0.539-0.715

11.11

0.134

37.0

0.510

0.621

 Europe

5

0.889

0.562-1.215

9.70

0.084

48.5

0.226

0.573

 China

7

0.864

0.579-1.149

22.58

0.002

69.0

0.236

0.322

 Others

4

0.859

0.552-1.166

9.76

0.021

69.3

0.885

1

Measurement

 Diet

18

0.714

0.591-0.836

60.25

<0.001

71.8

0.216

0.622

 Supplement and diet

2

0.884

0.654-1.115

0.76

0.683

0

0.015

0.043

 Serum

4

1.217

0.475-1.960

9.65

0.047

58.6

0.849

0.624

Sex

 Women

3

0.857

0.405-1.309

6.01

0.050

66.7

0.416

0.602

 Men

2

0.599

0.088-1.109

2.98

0.085

66.4

0.656

0.251

Pancreatic cancer

 Total

12

0.731

0.555-0.907

35.44

<0.001

69.0

0.089

0.054

Study design

 Cohort

7

0.800

0.512-1.089

28.43

<0.001

78.9

0.029

0.015

 Case-control

5

0.589

0.456-0.722

6.01

0.198

33.5

0.829

1

Country

 USA

4

0.885

0.565-1.206

9.08

0.028

67.0

0.604

0.497

 Europe

5

0.457

0.326-0.588

5.75

0.218

30.5

0.069

0.050

 Others

3

1.006

0.759-1.252

2.94

0.230

32.0

0.709

0.602

Measurement

 Diet

8

0.669

0.450-0.888

21.93

0.001

72.6

0.156

0.099

 Supplement and diet

5

0.756

0.559-0.952

6.65

0.156

39.8

0.831

0.49

 Serum

3

0.763

0.338-1.189

5.84

0.054

65.7

0.068

0.117

Sex

 Men

5

0.856

0.709-1.003

1.97

0.742

0

0.836

1

 Women

5

0.716

0.557-0.874

2.89

0.577

0

0.563

0.624

Abbreviations: EC: Esophageal Cancer; EAC: esophageal adenocarcinoma; ESCC: Esophageal squamous cell cancer; GC: Gastric Cancer; GCA: Gastric cardiac adenocarcinoma; OR: odds ration; CI: confidence interval.

Table 2 showed the results of specific subgroup analysis based on study designs, countries, histological type and folate intake measurement. All these results were similar in subgroup analysis suggested that folate intake were comprehensive associated with reduced risk of esophageal cancer.

As shown in Figure 3A, the linearity test of dose-response analysis suggested that with increased 100 μg/day folate intake from diet, the risk of esophageal cancer decreased 9% degree (OR=0.91, 95%CI=0.88-0.94). The non-linearity test (p<0.001) indicated that the lowest risk of esophageal cancer was at the dose of 405 μg/day (OR=0.69, 95%CI=0.57-0.83). After the dose of folate intake > 405 μg/day, the risk of esophageal cancer would increase after the fall.

Linearity and non-linearity relationships between dietary folate intake and risk of esophageal cancer (A), gastric cancer (B) and pancreatic cancer (C).

Figure 3: Linearity and non-linearity relationships between dietary folate intake and risk of esophageal cancer (A), gastric cancer (B) and pancreatic cancer (C).

Gastric cancer

Totally 5 studies were about American participants [15, 26, 28, 37, 42, 43], 5 were about European participants [35, 39, 42, 44, 58] and 7 were about Chinese participants [12, 14, 22, 31, 32, 34, 45]. In terms of the study design, 5 were cohort studies [12, 15, 34, 38, 39] and 16 were case-control studies [14, 22, 26, 28, 31, 32, 35-37, 40-45, 58]. Three studies clearly reported patients with gastric cardiac adenocarcinoma (GAC) [15, 28, 44] and 4 studies were about Non-GAC [15, 28, 32, 44]. Eighteen studies investigated dietary folate intake from food [22, 26, 28, 31, 32, 34-38, 40-43, 58] and 2 studies further examined dietary folate intake from food and supplement [15, 39]. Four studies reported detecting folate concentration in serum samples from patients [12, 14, 44, 45]. Two studies have respectively investigated the association between folate intake and risk of gastric cancer by sex [34, 37]. One study only included women participant [39]. Five case-control studies [22, 31, 32, 41, 42] and four cohort studies [15, 34, 38, 39] which evaluated the associations between dietary folate intake and risks of gastric cancer were included in dose-response analysis. One study didn’t set the lowest dose concentration group as reference group [15]. The reference group transformation has been described above.

As shown in Figure 2B, 5 cohort studies and 16 case-control studies were collected to analyze the association between dietary folate intake and risk of gastric cancer. The comprehensive pooled relative risk (RR) indicated a significant association between increased folate intake and decreased risk of gastric cancer (OR=0.762, 95%CI=0.648-0.876, Table 2). There was a significant heterogeneity (p<0.001, I2=67.6%) which suggested a further subgroup analysis.

Table 2 showed the results of specific subgroup analysis based on study designs, countries, histological type, folate intake measurement and sex. When stratified by cohort studies, 5 studies were included and indicated no statistically significant association existing between dietary folate intake and risk of gastric cancer (OR=0.967, 95%CI=0.801-1.134). The pooled OR of case-control studies suggested a high dietary folate intake was associated with a statistically significant decreased risk of gastric cancer (OR=0.696, 95%CI=0.563-0.829). Subgroup analysis by country demonstrated that there was a significant association between increased folate intake with decreased risk of gastric cancer in Americans (OR=0.627, 95%CI=0.539-0.715) and no associations in Chinese (OR=0.864, 95%CI=0.579-1.149), Europeans (OR=0.889, 95%CI=0.562-1.215) and other countries (OR=0.859, 95%CI=0.552-1.166). Subgroup analysis by histological type indicated that increased dietary folate intake were significantly associated both with Gastric cardiac adenocarcinoma (GCA) (OR=0.729, 95%CI=0.531-0.927) and non-GCA (OR=0.681, 95%CI=0.549-0.813). Subgroup analysis by measurement suggested that high dietary folate intake from diet was associated with a statistically significant decreased risk of gastric cancer (OR=0.714, 95%CI=0.591-0.836). However, there was no association between high dietary folate intake from diet and supplement and risk of gastric cancer (OR=0.884, 95%CI=0.654-1.115). Detecting folate levels in serum suggested that there was no association between folate intake and risk of gastric cancer (OR=1.217, 95%CI=0.475-1.960). Increased folate intake was associated with decreased risk of gastric cancer in men (OR=0.599, 95%CI=0.088-1.109, but not in women (OR=0.857, 95%CI=0.405-1.309).

As shown in Figure 3B, non-linearity (p=0.20) dose-response analysis indicated no relationship between folate intake from diet and risk of gastric cancer. However, a linearity relationship (p=0.03) was found and suggested that 1.5% decrease of gastric cancer for each 100 μg/day increase of dietary folate intake (OR=0.985, 95%CI=0.972-0.998).

Pancreatic cancer

Probands of 4 studies were in American participants [48, 50, 51, 53], 5 in Europeans [46, 47, 52, 54, 55] and 5 in other countries. In terms of the study design, 7 were cohort studies [46, 48, 49, 52-54, 56] and 5 were case-control studies [47, 50, 51, 55, 57]. Eight studies investigated dietary folate intake from food [47-50, 52, 56] and 5 studies further examined dietary folate intake from food and supplement [48, 50, 53, 54, 57]. Three studies reported detecting folate concentration in serum samples from patients [46, 51, 55]. Five studies have respectively investigated the association between folate intake and risk of pancreatic cancer by sex [46-48, 53, 56]. Total 7 studies were included in dose-response analysis [48-50, 52-54, 56].

As shown in Figure 2C, 7 cohort studies and 5 case-control studies were collected to analyze the association between dietary folate intake and risk of pancreatic cancer. The comprehensive pooled RR indicated a significant association between increased folate intake and decreased risk of pancreatic cancer (OR=0.731, 95%CI=0.555-0.907, Table 2). There was a significant heterogeneity (p<0.001, I2=69.0%) which suggested a further subgroup analysis.

Table 2 showed the results of specific subgroup analysis based on study designs, countries, folate intake measurement and sex. The pooled result of cohort studies suggested a weak association existing between dietary folate intake comparing highest levels vs. lowest levels and decreased risk of pancreatic cancer (OR = 0.800, 95%CI = 0.512-1.089). The pooled OR of case-control studies suggested a high dietary folate intake was associated with a statistically significant decreased risk of pancreatic cancer (OR=0.589, 95%CI=0.456-0.722). Subgroup analysis by country demonstrated that there was a significant association between increased folate intake with decreased risk of pancreatic cancer in Europeans (OR=0.457, 95%CI=0.326-0.588) and no associations in Americans (OR=0.885, 95%CI=0.565-1.206) and other countries (OR=1.006, 95%CI=0.759-1.252). Evaluating the association between risks of pancreatic cancer and increased folate intake from diet with (OR=0.756, 95%CI=0.559-0.952) or without supplement (OR=0.669, 95%CI=0.450-0.888) suggested that a superfluous folate supplement is not needed. Detecting folate levels in serum suggested that there was a statistically significant association between folate intake and risk of pancreatic cancer (OR=0.763, 95%CI=0.338-1.189). Increased folate intake was associated with decreased risk of pancreatic cancer in women (OR=0.716, 95%CI=0.557-0.874), but not in men (OR=0.856, 95%CI=0.709-1.003).

As shown in Figure 3C, the linearity test of dose-response analysis suggested that with increased 100 μg/day folate intake from diet, the risk of pancreatic cancer decreased 6% degree (OR=0.94, 95%CI=0.92-0.97,). The non-linearity test (p<0.001) also indicated that the risk of pancreatic cancer decreased with folate intake increasing.

Sensitivity analysis and publication bias

One included study of this meta-analysis was omitted each time to evaluate the stability of pooled results. The results remained similar when any result was removed from the pooled results in this meta-analysis. Begg’s test and Egger’s test were used to evaluate the publication bias, the results were summarized in Table 2. There were significant publication biases in the results which evaluate the associations between folate intake and esophageal cancer (Egger’s test: p=0.027; Begg’s test: p=0.023); esophageal cancer in diet (Egger’s test: p=0.01; Begg’s test: p=0.01); pancreatic cancer in cohort subgroup analysis (Egger’s test: p=0.029; Begg’s test: p=0.015) and gastric cancer in supplement and diet subgroup analysis (Egger’s test: p=0.015; Begg’s test: p=0.043). The trim-and-fill method was used to re-calculate the publication bias. All the new results remained similar to the original results. These results were considered as steady.

DISCUSSION

Folate is a water-soluble B vitamin and is found in many foods including fruits, vegetables legumes, cereals, and liver. Human can’t produce folate de novo and need to uptake folate from dietary intake [1, 59]. Folate plays an important role in the process of DNA synthesis, repair, and methylation, and was hypothesized to decrease risks of gastrointestinal cancers. Two main mechanisms of folate deficiency leads to carcinogenesis: (1) by leading complete convention of dUMP to dTMP, which makes mis-incorporation of uracil into DNA and induces breaks and mutations of chromosome; and/or (2) inducing alternations in expression of critical proto-oncogenes and tumor suppressor genes by causing aberrant methylated level of DNA [2, 3]. In addition, the polymorphisms of 5,10-methylenetetrahydrofolate reductase, a critical junction protein in folate metabolizing pathway by leading folate metabolites to DNA methylation pathway and away from the DNA synthesis pathway, can regulate the susceptibilities of several cancers [60-62].

Our meta-analysis found that increased folate intake was associated with reduced risks of upper gastrointestinal cancers including esophageal, gastric and pancreatic cancers. The dose-response further certified their relationship. Subgroup analysis indicated that the comprehensive inverse associations between dietary folate intake and esophageal cancer. Our data suggested different relationships between dietary folate intake and cancer risks in country, study design, disease type, measurement and sex subgroup analysis of gastric and pancreatic cancers.

The results of this meta-analysis showed that increased dietary folate intake significant decreased risk of esophageal cancer. These results are similar to previous study [10, 11, 63]. In the subgroup analysis based on country, histological type, study design and dietary measurement, our results suggested an inverse association between dietary folate intake and risks of esophageal cancer in all subgroups. Interesting, we observed a higher OR which suggested a weaker link between folate intake and esophageal cancer in supplement and diet subgroup than in diet subgroup. These results suggested an extra folate supplement is not needed in diet for preventing esophageal cancer. The results of dose-response analysis also indicated that with the folate intake > 450 μg/day, the risk of esophageal cancer would increase weakly comparing with the lowest OR, which suggested that a redundant and supplementary folate is not necessary. Zhang et al. found that the risk ration of breast cancer decreased when the dose of folate was low. However, with the folate dose increasing, a positive association was found between folate intake and breast cancer risk [7].

Different from previous studies [10, 11], our results showed a significant association between increased dietary folate intake and reduced gastric cancer risk. Although non-linearity model of dose-response analysis suggested no statistically significant association between folate intake and risk of gastric cancer, linearity model indicated a different result (p=0.03) which certificated our comprehensive pooled OR. Meta-analysis of genetic polymorphisms demonstrated that folate deficiency was associated with increased risk of gastric cancer [11, 64, 65]. Folate supplement can reverse methylation deficiency, stop global hypomethylation and prevent gastric carcinogenesis in hypergastrinemic transgenic mice [5]. Subgroup analysis indicated an inverse association between dietary folate intake and gastric cancer risk in case-control studies, but no association in cohort studies. A possible reason is that only 5 cohort studies were included in this analysis. Small number of studies and effects of multiple factors may affect recall bias and selection bias and restrict the precision of the last results. Similar to previous studies [11], our data showed a significant inverse association between folate intake and GCA or non-GCA, and a weak inverse link between folate intake and other gastric cancer. These results suggested that dietary folate intake plays different roles in different gastric cancers. In the subgroup analysis based on country, we observed an inverse association between folate intake and gastric cancer only in USA, but not in other countries. In addition, in the subgroup analysis based on measurement, our results showed an inverse association between folate intake coming from diet and risk of gastric cancer. However, no association between folate intake coming from diet and supplement and risk of gastric cancer was found. These results also suggested that an extra folate supplement is not needed in diet for preventing gastric cancer. And the excessive intake of folate may be a risk for gastric cancer since the highest values of 95%CI > 1.00. Different from previous estimate, serum evaluating suggested an increased risk of gastric cancer with high serum concentration. One possible explanation is that since the number of included studies about serum detection of folate and gastric cancer risk is too small, which provide insufficient statistical power to evaluate the risk. Animal experiments suggested a dual role of folate in cancer carcinogenesis: prevention or promotion, depending on the stage of cell transformation at the time of intervention and the dose of folate supplement [66, 67]. Significant decreased risks of gastric cancers were observed both in men and women with folate intake increased.

Results of previous meta-analysis about folate intake and pancreatic cancer risk were inconsistent. Bao et al. found folate intake was not associated with overall risk of pancreatic cancer using only prospective cohort studies [68]. However, other studies considered increased folate intake was associated with decreased pancreatic cancer risk [11, 69]. Our comprehensive meta-analysis found an inverse association between dietary folate intake and pancreatic cancer risk. Dose-response analysis indicated that a 100 μg/day increment in dietary folate intake was associated with a 6% risk decreasing for pancreatic cancer. Results of subgroup analysis based on country showed an inverse association between folate intake and pancreatic cancer risk in European. However, this association was not found in American and other countries. These results suggested that geographic variation or dietary habit may play an important role in the association. Subgroup analysis by sex indicated that women had higher pancreatic risk with low folate intake when compared with men. Similar to esophageal and gastric cancers, our data showed that an extra folate supplement is not needed in diet for preventing pancreatic cancer.

There are several limitations to current meta-analysis. First, the included studies about esophageal, gastric and pancreatic cancer have few cohort studies which may make influence on the actual result. Since, dose-response analysis didn’t separate cohort and case-control studies. Second, subgroup analysis based on measurement only included diet, diet and supplement and serum. Total folate intake and other folate intake measurements were not evaluated for lack of related studies. Third, significant heterogeneity were detected between the studies included in quantitative synthesis. Through further subgroup analysis, we still can’t find all the origin of heterogeneity. Forth, this meta-analysis used pooled results for lacking of individual data, which prevents us from finishing a more precise analysis. Last, some subgroup analysis which included small number of studies may not represent objective and exact results. Hence, our results should be treated as exploratory and with caution.

In conclusion, results of current meta-analysis indicated that higher level of dietary folate intake could help for preventing upper gastrointestinal cancers including esophageal, gastric and pancreatic cancers. Dose-response analysis indicated that with 100μg/day increment in dietary folate intake, the risk of esophageal, gastric and pancreatic cancers would decrease by 9%, 1.5% and 6%, respectively. In addition, our analysis indicated that more well-designed studies about associations between esophageal, gastric and pancreatic cancers and folate intake are necessary for further accurately evaluating subgroup analysis based on country, measurement, histological type and sex.

MATERIALS AND METHODS

Literature search

A systematically search was performed up to May 2th, 2017 by two reviewers (H. Z. and Y. Z.) within Pubmed, MEDLINE AND EMBASE, using the terms “folate, folic acid or vitamin B9”, “esophageal, oesophagus, gastric, stomach, or pancreatic” and “cancer, neoplasm or carcinoma”. In addition, we reviewed the reference lists from original reports and manually selected for other available publications. No language restrictions were imposed in the searching process.

Study selection

The studies were included with the following inclusion criteria: (i) the experimental design was a case-control or cohort study; (ii) studies reported the associations of esophageal, gastric, or pancreatic cancer risk with dietary folate intake from diet, dietary folate intake from diet and supplement and serum levels of folate; (iii) RR, hazard ration (HR) or OR with 95% CI was reported to estimate the relative risk of the highest folate intake vs. lowest folate intake; (iv) patient with disease was identified by histological diagnosis; (v) for dose-response analysis, the number of cases and participants and eligible dose concentration must be provided. The selected studies were only limited in using dietary folate intake as only measurement standard. The most recent study was included for duplicate publications.

Data extraction

The following information was selected independently by two authors (H. Z. and Y. Z.) according to the criteria listed previously: the first author’s name, publication year, country, study design, total sample size, sex, number of cases, number of controls, lowest folate level, highest folate level, difference between highest and lowest folate levels, measurement, range of exposure, histological type (ESCC, EAC, gastric cardiac adenocarcinoma (GAC); non-GAC), risk estimates and 95%CI for evaluating the highest folate levels vs. lowest folate levels. Adjusted rations were chosen in preference to the rations with the highest number of adjusted variables. For the studies which the reference groups were not the lowest dose concentration, the EXCEL macro document (RRest9) was used for the reference group transforming and data re-calculating according to the instructions [70]. All controversial questions were resolved by asking a third author.

Statistical analysis

The association of folate intake with esophageal, gastric and pancreatic cancers were examined by the pooled risk estimates (RR or OR) with 95%CI. The heterogeneity test was detected with I2 statistic. Cut-off points of I2 value for low, moderate and high degrees of heterogeneity were 25%, 50% and 75%, respectively. A fixed effect model was chosen when heterogeneity was negligible, otherwise, the random effects model was chosen [71]. Sensitivity analysis was investigated to assess robust of pooled results by omitting one study each time. The publication bias was determined by the Begg rank correlation test and Egger’s linear regression test [72]. P<0.05 was considered statistically significant, and all p-values were two-sided. The trim-and-fill method was used to re-calculate the publication bias when the P values of Begg test or Egger test >0.05. The new pooled results (RR or OR) were compared with the original results. The results were considered as steady if the new pooled results are similar to the original results. At last, we conducted a dose-response meta-analysis using the correlated natural logs of the RRs or ORs with their standard error (SE) across all folate intake categories [73]. To derive the dose-response curve, restricted cubic splines with four knots at the 5%, 35%, 65% and 95% percentiles of the distribution were used to assess for potential curvilinear relations. All data in this meta-analysis were performed using Stata 12.0 (StataCorp LP, College Station, TX, USA).

Abbreviations

CI, confidence interval; ESCC, esophageal squamous cell cancer; EAC, esophageal adenocarcinoma; EBIS, ErnahrungsBeratungs und Informations-System; FFQ, food frequency questionnaire; GAC, gastric cardiac adenocarcinoma; HR, hazard ration; OR, odds ratio; PC, Pancreatic Cancer; RR, relative risk.

Author contributions

H. Z. performed search, Y. Z. and W. L. prepared tables and figures, C. T. wrote the manuscript and performed power calculation. All authors reviewed the manuscript.

ACKNOWLEDGMENTS

This research was supported by the Nature Science Foundation of Hubei Province (2011CDB520), without commercial or not-for-profit sectors.

CONFLICTS OF INTEREST

No conflict of interests is stated by authors.

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