Human Genetics

, Volume 125, Issue 4, pp 431–435

FAS −1,377 G/A polymorphism is associated with cancer susceptibility: evidence from 10,564 cases and 12,075 controls

Authors

  • Li-Xin Qiu
    • Department of Medical Oncology, Cancer HospitalFudan University
    • Department of Oncology, Shanghai Medical CollegeFudan University
  • Jian Shi
    • Department of Gastroenterology, Shanghai Changzheng HospitalSecond Military Medical University
  • Hui Yuan
    • Department of Epidemiology and Biostatistics, School of Public HealthAnhui Medical University
  • Xin Jiang
    • Department of Anesthesiology, Shanghai Changzheng HospitalSecond Military Medical University
  • Kai Xue
    • Department of Medical Oncology, Cancer HospitalFudan University
    • Department of Oncology, Shanghai Medical CollegeFudan University
  • Hai-Feng Pan
    • Department of Epidemiology and Biostatistics, School of Public HealthAnhui Medical University
    • Department of Medical Oncology, Cancer HospitalFudan University
    • Department of Oncology, Shanghai Medical CollegeFudan University
    • Department of Infection and Liver Diseases, The First Affiliated Hospital of Wenzhou Medical College
Original Investigation

DOI: 10.1007/s00439-009-0639-4

Cite this article as:
Qiu, L., Shi, J., Yuan, H. et al. Hum Genet (2009) 125: 431. doi:10.1007/s00439-009-0639-4

Abstract

Published data on the association between FAS −1,377 G/A polymorphism and cancer risk are inconclusive. To derive a more precise estimation of the relationship, a meta-analysis was performed. A total of 17 studies including 10,564 cases and 12,075 controls were involved in this meta-analysis. Overall, significantly elevated cancer risk was associated with AA variant genotype when all the eligible studies were pooled into the meta-analysis (for AA vs GG: OR = 1.19; 95% CI = 1.01–1.40; Pheterogeneity = 0.05; for recessive model: OR = 1.21; 95% CI = 1.04–1.41; Pheterogeneity = 0.05). In the subgroup analysis by ethnicity, borderline statistically significantly increased risks were found among Asians for recessive model (OR = 1.20; 95% CI = 1.00–1.45; Pheterogeneity = 0.01). In the subgroup analysis by population-based controls or hospital-based controls, statistically significantly increased risks were found among groups with population-based controls for AA versus GG (OR = 1.27; 95% CI = 1.02–1.58; Pheterogeneity = 0.05) and recessive model (OR = 1.25; 95% CI = 1.00–1.59; Pheterogeneity = 0.01). For breast cancer, borderline statistically significantly increased risks were found for AA versus GG (OR = 1.29; 95% CI = 1.00–1.67; Pheterogeneity = 0.41). In summary, this meta-analysis suggests that the FAS −1,377 G/A polymorphism is associated with cancer susceptibility.

Introduction

Cancer is projected to become the leading cause of death worldwide in the year 2010, according to the 2008 edition of the World Cancer Report from the International Agency for Research on Cancer, which has become a major public health challenge. New markers for identifying high-risk populations as well as novel strategies for early detection and preventive care are urgently needed. The mechanism of carcinogenesis is still not fully understood. It has been suggested that low-penetrance susceptibility genes combining with environmental factors may be important in the development of cancer (Lichtenstein et al. 2000). In recent years, several common low-penetrant genes have been identified as potential cancer susceptibility genes. An important one is FAS, which plays an important role in the apoptosis and cancer development (Huang et al. 1997). A functional single nucleotide polymorphism at the −1,377th nucleotide (rs2234767), with a G to A change, has been reported by several studies to have an impact on FAS expression and cancer risk (Crew et al. 2007; Kang et al. 2008; Krippl et al. 2004; Koshkina et al. 2007; Lai et al. 2005; Li et al. 2006a, b; Park et al. 2006; Sibley et al. 2003; Sun et al. 2004, 2005; Ter-Minassian et al. 2008; Yang et al. 2008; Zhang et al. 2005, 2006, 2007a, b), but the results are inconclusive, partially because of the possible small effect of the polymorphism on cancer risk and the relatively small sample size in each of published studies. Therefore, we performed a meta-analysis of the published studies to derive a more precise estimation of this association.

Materials and methods

Publication search

PubMed and Embase were searched using the search terms: “FAS”, “CD95”, “polymorphism” and “cancer” (last search was updated on 10 October 2008). All eligible studies were retrieved, and their bibliographies were checked for other relevant publications. Review articles and bibliographies of other relevant studies identified were hand-searched to find additional eligible studies. Only published studies with full text articles were included. When more than one of the same patient population was included in several publications, only the most recent or complete study was used in this meta-analysis.

Inclusion criteria

The inclusion criteria were: (a) evaluation of the FAS −1,377 G/A polymorphism and cancer risk, (b) case-control studies, (c) sufficient published data for estimating an odds ratio (OR) with 95% confidence interval (CI), and (d) the number of case and control was more than 100.

Data extraction

Information was carefully extracted from all eligible publications independently by two of the authors (Qiu and Shi) according to the inclusion criteria listed above. Disagreement was resolved by discussion between the two authors. If these two authors could not reach a consensus, another author (Li) was consulted to resolve the dispute and a final decision was made by the majority of the votes. The following data were collected from each study: first author’s surname, publication date, country origin, ethnicity, cancer type, characteristics of controls, genotyping methods, total number of cases and controls, and numbers of cases and controls with the GG, GA, and AA genotypes, respectively. For data not provided in tabular form or the main text, the required information were obtained by contacting corresponding authors as possible as we can. Different ethnicity descents were categorized as European and Asian.

Statistical methods

Crude ORs with 95% CIs were used to assess the strength of association between the FAS −1,377 G/A polymorphism and cancer risk. The pooled ORs were performed for additive model (GA vs GG; AA vs GG), dominant model (AA + GA vs GG), and recessive model (AA vs GG + GA), respectively. Heterogeneity assumption was checked by the chi-square-based Q test (Cochran 1954). A P value >0.10 for the Q test indicates a lack of heterogeneity among studies, so the pooled OR estimate of the each study was calculated by the fixed-effects model (the Mantel–Haenszel method) (Mantel and Haenszel 1959). Otherwise, the random-effects model (the DerSimonian and Laird method) was used (DerSimonian and Laird 1986). Subgroup analyses were performed by ethnicity, source of controls, cancer type. An estimate of potential publication bias was carried out by the funnel plot, in which the standard error of log (OR) of each study was plotted against its log (OR). An asymmetric plot suggests a possible publication bias. Funnel plot asymmetry was assessed by the method of Egger’s linear regression test, a linear regression approach to measure funnel plot asymmetry on the natural logarithm scale of the OR. The significance of the intercept was determined by the t test suggested by Egger (P < 0.05 was considered representative of statistically significant publication bias) (Egger et al. 1997). All the statistical tests were performed with STATA version 10.0 (Stata Corporation, College Station, TX).

Results

Study characteristics

A total of 17 publications met the inclusion criteria (Crew et al. 2007; Kang et al. 2008; Krippl et al. 2004; Koshkina et al. 2007; Lai et al. 2005; Li et al. 2006a, b; Park et al. 2006; Sibley et al. 2003; Sun et al. 2004, 2005; Ter-Minassian et al. 2008; Yang et al. 2008; Zhang et al. 2005, 2006, 2007a, b). Totally, 10,564 cases and 12,075 controls were used in the pooled analyses. Table 1 lists the studies identified and their main characteristics. Of the 17 studies, sample sizes ranged from 314 to 3,671. There were eight studies of Europeans and nine studies of Asians. Controls were mainly matched for sex and age, of which nine were population-based and eight were hospital-based.
Table 1

Main characteristics of all studies included in the meta-analysis

Surname

Year

Country

Ethnicity

Cancer type

Sample size case/control

Source of controls

Genotyping method

Sibley

2003

USA

European

AML

471/931

Hospital

PCR–RFLP

Sun

2004

China

Asian

Esophageal

588/648

Population

PCR–RFLP

Krippl

2004

Austria

European

Breast

499/497

Population

TaqMan

Lai

2005

China

Asian

Cervical

318/318

Hospital

TaqMan

Sun

2005

China

Asian

Cervical

314/615

Population

PCR–RFLP

Zhang

2005

China

Asian

Lung

1,000/1,270

Population

PCR–RFLP

Li

2006

China

Asian

Bladder

216/252

Hospital

PCR–RFLP

Park

2006

Korea

Asian

Lung

582/582

Hospital

PCR–RFLP

Li

2006

USA

European

Melanoma

602/603

Hospital

PCR–RFLP

Zhang

2006

USA

European

SCCHN

721/1,234

Hospital

PCR–RFLP

Zhang

2007

China

Asian

Breast

840/839

Population

PCR–RFLP

Crew

2007

USA

European

Breast

1,057/1,106

Population

TaqMan

Koshkin

2007

USA

European

Osteosarcoma

123/510

Hospital

PCR–RFLP

Zhang

2007

Sweden

European

Melanoma

229/351

Population

PCR–RFLP

Ter-Minassi

2008

USA

European

Lung

2,174/1,497

Hospital

TaqMan

Kang

2008

Korea

Asian

Cervical

154/160

Population

PCR–RFLP

Yang

2008

China

Asian

Pancreatic

397/907

Population

PCR–RFLP

AML acute myeloid leukemia, SCCHN squamous cell carcinoma of the head and neck

Meta-analysis results

Table 2 lists the main results of this meta-analysis. Overall, significantly elevated cancer risk was associated with AA variant genotype (for AA vs GG: OR = 1.19; 95% CI = 1.01–1.40; Pheterogeneity = 0.05; for recessive model: OR = 1.21; 95% CI = 1.04–1.41; Pheterogeneity = 0.05) when all the eligible studies were pooled into the meta-analysis. In the subgroup analysis by ethnicity, borderline statistically significantly increased risks were found among Asians for recessive model (OR = 1.20; 95% CI = 1.00–1.45; Pheterogeneity = 0.01). In the subgroup analysis by population-based controls or hospital-based controls, statistically significantly increased risks were found among groups with population-based controls for AA versus GG (OR = 1.27; 95% CI = 1.02–1.58; Pheterogeneity = 0.05) and recessive model (OR = 1.25; 95% CI = 1.00–1.59; Pheterogeneity = 0.01). For breast cancer, borderline statistically significantly increased risks were found for AA versus GG (OR = 1.29; 95% CI = 1.00–1.67; Pheterogeneity = 0.41).
Table 2

Main results of pooled ORs in the meta-analysis

 

N

GA versus GG

AA versus GG

AA + GA versus GG

AA versus GG + GA

OR (95%CI) Ph

OR (95%CI) Ph

OR (95%CI) Ph

OR (95%CI) Ph

Total

17

0.99 (0.90–1.10) 0.00

1.19 (1.01–1.40) 0.05

1.02 (0.93–1.13) 0.00

1.21 (1.04–1.41) 0.05

Ethnicitiy

 Asian

9

0.95 (0.84–1.08) 0.06

1.16 (0.95–1.42) 0.02

1.00 (0.90–1.12) 0.20

1.21 (1.00–1.45) 0.01

 European

8

1.04 (0.88–1.24) 0.00

1.11 (0.66–1.88) 0.30

1.05 (0.88–1.26) 0.00

1.22 (0.93–1.61) 0.40

Control source

 Hospital

8

0.95 (0.77–1.18) 0.00

1.06 (0.86–1.30) 0.36

0.97 (0.79–1.20) 0.00

1.11 (0.93–1.33) 0.66

 Population

9

1.02 (0.92–1.14) 0.08

1.27 (1.02–1.58) 0.05

1.06 (0.97–1.16) 0.17

1.25 (1.00–1.59) 0.01

Cancer types

 Breast

3

1.20 (0.99–1.47) 0.12

1.29 (1.00–1.67) 0.41

1.22 (0.98–1.50) 0.07

1.16 (0.91–1.48) 0.54

 Cervical

3

0.84 (0.63–1.12) 0.15

0.98 (0.66–1.45) 0.20

0.88 (0.67–1.14) 0.17

1.10 (0.77–1.56) 0.22

 Lung

3

0.96 (0.86–1.07) 0.64

1.18 (0.82–1.70) 0.05

1.01 (0.91–1.12) 0.53

1.23 (0.86–1.74) 0.04

PhP value of Q test for heterogeneity test

Publication bias

The shapes of the funnel plots did not reveal any evidence of obvious asymmetry (figures not shown). Also, the results of Egger’s test still did not suggest any evidence of publication bias (P = 0.52 for GA vs GG, P = 0.56 for AA vs GG, P = 0.46 for dominant model, and P = 0.62 for recessive model, respectively).

Discussion

It is well recognized that there is individual susceptibility to the same kind of cancer even with the same environmental exposure. Host factors, including polymorphisms of genes involved in carcinogenesis may have accounted for this difference. Therefore, genetic susceptibility to cancer has been a research focus in scientific community. Recently, genetic variants of the FAS gene in the etiology of several cancers have drawn increasing attention. Growing number of studies have suggested that −1,377 A in the promoter region of the FAS gene was emerging as a low-penetrance tumor susceptibility allele in the development of cancer. However, the results are inconclusive. To better understanding of the association between this polymorphism and cancer risk, a pooled analysis with a large sample, subgroup analysis performed, and heterogeneity explored is necessary.

Our results indicated that the FAS −1,377 A allele is a low-penetrant risk factor for developing cancer. This finding is biologically plausible. It has been proven that the G–A change may destroy stimulatory protein (Sp) 1 and signal transducer and activator of transcription (STAT) 1 protein binding element, and thus diminish promoter activity and decrease FAS expression (Sibley et al. 2003). Because of the role that FAS playing in carcinogenesis and cancer progression and their aberrant expression in various types of cancer, the functional polymorphism in FAS may have an impact on cancer susceptibility attributable to the reduced FAS expression.

In the subgroup analysis by ethnicity, an increased risks in FAS −1,377 AA carriers were found among Asians but not in Europeans, suggesting a possible role of ethnic differences in genetic backgrounds and the environment they lived in. In addition, the influence of the FAS −1,377 A allele might be masked by the presence of other as-yet unidentified causal genes involved in cancer development.

Our results indicated that significantly increased risks in FAS −1,377 AA carriers were found among studies using the population-based controls but not among studies with hospital-based controls. This reason may be that the hospital-based studies have some biases because such controls may just represent a sample of ill-defined reference population, and may not be representative of the general population very well, particularly when the genotypes under investigation were associated with the disease conditions that the hospital-based controls may have. Therefore, using a proper and representative population-based control subjects is very important to reduce biases in such genetic association studies.

Our results indicated that significantly increased risks in FAS −1,377 AA carriers were found in breast cancer subgroup but not in cervical cancer subgroup and lung cancer subgroup. This reason may be that different kinds of cancer may have different mechanism of carcinogenesis. FAS polymorphisms may exert different effects in different kinds of cancer. In addition, it also likely that the observed different effects may be due to chance because studies with small sample size may have insufficient statistical power to detect a slight effect or may have generated a fluctuated risk estimate. Considering the limited studies and total population numbers of one same kind of cancer included in the meta-analysis, our results should be interpreted with caution.

Heterogeneity is a potential problem when interpreting the results of all meta-analyses. Significant between-study heterogeneity existed in overall comparisons. After subgroup analyses by ethnicity or cancer type, the heterogeneity was effectively decreased or removed. The reason might be that differences of genetic backgrounds and the environment existed among different ethnicities, and different kinds of cancer may have different mechanism of carcinogenesis.

Despite of some limitations, this meta-analysis suggests that the FAS −1,377 G/A polymorphism is associated with cancer susceptibility. However, large sample studies including different ethnic groups with a careful matching between cases and controls should be considered in future association studies to confirm the results from our meta-analysis. Also, further evaluating the effect of gene-gene (such as FAS −670 A/G polymorphism and FASL −844 C/T polymorphism) and gene-environment interactions on the FAS −1,377 G/A polymorphism and cancer risk are necessary.

Copyright information

© Springer-Verlag 2009