Candidate gene studies in gallbladder cancer: A systematic review and meta-analysis

Abstract

Gallbladder cancer (GBC) is the most frequent biliary tract malignancy. Wide variations in GBC incidence and familial and epidemiological data suggest involvement of a genetic component in its etiopathogenesis. A systematic review of genetic association studies in GBC was performed by applying a meta-analysis approach and systematically reviewing PubMed database using appropriate terms. Odds ratios (ORs) and 95% confidence intervals (CIs) were appropriately derived for each gene–disease association using fixed and random effect models. Meta-regression with population size and genotyping method was also performed. Study quality was assessed using a 10-point scoring system designed from published guidelines. Following a review of 44 published manuscripts and one unpublished report, 80 candidate gene variants and 173 polymorphisms were analyzed among 1046 cases and 2310 controls. Majority of studies were of intermediate quality. Four polymorphisms with >3 separate studies were included in the meta-analysis [OGG1 (rs1052133), TP53 (rs1042522), CYP1A1 (rs1048943) and GSTM1 null polymorphism]. The meta-analysis demonstrated no significant associations of any of the above polymorphisms with GBC susceptibility except TP53 (rs1042522) polymorphism. To conclude, existing candidate gene studies in GBC susceptibility have so far been insufficient to confirm any association. Future research should focus on a more comprehensive approach utilizing potential gene–gene, gene–environment interactions and high-risk haplotypes.

Introduction

Gallbladder cancer (GBC) is the most frequent biliary tract malignancy and the fifth most common malignant neoplasm of the digestive tract [1]. Despite recent advances in the diagnosis and management of gastrointestinal cancers, GBC remains a challenging tumour with a poor overall prognosis. Many of these tumours are not resectable at the time of presentation, and the 5-year survival rate is <10% in most of the reported series [2]. GBC incidence varies greatly throughout the world, highest being in Native American and South American populations, and people from Poland and Northern India. Between 17,000 and 18,000 new cases of GBC are diagnosed in India each year, and the annual death rate is almost comparable [3]. The frequency increases with age and reaches to peak during the seventh and eighth decades of life [4]. GBC incidence also shows striking gender bias and affect females 2–3 times more frequently than males [4].

Several epidemiological studies have been conducted to estimate the effects of environmental factors on GBC risk to elucidate the large ethnic variations in risk [5], [6]. Yet, no single environmental factor has persistently been linked with GBC risk. It has been observed that Indian migrants to different countries have a higher risk of acquiring GBC as compared to the respective native populations [7]. Thus, the wide geographical, ethnic and interindividual variations observed in the incidence of GBC suggest the involvement of a genetic component in its etiopathogenesis.

The discovery of common genetic polymorphisms in human DNA has led to the publication of a large number of association studies in GBC [9], [10], [11], [12], [13], [14], [15], [16], [17], [18], [19], [20], [21], [22], [23], [24], [25], [26], [27], [28], [29], [30], [56]. However, a number of contradictory findings have been reported, and in several cases it has proved difficult to reproduce initial results. Also due to the high false positive associations, the possibility of a true association is well dependent on the quality of the studies concerned [31]. The major flaw with the individual studies is small sample sizes and therefore insufficient statistical power to detect positive associations and incapability to demonstrate the absence of an association. This necessitates the use of meta-analysis to provide an integrative approach by pooling the results of independent analyzes, thereby increasing statistical power and resolution [32], [33], [34], [35]. Thus, to get a better insight in the GBC pathogenesis, the present study was undertaken to explore the role of candidate gene polymorphisms in GBC susceptibility by applying a meta-analytical approach and systematically reviewing the available data.

Moreover, to draw a preliminary conclusion, we also carried out a systematic quality review of the published literature on genetic association studies in GBC. This was accomplished by strictly following the various guidelines and checklists that have been published on the conduct of genetic association studies in complex diseases [36], [37], [38], [39]. Using the criteria as described by Clark and Baudouin [40], we analyzed each publication to highlight the quality issues in the conduct and interpretation of these studies and also to establish if the existing data supports any polymorphism to be conclusively associated with GBC.