Genetic predisposition to gastro-oesophageal cancer

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Gastro-oesophageal cancers were ranked as the second cause of death from cancer worldwide despite a steady decrease in incidence for squamous cell carcinoma (SCC) of the oesophagus and distal gastric cancers. Adenocarcinoma of the oesophagus (OAC) is the tumour whose incidence has seen the highest increase in the past 30 years. Most of these cancers are strongly associated with environmental and life style risk factors such as smoking and alcohol for SCC, gastro-oesophageal reflux for OAC and Helicobacter pylori for distal gastric cancer. It may therefore be unsurprising that SCC is associated with polymorphisms in ALDH2 and ADH1B1, enzyme involved in alcohol metabolism, and with CYP1A1, involved in xenobiotics detoxification. OAC, whose incidence in absolute terms remains low, has been much less studied and at best the associations identified with risk are weak. Diffuse type gastric cancers while relatively uncommon have a strong genetic association with mutation of the CDH1 gene and prostate specific cancer antigen (PSCA) was demonstrated in a GWAS to be associated with an increased risk of diffuse gastric cancer but not intestinal type gastric cancer. This family of cancer is more associated with polymorphisms at the IL-1β, IL-1RN loci and MHTFR loci. Specific strains of H pylori containing the virulence factors VacA s1, VacA m1 and cag A together with polymorphism at the IL-1β and IL-1RN loci have up to a 87-fold increase in risk for developing intestinal type gastric cancer. While progress has been made to identify genetic variants associated with upper-gastrointestinal cancers, the relative small prevalence for some subtypes underlies the need for consortia, especially in view of the large variations in the prevalence of polymorphisms between different populations.

Introduction

Gastro-oesophageal cancers comprise a significant proportion of cancers affecting the upper gastrointestinal tract. Worldwide, gastric cancer was the fourth most common cancer in 2002 with an estimated incidence of 990,000 newly diagnosed patients [1], despite a steady decrease in incidence and mortality in the past 30 years. While progress has been made with regards to treatment, it remained the second cause of death from cancer with an estimated 700,000 annual deaths recorded. Oesophageal cancer was ranked the eighth most common cancer and sixth most common cause of death [1]. It is predicted that by 2030, gastric cancer will be the 10th leading cause of mortality [2].

However, a closer examination of the incidence figures reveals that their epidemiology has changed significantly over the past 20 years in the western world. There has been a steady decline in the incidence of squamous cell carcinoma of the oesophagus (SCC) and distal gastric cancer [3] (see Figure 1 for UK data). Over the same time period proximal gastric cancer (cardia) and adenocarcinomas of the oesophagus and gastro-oesophageal junction (OAC) have increased dramatically [4, 5, 6] (Figure 1). The ratio of OAC to SCC in the westernised world changed from 1:4.7 in 1975 to 1:0.43 in 1998 [7]. However, in terms of absolute numbers squamous oesophageal cancer and distal gastric cancer still predominate with a four times higher incidence of SCC compared to adenocarcinoma (OAC) in the developing world compared to the westernised world [7] (see Figure 2). In addition there are disease hotspots. For example, squamous cell carcinoma of the oesophagus has up to a 10-fold increase in incidence in China [8], the Transkei region of South Africa [9] and Iran [10]. These relatively rapid temporal and geographical variations in incidence suggest a strong role for environmental factors. Squamous cell carcinoma of the oesophagus is related to factors such as smoking and hot alcohol ingestion [11]. In the West the number of smokers has rapidly declined and there is a test and treat policy for Helicobacter pylori infection that is now known to be the primary causative factor of distal gastric cancer [12]. The increasing incidence of cardia and junctional adenocarcinomas is thought to be as a consequence of obesity and increasing reflux problems secondary to western diet and lifestyles [13]. On the other hand, there are rare familial cancer syndromes that can cause gastro-oesophageal cancer such as Tylosis and Hereditary Diffuse Gastric Cancer (HDGC). Our knowledge of cancer causation in general suggests that inherited factors are likely to play some role. For sporadic cancers at this site, multiple low penetrance susceptibility genes are likely to contribute although our understanding of their contribution is still relatively limited.

The most likely polymorphisms to be associated with oesophageal and gastric cancers are summarised Table 1.

Section snippets

Oesophageal cancer

SCC tends to occur proximally in the oesophagus and OAC distally. As discussed briefly above, despite originating from the same organ, these two tumour types have very different aetiology and epidemiology but are both characterised by a male predominance [1] (Figure 2). The main risk factors throughout the world for SCC are alcohol and tobacco smoking [11] and other factors depend on the region of the world (hot beverages in Iran and South America, tobacco chewing and nutritional deficiencies

Oesophageal squamous cell carcinoma

While a gene by gene analysis of all polymorphisms identified in SCC is beyond the scope of this article, there are several meta-analyses and reviews in the literature [20, 21, 22]. Most of the candidate gene studies in SCC were related to genes involved in alcohol metabolism, detoxification of xenobiotics and folate metabolism. Most of the populations involved in these studies were Japanese, Chinese and European where the main risk factors for SCC are alcohol consumption and tobacco smoking [11

Adenocarcinomas of the oesophagus and gastro-oesophageal junction

There is a general paucity of gene association studies of OAC despite its increasing incidence in the westernised world; however its low incidence in absolute terms (∼8000 cases per annum in the UK) may explain the difficulty of performing studies requiring large sample sizes and as well as an independent replication cohort. In most cases, studies compared cohorts of controls, Barrett's oesophagus and OAC patients.

A number of small observational studies describing multiple family members

Gastric cancer

Gastric cancer is of two main types: a distal, intestinal type usually associated with the presence of H. pylori and the diffuse type containing signet ring cells often referred to as linitis plastica. There are also proximal intestinal gastric cancers affecting the cardia that can be considered as part of the spectrum of gastro-oesophageal junctional cancers discussed above.

The vast majority of gastric cancers are sporadic although it has now been established that 1-3% of gastric cancers arise

Conclusions

As for most cancers, some degree of familial predisposition exists for gastro-oesophageal cancers. Most studies of gastro-oesophageal cancers suffer from a lack of power, partly overcome by meta-analyses and pooled studies. Conflicting reports exist for most candidate genes and with the advent of new high-throughput technology one hopes that sufficiently powered genome wide association study will be performed. The relative small prevalence for some subtypes underlies the need for consortia,

Conflict of interest

None to declare.

References and recommended reading

Papers of particular interest, published within the annual period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

Acknowledgements

The authors are supported by the Medical Research Council, Cancer Research UK, Cambridge Experimental Cancer Medicine Centre and the National Institute for Health Research Cambridge Biomedical Research Centre.

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