Genetic epidemiology of oesophageal cancerChapter 1

The majority of oesophageal cancers are carcinomas–either squamous cell (SCC) or adenocarcinoma (AC). Rarer types include small cell cancer and nonepithelial tumours such as sarcomas (e.g. leiomyosarcoma and rhabdomyosarcoma), malignant melanoma and lymphoma. Oesophageal cancer is the 10th commonest cancer in the world overall, but it is the 5th commonest cancer in less developed countries, most of these being SCCs. It has the distinction of having the widest variation in incidence worldwide of any cancer, there being a 15-fold geographical variation in men and a 20-fold variation in women. The highest rates are found in China, Iran and South Africa and lowest rates in central Africa and central America. In these high-risk countries, the majority of oesophageal cancer is due to SCC, but in low-risk countries, particularly certain Western countries, the incidence of AC is rising rapidly and it is the most rapidly increasing of all cancers.

Both SCC and AC are associated with increasing age, and are diseases of middle to late life. SCC has roughly an equal gender incidence, particularly in areas of high incidence; however, in areas of low incidence, men predominate just as with AC.

Both tobacco and alcohol have been identified as major risk factors for oesophageal SCC and are synergistic. Smoking cigarettes increases the risk three- to sevenfold [2], whilst alcohol confers a three- to fivefold risk. Individuals who smoke and drink have a ninefold increased risk. Cigar and pipe smokers have a risk similar to cigarette smokers [2].3

In the United States, age-adjusted incidence of oesophageal cancer is almost twice as high in African American races than in Caucasians and exceeds that for Hispanics, Asian Americans and Native Americans; however, AC is mainly a disease of Caucasian males [4].

SCC was found to be associated with lower socioeconomic status in one study.

N-Nitroso compounds are known carcinogens, thought to act by causing the development of alkyl adducts in DNA. In animals, they have been implicated in the development of several cancers, including in the nasal cavity, oesophagus and stomach [5], although direct evidence for human cancers is lacking. Furthermore, 45–75% of exposure comes from endogenous synthesis of ingested nitrites or nitrates and the remainder from tobacco smoking, occupational exposure and food sources such as vegetables. Pickled vegetables and other foodstuffs may be a source of nitroso compounds, particularly in endemic areas such as China, either directly or secondary to contamination by toxin-producing fungi.

These compounds are contained in a drink called maté which is made by making infusions of the herb Ilex paraguayensis with hot water–a practice common in certain parts of South America, which also has high rates of oesophageal cancer [5]. It is not certain whether it is the polycyclic aromatic hydrocarbons (PAH) alone or the fact that the maté is often drunk very hot (see below) which is the important factor.

Diets low in fresh fruit and vegetables have been postulated to be conducive to the development of oesophageal cancer, most of the evidence coming from case–control studies. Conversely, diets high in fresh fruit and vegetables have been shown to lower the risk of oesophageal cancer although the vast majority of the evidence has been in relation to SCC [6]. What evidence there is does not support a reduced risk of AC with diets high in fruit and vegetables.

Low levels of selenium, zinc and folic acid have been associated with increased risk of SCC. Diets high in folic acid have been shown to reduce the risk of oesophageal cancer.4

Initial evidence supporting a link between oesophageal cancer and poor oral hygiene appear to be confirmed by later studies. However, most of the studies did not take account of other, potentially confounding, factors.

Repetitive thermal injury to the oesophageal mucosa from the ingestion of hot food and drinks has been considered a cause of oesophageal cancer. More than half of 59 case–control and cohort studies have shown a significantly increased risk with ingestion of hot liquids although the methodology has been criticised and, in the majority of studies, oesophageal SCC and AC were not differentiated.

Traditionally, oesophageal SCC was said to be increased in certain occupations related to alcohol production, such as draymen and publicans, although the evidence for this was contaminated by confounding factors which were not adjusted for in the analysis. Occupations characterised by exposure to asbestos, silica and other substances such as sulphuric acid have been associated with an increased risk of this cancer [6].

Case–control studies in patients with achalasia have indicated that oesophageal SCC occurs in 3–7% of this population, compared with 2% in the general population [7].

Symptomatic gastro-oesophageal reflux is one of the strongest risk factors for oesophageal AC. The risk is increased depending on the length of the history, the frequency of symptoms and presence of nocturnal reflux [8].

Barrett's oesophagus (BO) is a condition in which the normal squamous mucosa is replaced with columnar epithelium in the distal oesophagus as a result of chronic gastro-oesophageal reflux and is strongly associated with the development of oesophageal AC. The prevalence of BO is 1.6% in the general population and 10–15% in patients with reflux who have undergone upper gastrointestinal endoscopy. The risk of AC in patients with Barrett's oesophagus is 0.5% per year. Barrett's oesophagus is most commonly diagnosed in middle to late life, with the average age at diagnosis being 55. More men are diagnosed than women and it is most common in Caucasian populations, less common in black and Hispanic populations and least common in Asian populations. Barrett's oesophagus is associated with smoking and obesity. The risk of AC in BO is approximately 1% [9].

The mechanism whereby obesity increases the risk of oesophageal AC is probably indirect, through the promotion of gastro-oesophageal reflux as a result of increased intra-5abdominal pressure and the subsequent development of BO. A meta-analysis showed an increased odds ratio (OR) of 2.78 (1.85–4.16) for AC in patients with a body mass index greater than 30 [10,11].

Coeliac disease is associated with an increased risk for a number of malignancies including oesophageal SCC for which the risk is increased eightfold [12].

Approximately 2% of patients who have had a SCC of the upper aerodigestive tract will go on to develop a metachronous SCC of the oesophagus [13].

This is due to the ingestion of strong alkalis such as sodium or potassium hydroxide contained in drain-cleaning fluid and other household cleaning products. Most cases occur in children under the age 5 when they are accidental and the rest in adults as a result of psychotic or suicidal behaviour. It results in scarring and stricture formation in the oesophagus. SCC develops after approximately 40 years [14].

Radiotherapy to the mediastinum for the treatment of a number of cancers including breast cancer, lung cancer and lymphoma increases the risk of both types of oesophageal cancer [15].

Patients with this condition, which comprises a triad of features, namely dysphagia, iron deficiency anaemia and oesophageal webs, have a greater risk of SCC [16] although some cases of this syndrome may be due to undiscovered coeliac disease.

A meta-analysis of 19 studies suggested an inverse relationship between the presence of CagA-positive Helicobacter pylori (H. pylori) and the risk of AC [17]. It has been suggested that the decline of H. pylori infection may be partly responsible for the increase in AC over the past decades.

A population-based, cohort study of cholecystectomised patients in Sweden found an increased risk of AC (standardized incidence ratio, 1.3; 95% CI, 1.0–1.8) but not of SCC (SIR, 0.9; 95% CI, 0.7–1.1) [18]. The rationale behind the study was that duodenogastric reflux of bile occurred after cholecystectomy and gastro-oesophageal reflux of bile is associated with Barrett's oesophagus.

Human papilloma virus (HPV) has been implicated in the development of both benign and malignant squamous cell tumours of the oesophagus; 21.3% of squamous cell papillomas and 22.9% of SCCs of the oesophagus were positive for HPV infection [19].6

A number of medications may increase the risk of AC by causing relaxation of the lower oesophageal sphincter, thereby promoting gastro-oesophageal reflux. These include β-adrenergic agonists (bronchodilators), calcium channel blockers, nitrates, phosphodiesterase inhibitors (aminophylline), anticholinergics, γ-aminobutyric acid agonists (baclofen), benzodiazepines and hormone replacement therapy (HRT). The available evidence has been conflicting.

Early studies on the possible link between bisphosphonate use and oesophageal cancer showed conflicting results. In a series of population-based case–control studies in two large primary care databases, exposure to bisphosphonates was not associated with increased risk [20], although a limitation of this study was that no attempt was made to differentiate the two main types of oesophageal cancer.

There is epidemiological evidence to indicate that these medications may reduce the risk of oesophageal cancer, particularly AC, by approximately 40%, although one study found that using the selective COX inhibitor, celecoxib, did not appear to have any effect [21]. The mechanism of this action is thought to be by the inhibition of the enzyme cyclooxygenase.

Unfortunately, studies looking at the effects of these medications in oesophageal cancer have not produced any consistent results. Theoretically, they could work by reducing the acid content of the gastric refluxate, the stimulant to mucosal change in Barrett's oesophagus. Alternatively, by reducing gastric acid, they may encourage gastric colonisation by bacteria that are capable of producing gastric carcinogens such as N-nitrosamines.

It has been speculated that HRT may be implicated in a number of cancers including cancers of the oropharynx, stomach and colon. A meta-analysis of three case–control studies from Europe provided evidence for a beneficial effect of HRT in oesophageal cancer. This result is all the more surprising considering the fact that HRT has been shown to increase the risk of reflux (vide supra).

Oesophageal SCC, like most solid tumours, has been shown to harbour many somatic mutations, which may be driver or bystander events. Early whole genome searches for causative genes used the technologies of the time, namely, restriction fragment-length polymorphisms (RFLP) and loss of heterozygosity (LOH) or allelic imbalance (AI) of microsatellite alleles, to identify commonly deleted or duplicated regions. However, by today's standards, these studies used widely spaced markers and fairly modest tumour 7numbers. The most commonly identified regions by these methods were 3p (35–41%), 5q (36–53%), 9p (36–65%), 9q (31–60%), 13q (43–53%), 17p (55–62%), 17q (33–71%), 18q (38–46%) and 21q (65%). Studies investigating the progressive accumulation of genetic defects, ranging from low-grade to high-grade dysplasias and carcinoma, demonstrated early loss of genetic regions at 3p21, 9p22 and 17p13 in dysplastic lesions that mirrored similar evidence from head and neck cancers [22,23] and suggests some commonality in the mutational pathway of these squamous cell aerodigestive tract cancers.

In areas of high incidence, such as Iran and China, familial aggregation of squamous cancer has been recorded [29], but this is not observed in areas of low incidence suggesting that common environmental rather than hereditary risk factors are responsible.

Many gastro-oesophageal cancers are strongly associated with environmental and life style risk factors. For oesophageal SCC, alcohol is an important risk factor and, in Asian populations, even light alcohol use appears to be associated with susceptibility [32]. Because exposure to high levels of acetaldehyde, the principal metabolite of alcohol, may be the cause, it is not a surprise that genome-wide SNP array studies identified chromosomes 4q23 and 12q24, where the major alcohol-metabolising enzymes, ADH cluster and ALDH2 genes, respectively, are located.

Tylosis (hyperkeratosis palmaris et plantaris) is a focal, nonepidermolytic form of keratoderma. It is inherited as an autosomal dominant condition. Two types of tylosis are recognised. In type B, the hyperkeratosis appears in the first year of life but, in type A, it does not appear until about puberty. Type B is not associated with malignancy, but type A is associated with SCC of the oesophagus that usually manifests in middle to later life. Type A is also associated with other features such as oral leucokeratosis and follicular hyperkeratosis. The gene for type A tylosis has been localised to chromosome 17q25 and has been identified as RHBDF2 [37]. This 30.5-kb gene encodes a protein of 856 amino acids that is a member of a class of proteins known as rhomboids. Rhomboid proteins are intramembrane serine proteases that cleave substrates in or near the transmembrane domains. The protein product of RHBDF2 is classified as an inactive or irhomboid due to the fact that it lacks the typical proteolytic site made up of a serine, a histidine and an aspartic acid residue. Altered expression and localisation of this protein have subsequently also been shown in sporadically occurring oesophageal SCC, thus validating the AI data at 17q and implicating the gene product, iRhom2, in many of these cancers (Risk, unpublished data, 2013). Further, the iRhom2 protein has been shown to control processing of the major ‘sheddase,’ ADAM17, which controls the membrane shedding of many epidermal growth factor receptor ligands, inflammatory cytokines and adhesion molecules [38]. Indeed, in cell lines derived from tylotic skin, increased ADAM17 processing is detected together with increased production of ADAM17 substrates in response to inflammatory stimuli, whilst increased EGF signalling and cell migration are also observed (Kelsell, personal communication, 2014). Five families have been documented and, in four of these families, a mutation has been found in the RHBBF2 gene. The risk of developing oesophageal SCC in the Liverpool family has been calculated to be 95% at the age of 65 [39].9

This condition is characterised by cutaneous pigmentation, premature greying, nail dystrophy, leucoplakia, thrombocytopenia, anaemia, testicular atrophy and a predisposition to cancer, including oesophageal cancer.

Fanconi's anaemia is a rare, mainly autosomal recessive disorder, resulting in failure of DNA repair. It, therefore, leads to the development of haematological (acute myeloid leukaemia) and nonhaematological (head and neck, oesophageal, gastrointestinal, vulvar and anal) malignancies.

This is one of a number of inherited disorders resulting in the formation of skin blisters on minimal trauma. Patients have an increased of cancer of the skin and oesophagus.

The demography of oesopahgeal cancer has been changing over the past few decades. Not only has adenocarcinoma overtaken squamous cancer as the most frequent oesophageal cancer in Western countries, but there has been an improvement in the 5-year survival rate as a result of the earlier recognition and treatment of less advanced lesions. Several predisposing environmental risk factors have been identified, the removal of which should potentially result in further reductions in incidence and mortality, although at present this remains to be seen.